Medical Science

2017-12-31T23:59:00.000-08:00

Medical science is a vast topic and this site is intended only for an exploration of some topics of interest to the site author. The content is not intended as a guide to medical treatment, rather the basic biological sciences that underpin medical practice will be explored.

Site Map

Cancer : Immunology :

For information concerning health questions : see Medline Plus or other comprehensive websites.

animations

2017-12-30T23:59:00.000-08:00

Animations on YouTube:
DNA MUTATION 01:17
Recombinant DNA 04:35
DNA Replication 01:34
DNA Mismatch Repair 01:20
Beginning of Life 03:16
The Inner Life of the Cell - Full Version 08:10
DNA REPAIR 00:40
Transcription (Animation) 02:50
DNA REPLICATION 01:39
DNA STRUCTURE 01:11
DNA Transcription 00:55
DNA PACKAGE 00:45
Cell Division Motion Reconstruction 00:36
HIV Biology 02:19
DNA RNA 04:16
CELL wrapping & DNA replication 03:06
Molecular Visualization of DNA 01:23
DNA Replication 01:39
DNA Structure 01:19
Secretory Pathway 01:16

fever

2017-05-19T19:03:00.000-07:00

Fever, febrile illness, pyrexia: elevation of body temperature due to circulating pyrogens caused by:

endotoxins

immune complexes and inflammation

infection

microbial toxins

tissue injury

Hyperthermia: dysregulation of body temperature (elevated) due to:

decreased heat dissipation

anticholinergic drugs

autonomic dysfunction

dehydration

heatstroke (classic)

neuroleptic malignant syndrome

occlusive clothing/dressings

increased heat production

catatonia (lethal catatonia)

delerium tremens

drugs – amphetamines, (anesthetics), cocaine, salicylate intoxication

exertional hyperthermia and exertional heatstroke

heatstroke

malignant hyperthermia of anesthesia

pheochromocytoma crisis

tetanus (generalized)

thyroid storm (thyrotoxicosis)

serotonin syndrome

status epilepticus

hypothalamic dysfunction

cerebrovascular accident

encephalitis

granulomatous infections

hypothalamic insult caused by infection, tumor, or drugs

idiopathic hypothalamic dysfunction

neuroleptic malignant syndrome

sarcoidosis

trauma

tumors

pain

2017-05-07T23:16:00.000-07:00

Pain results from tissue injury or inflammation:

acute vs chronic

neuropathic – due to damage or dysfunction of the central or peripheral nervous system

nociceptive – somatic or visceral – due to stimulation of nocireceptors (peripheral pain receptors) and conducted by A delta fibers and C fibers (sensory nerve fibers)

psychosomatic – categorized as somatoform disorders – chronic pain disorders, somatization disorders, hypochondriasis

Cancer

2011-10-24T10:48:00.000-07:00

Cancers arise when cells escape normal controls on cellular proliferation.

Cancer is not a single disease, rather the term encompasses a group of conditions that share the characteristic process of uncontrolled proliferation of cells that are typically capable of local infiltration into other tissues (invasion). This propensity for invasion and migration is associated with the capacity of malignant tumors to metastasize to sites distant from the point of origin.

This propensity for invasion and metastasis is a critical feature that distinguishes malignant tumor from benign tumors. Benign tumors evidence as local overgrowth, but fortunately have minimal or no propensity for tissue infiltration and metastasis.

Cancers are named for the tissue/organ in which they originate. However, the tissue type of cancers from a particulary organ can vary, and even cancers of the same tissue type can vary considerably in degree of undifferentiation, sensitivity to chemotherapeutic agents, growth rate, invasiveness, and metastatic potential.

Alteration of a gene that usually controls cell growth can promote the uncontrolled growth characteristic of cancer. Proto-oncogenes are the normal forms of dominant genes that function in the various signal transduction cascades involved in regulation of cell growth, proliferation and differentiation – and the malignantly transformed versions of proto-oncogenes are termed oncogenes.

For example, mutation in a proto-oncogene, such as a gene that encodes an intracellular signaling protein that is normally activated only by extracellular growth factors, converts the proto-oncogene into an oncogene. The malignantly transformed oncogene encodes an altered form of the signaling protein that now behaves as though activated even in the absence of controlled growth factor binding. The malignant cell line has escaped normal gene regulation and cell cycle control mechanisms and exhibits unchecked proliferation.

There are many excellent sites with information for those affected by cancer, so the purpose of this site, in conjunction with the companion sites, is an exploration of the cell and molecular biology of malignancy.

synonyms : cancer, tumor, malignancy, neoplasm; cancerous, tumorous, malignant, neoplastic; cancer, neoplasia, oncology.

related items ¤¤ adenoviruses ¤ amplification ¤ carcinogenesis ¤ c-Fos ¤ c-Jun ¤ c-Myc ¤ c-Sis ¤ estrogen receptors ¤ gene amplification ¤ genetic predispositon ¤ HBV ¤ HIV ¤ HPV ¤ HTLV-I ¤ immune evasion ¤ irradiation ¤ malignant transformation ¤ metastasis ¤ mitogens ¤ mutagens ¤ MYC ¤ mutations ¤ neoplasia ¤ neoplastic mutations ¤ NF-κB ¤ non-mutagenic carcinogens ¤ oncogenes ¤ p53 ¤ proliferation ¤ proto-oncogenes ¤ radiation ¤ Ras ¤ Rb ¤ retroviral mechanisms of carcinogenesis ¤ retroviruses ¤ signaling molecules ¤ SRC genes ¤ T-antigens ¤ TP53 ¤ tumor antigens ¤ tumor suppressors ¤ tumorigenic viruses ¤ viral carcinogens ¤ v-Fos ¤ v-Sis ¤ v-Myc ¤

cancer staging

2011-10-24T10:47:00.000-07:00

Diagnostic evaluation of malignancy includes determination of the cancer's pathology (tissue type, organ of origin) in addition to staging of the cancer to determine degree of local, regional, and distant spread. Clinical and pathological staging is important to decisions concerning therapy, and to estimating prognosis (a statistical measure).

The stage of a cancer is influenced by:
¤ the carcinoma's biological aggressiveness
¤ time elapsed before clinical/pathologic diagnosis – c, cs = clinical; p, ps = pathological
¤ time elapsed before/since institution of anti-cancer treatment
¤ the tumor's sensitivity to cytotoxic therapies

Cancers commence as in situ colonies of cells that have escaped normal cellular controls. Local overgrowth of the primary tumor (localized) is followed by local tissue infiltration, and ultimately by malignant penetration of adjacent tissues (regional), blood vessels or lymphatics, with shedding and transport of malignant cells and ultimate colonization of distant organs (distant, secondary tumors, metastases).

Staging systems reflect this biological progression and the tissue type. The system of staging employed will depend, to some extent, upon the specific form of cancer involved – whether it is a solid tumor or hematologic, whether it belongs to a group staged by a specific system, such as the Ann Arbor staging classification that is commonly employed to stage lymphomas.

Cell type and grade is used to stage carcinomas of the brain and spinal cord.

TNM system – Tumor, Node, Metastasis
T refers to the primary (solid) tumor – X (cannot be evaluated), 'is' (in situ), 0 - 4 (size/extent)
N refers to regional lymph node involvement – X, 0-4 (extent)
M refers to metastasis – X, 0 = no metastasis, 1 = metastasis

Ann Arbor System (lymphomas)
Stage I – single region, typically a single lymph node and the surrounding area
Stage II – two regions on same side of diaphragm, an affected lymph node or organ within the lymphatic system and a second affected area
Stage III – both sides of diaphragm, including organ or area adjacent to lymph nodes or spleen
Stage IV – diffuse or disseminated involvement of one or more extralymphatic organs, including any involvement of the liver, bone marrow, or nodular involvement of the lungs.

Modifications to Ann Arbor
A = absence of constitutional symptoms
B = presence of constitutional symptoms (night sweats, fevers, unexplained weight loss of >10%)
E = "extranodal" (not in the lymph nodes) or spread from lymph nodes to adjacent tissue
X = largest deposit if >10 cm large ("bulky disease"), or mediastinum is wider than 1/3 of the chest on a chest X-ray

"Staging: Questions and Answers" at the National Cancer Institute
International Union Against Cancer, TNM

carcinogenesis

2011-10-24T06:47:00.000-07:00

Carcinogenesis involves damage-induced genetic alterations (mutations) that produce cancers. Mutagenesis causes genetic alterations that may, or may not, result in cancer.
Tables Malignant Transformation Oncogenes Proto-oncogenes

Many of the most powerful biological regulators of cell growth and proliferation are encoded by unstable mRNAs, which are targeted for rapid degradation by the cell. The loss of rapid degradation of these growth-promoting mRNAs can result in oncogenic transformation of the cell. Targeted degradation of proto-oncogene mRNAs and short-lived cytokines is controlled both by an AU-rich element (ARE) located in the 3' noncoding region, and by several proteins that bind the ARE sequence. Activation of the ARE for mRNA decay involves cotranslation of the mRNA by ribosomes, and employs the ubiquitin-proteasome pathway.[s]

Carcinogenesis typically results from a series of mutations that affect regulation of proliferation.
m1: inactivation of a tumor suppressor gene results in cell proliferation
m2: mutation inactivates a DNA repair gene
m3: mutation of a proto-oncogene generates an oncogene
m4: mutation inactivates more cancer suppressor genes, resulting in cancerous proliferation

Carcinogenic agents include:
Mutagenic carcinogens
Non-mutagenic carcinogens
Irradiation
Viruses (tumorigenic viruses) Transforming retroviruses and DNA tumor viruses encode oncogenes.
Genetic predisposition (Table of Hereditary Cancers)

Mutagenic carcinogens: ‘genotoxic’ carcinogens are DNA reactive and induce DNA damage. Tobacco smoke is probably the most notorious mutagenic carcinogen, producing, in addition to cardiovascular damage, cancers of the head and neck, lung, and bladder.

Non-mutagenic carcinogens: ‘non-genotoxic’ carcinogens are reported to have have significantly higher computed octanol/water partition coefficients than mutagenic carcinogens, suggesting that their ability to induce tumors may be associated with membraneous receptor sites and/or a longer residence time in the animal [r]. Estrogen can promote the growth of some breast cancers.

Irradiation:

Viruses: transforming retroviruses carry oncogenes mutated from cellular genes that are involved in mitogenic signaling and growth control. DNA tumor viruses encode oncogenes of viral origin that are essential for viral replication and cell transformation; viral oncoproteins complex with cellular proteins to stimulate cell cycle progression and led to the discovery of tumor suppressors. Viral systems support the concept that cancer development occurs by the accumulation of multiple cooperating events.[s]

Genetic predisposition: a variety of inherited genetic abnormalities render affected individuals more prone to malignancy. For example, hereditary non-polyposis colon cancer (HNPCC) is a form of colon cancer frequently associated with defects in the genes encoding MSH2 (about 35% of identified gene-defect cases) and MLH1 (about 60% of identified gene-defect cases). HNPCC is characterized by early age of onset and autosomal dominant inheritance with high penetrance. (Table of Hereditary Cancers)

∞ Cancer ∞ carcinogenesis ∞ oncogenes ∞ proliferation ∞ retroviruses ∞ signaling molecules ∞ tumorigenic viruses ∞ site map ∞

Tables Apoptosis vs Necrosis Apoptosis Cell Adhesion Cell signaling Malignant Transformation Oncogenes Proto-oncogenes Regulatory Proteins Sequences Table of Hereditary Cancers .

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estrogen receptors

2011-08-06T04:08:00.000-07:00

Estrogen receptors (ERs) are located in the nucleus of estrogen-sensitive tissues (breast, endometrium, brain, bone, liver, heart). When the steroid hormone estrogen enters the nucleus of receptive tissues, it forms complexes with estrogen receptors, which then bind to estrogen response elements of DNA, activating expression of genes via stimulation of co-activators. The effects of estrogen stimulation vary from one tissue to another (pleiotropy).

anti-estrogenic drugs : cancers : co-activators, co-regulators, co-repressors : ERs : pleiotropy : raloxifene : selective estrogen receptor modulators : SERMs : Tamoxifen :

Two subtypes of estrogen receptors, ERα and ERβ, are known to mediate estrogen signaling through their function as ligand-dependent transcription factors [4]. After crossing the cellular membrane, estrogens bind to receptors ERα and ERβ, leading to receptor activation.

ERs interact with cis-regulatory elements of target genes:
a) by direct binding to conserved estrogen response elements (EREs; 5'-GGTCANNNTGACC-3', where N is any nucleotide), or
b) indirectly through association with AP1 or Sp1 transcription factor complexes and their respective binding sites [5-9].

Co-activators and co-repressors complex with estrogen receptors to regulate estrogen responses [10]. Cyclical turnover of transcriptional complexes and estrogen receptors at the regulatory elements of target genes provides an additional regulatory mechanism [11-13].

Potential mechanisms for the observed pleiotropic effects of estrogens include tissue-specific distribution of co-regulators, associated transcription factors complexes, and receptor subtypes and splice variants [14]. The consequence of ER activation appears to be alterations in transcriptional activity and expression profiles of target genes. Several genes, including those for trefoil factor 1/pS2, cathepsin D, cyclin D1, c-Myc and progesterone receptor, are positively regulated by ERα [15-20].[fft-s]

Because estrogen can stimulate cellular proliferation in tissues with estrogen-receptors, it is associated with increased risk of breast and endometrial carcinomas in replicating cells. Anti-estrogen chemotherapeutic agents compete with estrogen for binding to estrogen receptors, blocking estrogen activation of oncogenes. Selective estrogen receptor modulators, or SERMs, are a class of anti-estrogen drugs that selectively stimulate or inhibit the estrogen receptors of different target tissues.

Tamoxifen was the first SERM employed as an adjuvant treatment of estrogen receptor-positive breast cancers. It exerts an antiestrogenic effect by binding to the estrogen receptors of breast cells, preventing binding to coactivators and thus preventing activation of cell proliferation oncogenes. Because Tamoxifen stimulates endometrial estrogen receptors, increasing the risk of endometrial carcinoma, its use is restricted to treatment and it is not employed for prophylaxis of breast cancers. Another SERM, raloxifene is used to prevent osteoporosis and has demonstrated effectiveness against breast cancer without the problematic endometrial stimulation of Tamoxifen.

anti-estrogenic drugs : cancers : co-activators, co-regulators, co-repressors : ERs : pleiotropy : raloxifene : selective estrogen receptor modulators : SERMs : Tamoxifen :

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gene amplification

2011-06-20T10:56:00.000-07:00

Gene amplification involves the production of multiple copies of a gene through repeated copying of the gene.

Amplification is distinct from duplication, which is precise genome doubling preparatory to cell division, and from endoreduplication, which leads to endopolyploidy. When many copies of the amplified region are produced, they can form their own small pseudo-chromosomes called 'double-minute chromosomes'.

Gene amplification results from dysfunction in malignant cell lines. However, some organisms have evolved mechanisms for gene amplification in order to provide needed gene products in large quantities. Such functional mechanisms include:
a. The elaboration of small "extrachromosomal" units that replicate to high copy number (rDNA);
b. Tandem gene duplications (DHFR);
c. Localized endoreduplication of chorion genes.

Different organisms employ different mechanisms. Sometimes, as for double-minute chromosomes and human secretin receptor gene* (HSR), more than one mechanisms is employed within an organism.

Some mutants in developmentally expressed genes of plants result from heritable gene amplification. Gene amplification can be regulated developmentally, temporally, or environmentally.

Neoplastic cells can amplify, or copy, DNA segments in response to cellular signals or environmental events. When an oncogene is included in the amplified region, then the resulting overexpression of the oncogene gene leads to deregulated cell growth. Examples include amplification of the MYC oncogene in a wide range of tumors, and amplification of the ErbB-2 or HER-2/neu oncogene in breast and ovarian cancers. Clinical treatments have been designed to target cells overexpressing the HER-2/neu oncogene protein product.

Resistance of cancer cells to chemotherapeutic agents is linked to amplification of the gene that prevents absorption of the drug by the cell. A gene called MDR, for 'multiple drug resistance', is commonly involved. The protein product of the MDR gene acts as a membrane pump that selectively ejects molecules, including chemotherapy agents, rendering the drugs ineffective.

* the human secretin receptor (hSR) is an important glycoprotein receptor involved in regulation of the secretion of pancreatic bicarbonate, water, and electrolytes.

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immune evasion

2011-04-12T11:35:00.000-07:00

Tumors employ a variety of mechanisms to evade the immune system.

Evasive mechanisms range from a passive failure to express major histocompatibility complexes (MHC) and co-stimulatory molecules 4,5 to active strategies such as the production of immunosuppressive cytokines and other factors 6,7 . Passive and active processes are also involved in the Fas counterattack.[s]

The Fas ligand (FasL, C95L) is expressed by cells of the lymphoid/myeloid series and by non-lymphoid cells, where it contributes to the 'immune privilege' of cancer cells by inducing apoptosis in infiltrating proinflammatory immunocytes 9,10 . Simultaneously, many cancer cells can be relatively resistant to Fas-mediated apoptosis.

This resistance to Fas-mediated apoptosis might result from downregulation of Fas, or release of soluble Fas, or of abnormalities in the level of several signal transduction cascade proteins. Neoplastic Fas resistance might also result from downregulation of caspase 1, Bax or Bak, and upregulation of FLIP, FAP-1 or Bcl2. Further, some components of the pathway exhibit mutations, including Fas itself and caspase 8. Some mutations of oncogenes and tumor suppressor genes, which are commonly found in tumors, could impair Fas signaling (p53 and Ras) or could cooperate with Fas resistance (c-Myc) in certain tumor cells. Many cancer cells express FasL, so are able to counterattack and kill Fas-sensitive tumor- infiltrating lymphocytes (TILs).[s]

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metastasis

2010-12-20T04:55:00.000-08:00

Metastasis is cell motility run amok.

Malignant tumors exhibit not only uncontrolled proliferation and local invasion, but the ability to set up distant colonies. Growth and survival of metastatic tumor cells depend upon angiogenesis and the ability of tumor cells to evade detection by the immune system.

Metastasizing cells escape normal cellular adhesion mechanisms and shed from the primary tumor. Local invasion can enable the 'escapee' cells to penetrate lymphatics and/or blood vessels. Local infiltration of lymph nodes is associated with an increased likelihood of metastasis, so determination of whether or not lymph nodes are involved is important in cancer staging.

Having been transported via circulation of lymph or blood, the malignant cells invade distant tissues where they establish focal colonies of proliferating cells (secondaries). Metastatic cancers are named for the tissue in which the primary tumor originated, for example, breast cancer metastatic to lung or bowel cancer metastatic to liver. Tumors originating in certain tissues often display a propensity for metastasis to specific tissues and organs.

[links: images: CT scans: Kidney metastases : Liver metastases : Lymph node : Spleen metastasis ]

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mitogens

2010-12-16T04:09:00.000-08:00

A Mitogen, or somatomedin, is any molecules that stimulates a cell to divide.

Most mitogens are proteins, and they stimulate signal transduction pathways that utilize mitogen activated protein kinases. Mitogens include cytokines, growth factors, hormones, neurotransmitters, cellular stress proteins, and cell adhesion ligands. For example, antigen stimulation of cell adhesion immunoglobulins triggers mitosis in B cells.

Mitogen activated protein kinases (MAP kinases) act as switch kinases that transmits information of increased intracellular tyrosine phosphorylation to that of serine/threonine phosporylation. MAPK-activated protein kinases (or MKs; formerly MAPKAP kinases) respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs.(ffta)

The signaling cascade is:
mitogen → MAPKK kinase (MAPKKK) → MAPK kinase (MAPKK) → MAP kinase (MAPK) → signaling

Among the substrates of ERK are the members of the p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases (10). RSK plays an active role in nuclear signaling by phosphorylating the cyclic AMP response element binding protein (CRE-binding protein, CREB) (33), c-Fos (5), and IB (27). Phosphorylation of Bad (3, 29) and C/EBPß (4) by RSK can protect cells from apoptosis. RSK has also been implicated in cell cycle regulation. RSK phosphorylates histone H3 (25), suggesting that RSK may regulate chromatin remodeling.[s-fft]

MAP kinases are also called ERKs for extracellular-signal regulated kinases, microtubule associated protein-2 kinase (MAP-2 kinase), myelin basic protein kinase (MBP kinase), ribosomal S6 protein kinase (RSK-kinase) and EGF receptor threonine kinase (ERT kinase). Maximal MAP kinase activity requires phosphorylation of both tyrosine and threonine residues. Activators of the extracellular-signal regulated kinase family (ERKs) of MAPKs include the mitogens, Ras [fft], polypeptide growth factors PDGF, CSF-1, IGF-1, EGF insulin, PMA.

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neoplastic mutations

2010-11-20T08:11:00.000-08:00

Mutation of proto-oncogenes may convert them to oncogenes, while mutation of tumor suppressor genes may cause a loss of anti-proliferative functions.

Based on computational analysis of mutations affecting CAN-genes (candidate cancer genes) in breast and colorectal carcinomas, it has been estimated that cancers average 17 mutations (mostly SNPs) occurring within at least 90 genes [↓]. Cancers originating in the same tissue display mutation of different genes, and mutated genes contributing to breast cancer are different from genes mutated in colorectal cancers. Many of the mutated genes are involved in pathways involved in cell adhesion, cell movement, and cell signaling. Because each of the affected pathways incorporates multiple genes, mutations in different genes within a pathway could have similar consequences.

G-T mismatch in the Ras proto-oncogene can cause an alteration of the amino acid at position 12 from glycine to valine, causing the Ras oncogene-encoded G-protein to remain continuously activated when it cannot release GTP. Mutations that prevent GTP hydrolysis favor constitutive activation as RAS-GTP, Ras^D. The commonest mutations are at the 12 (Gly→Val) → GAP insensitive, and the 61 positions → stabilizing against GTP hydrolysis.

The Consensus Coding Sequences of Human Breast and Colorectal Cancers.
The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we have determined the sequence of well-annotated human protein coding genes in two common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ~90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J,
Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The Consensus Coding Sequences of Human Breast and Colorectal Cancers. Science. 2006 Sep 7; [Epub ahead of print] HHMI news.

[Analysis, identification and correction of some errors of model refseqs appeared in NCBI Human Gene Database by in silico cloning and experimental verification of novel human genes] [Yi Chuan Xue Bao. 2004] PMID: 15478601
Genetic alterations in the adenoma--carcinoma sequence. [Cancer. 1992] PMID: 1516027
Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells. [Int J Cancer. 2001] PMID: 11391615
Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. [Am J Hum Genet. 2006] PMID: 16685647
Causes and consequences of microsatellite instability in endometrial carcinoma. [Cancer Res. 1999]

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oncogenes

2010-10-21T11:10:00.000-07:00

Alteration of a gene that normally controls cell growth can promote the uncontrolled growth characteristic of cancer. The normal form of the gene is termed a proto-oncogene, and the malignantly transformed gene is termed an oncogene.

Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb :
Tumor Suppressor Genes: TP53

Damaged genes are passed down through the cancer cell line, and may be dominant or recessive genes:

Recessive: tumor suppressors, growth suppressors, recessive oncogenes or anti-oncogenes. Malignant transformation can result from genetic damage to genes coding for growth factors, growth factor receptors and/or proteins for signal transduction cascades.

Dominant: Proto-oncogenes participate in a variety of normal cellular functions, but have the potential to tranform into cellular oncogenes when damaged. Proto-oncogenes normally function in the various signal transduction cascades that regulate cell growth, proliferation and differentiation. Cellular proto-oncogenes resident in transforming retroviruses are designated as c- (cellular origin) as opposed to v- (retroviral origin). Oncogenes are malignantly transformed proto-oncogenes - table Oncogenes Proto-oncogenes

14-3-3 proteins are a family of highly conserved cellular proteins that play key roles in the regulation of central physiological pathways. More than 200 14-3-3 target proteins have been identified, including proteins involved in mitogenic and cell survival signaling, cell cycle control and apoptosic cell death. Importantly, the involvement of 14-3-3 proteins in the regulation of various oncogenes and tumor suppressor genes points to a potential role in human cancer. Tzivion G, Gupta VS, Kaplun L, Balan V. 14-3-3 proteins as potential oncogenes. Semin Cancer Biol. 2006 Jun;16(3):203-13. Epub 2006 Apr 1.

Oncogenes: c-Fos : c-Jun : c-Myc : c-Sis : Ras : Rb :
Tumor Suppressor Genes: TP53
Proto-oncogene/oncogene families ● growth factor genes ● receptor tyrosine kinases ( RTKs) ● membrane ssociated non-receptor tyrosine kinases (PTKs) ● G-protein coupled receptors (GPCRs) ● Serine/Threonine Kinases ● nuclear DNA-binding/transcription factors ●

¤ Cancer ¤ carcinogenesis ¤ oncogenes ¤ proliferation ¤ p53 ¤ retroviruses ¤ Rb ¤ signaling molecules ¤ tumor suppressors ¤ tumorigenic viruses ¤ site map ¤ Tables Oncogenes Proto-oncogenes Malignant Transformation Regulatory Proteins Sequences Cell signaling Cell Adhesion Apoptosis vs Necrosis Apoptosis

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retroviruses

2010-07-20T04:03:00.000-07:00

Retroviruses employ the RNA-dependent DNA polymerase (reverse transcriptase) within their capsid to replicate their RNA genome into a DNA intermediate, which can be incorporated into the host cell's DNA by an integrase enzyme.

Reverse transcriptase activity, exclusive of retroviral infection, occurs in most eukaryotes, generating and inserting retrotransposons into the host genome. The ability for strand displacement DNA synthesis, unassisted by other proteins, plays an important role in generation of the long terminal repeat sequences in the duplex DNA product of retroviral reverse transcription. Reverse transcriptases are found in retroviruses, retrotransposons, group II introns, bacterial msDNAs, hepadnaviruses, caulimoviruses, and HIV-1. Some 8% of the human genome is composed of endogenous retroviral material, and many endogenous retroviruses participate in control of gene transcription, cell fusion during placental development, and resistance to exogenous retroviral infection.

Right - click to enlarge image – retroviral infection and oncogenesis.
When a normal cell (1) is infected by a retrovirus (2), the viral reverse transcriptase reverse-transcribes the viral RNA into 'viral' DNA (v), which an integrase randomly integrates (inserts) into the host cell's genome (3-c-v). New viral particles are produced and shed by the infected cell (4) and some of these may contain proto-oncogene fragments of the host's genome (purple virion). Occasionally, the transducted sequence undergoes mutation (m) into an oncogene (5) that is subsequently integrated into the genome of a second normal cell (6), which becomes transformed into a tumorigenic line (7). Under the influence of other carcinogens, normal cells may suffer mutation (m) of a proto-oncogene to an oncogene (8).

Mechanisms of retroviral carcinogenesis:
1. Powerful transcriptional promoter sequences are located at the termini (ends) of the retroviral genome. These sequences are the 'long terminal repeats' (LTRs) that promote the transcription of the viral DNA into new virus particles.

Sometimes, in a process termed transduction, the process of integration causes rearrangement of the viral genome by incorporation of a portion of the host's genome into the viral genome. Occasionally, transduction provides the virus with a host gene that is normally involved in cell cycle control. The gene acquired from the host may be altered during the transduction process, in addition to its being transcribed at a higher rate by virtue of its association with the retroviral LTRs. In such cases, the transduced gene confers a growth advantage to the infected cell, causing the unrestricted cellular proliferation characteristic of tumorigenesis. These transduced host-cell-cycle genes function as oncogenes. The host gene that has been transduced is normally a cellular gene that functions as a proto-oncogene in its unmodified, non-transduced form. The genomes of transforming retroviruses contain numerous oncogenes.

2. Long terminal repeats possess powerful transcription promoting effects. Retroviral genome integration into the host genome occurs randomly. Sometimes this integration process places the LTRs close to a gene that codes for a growth regulating protein. Abnormally elevated levels of expresson of such proteins can induce cellular transformation – 'retroviral integration induced transformation'. HIV induces certain forms of cancers by this integration induced transformation process.

In most cases, cellular transformation by DNA tumor viruses result from viral protein-host protein interaction. Proteins encoded by the DNA tumor viruses are termed tumor antigens or T antigens, and they can interact with cellular proteins. The interaction of T antigens with cellular proteins sequesters the cellular proteins away from their normal functional locations within the cell. Proteins sequestered by viral T antigens are predominantly tumor suppressor proteins, and the loss of their normal suppressor functions results in cellular transformation.

¤ Cancer ¤ carcinogenesis ¤ oncogenes ¤ proliferation ¤ retroviruses ¤ signaling molecules ¤ tumor suppressors ¤ tumorigenic viruses ¤
Tables Malignant Transformation Oncogenes Proto-oncogenes

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signaling molecules

2010-06-16T17:10:00.000-07:00

Eukaryotic cells coordinate cell growth with the availability of nutrients in their environment. Mutation of molecules involved in cell-growth signaling can result in the uncontrolled cellular proliferation that is characteristic of neoplasia. Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases.

A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades.[↓]

ATM : ATR : DNA-PK : FRAP1 : kinases : MAPK : mTOR : Paks : PI-3-K : PIKK : PKC : Ras : receptor tyrosine kinases : serine/threonine kinases :

The mTOR protein kinase receives stimulatory signals from nutrients as well as Ras and phosphatidylinositol-3-OH kinase (PI(3)K) downstream from growth factors. Functioning as a critical growth-control node, mTOR is the 'mammalian target of rapamycin', a fungal derivative that halts protein synthesis by complexing with immunophilin FK-506 binding protein FKBP12 peptide prolyl cis/trans isomerase.

Officially termed FRAP1 for FK506 binding protein 12-rapamycin associated protein 1, mTOR is a serine/threonine kinase that regulates regulates translation and cell division. FRAP1 (mTOR) is an evolutionarily conserved member of the phosphoinositol kinase-related kinase (PIKK) family that includes DNA-PK, ATM, ATR and several other proteins. mTOR participates in the regulation of cell growth through initiation of gene translation in response to nutrients by integratating input from multiple upstream pathways, including growth factors, mitogens, leucine, insulin, and nutrients. mTOR initiates translation by activating the ribosomal p70S6k protein kinase (S6K1) and by inhibiting the eIF4E inhibitor 4E-BP1. FRAP1 is considered to be involved in numerous additional cellular functions including actin organization, membrane trafficking, secretion, protein degradation, protein kinase C signaling, ribosome biogenesis and tRNA synthesis. mTOR may contribute to the regulation of two pathways, referred to as TORC1 and TORC2 (for TOR Complex 1 and 2).

Components of the Ras and PI(3)K signalling pathways are mutated in most human cancers. The high frequency of mutations in these pathways suggests that the loss of growth-control checkpoints and the promotion of cell survival in nutrient-limited conditions may be an obligate event in carcinogenesis.[r]

p21-activated kinases (Paks) are serine/threonine kinases that function as downstream nodes oncogenic signalling pathways. Paks are well-known regulators of cytoskeletal remodelling and cell motility that promote cell proliferation, regulate apoptosis and accelerate mitosic abnormalities, resulting in tumorigenesis and cell invasiveness. Alterations in Pak expression have been detected in human tumours

Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases. A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades. Faivre S, Djelloul S, Raymond E. New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol. 2006 Aug;33(4):407-20.

~ activator ~ cadherins ¤ Cancer ¤ carcinogenesis ~ cyclin-dependent kinases ~ cytokines ~ gene regulation ¤ genetic predispositon~ growth factors ¤ oncogenes ¤ malignant transformation ¤ mitogens ¤ mutagens ¤ neoplasia ¤ non-mutagenic carcinogens ¤ p53 ¤ proliferation ¤ proto-oncogenes ~ promoters ¤ Ras ¤ Rb ~ receptor tyrosine kinases ~ regulatory proteins ~ replication ~ repressor ~ response elements ~ retrotransposons ~ restriction enzmes ~ reverse transcriptase ~ Rho GTPase ~ ribosomes ~ serine/threonine kinases ¤ signaling molecules ~ silencers ¤ T-antigens ¤ TP53 ~ transcription ~ transcription factors ~ translation ¤ tumor antigens ¤ tumor suppressors ¤ tumorigenic viruses ¤ viral carcinogens ¤

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Immunology Overview

2007-12-31T23:59:00.000-08:00

Immunology is the study of the immune system, which defends the body against foreign intrusion by pathogens. (right - colorized scanning electron micrograph of red blood cells - erythrocyte, platelet, leukocyte)

The immune system is intimately connected with the hematologic system since white blood cells (leukocytes, including B- and T-lymphocytes) are key players in the lymphoid system. Cellular participants in the immune and inflammatory responses include :
● phagocytic cells (dendritic cells, monocytes and macrophages, and granulocytes)
● antigen presenting cells (dendritic cells, macrophages, B lymphocytes, helper T cells)
● antibody producing cells (plasma cells)
● cytotoxic cells (CTL, NK, NKT)
● regulatory cells (APCs, helper T cells, regulatory T cells)
● cells-in-waiting (memory B cells, monocytes, naïve B cells, Tc)
● chemical releasing cells (basophils, eosinophils, neutrophils; mast cells - histamine, cytokines; hepatocytes - complement proteins)

An antigen is any molecule that stimulates an immune response. Most antigens are proteins or polysaccharides, though small molecules coupled to carrier proteins (haptens) can also be antigenic. The segment of an antigenic molecule to which its cognate antibody binds is termed an epitope or antigenic determinant. Immune responses ideally distinguish between self and other. Anergy toward self-targets operates as one self-tolerance mechanism to control the autoreactive cells found in disease-causing autoimmunity.

Immune responses are classifed as passive or active, innate or adaptive, and cellular or humoral.

These categories are not mutually exclusive. For example, both innate and adaptive immune responses employ cellular responses. Similarly, humoral and cellular responses intersect rather than being mutually independent (e.g., helper T cells assist in activation of B cells, opsonization). Unfortunately, some terminology employed in immunology predates understanding of mechanisms, so some commonly used names do not immediately reflect the distinction between cell types (NK cells versus NKT cells) or origins (lymphoid versus myeloid origins of dendritic cells). Similarly revision of chemical terminology has resulted in misleading terminology of biochemical components (e.g., complement C4b•2b was formerly termed C4b•2a).

Passive measures to prevent pathogenic incursions are provided by physical barriers to invasion – the skin, secretions, and ciliary action. Should pathogens pass beyond the physical barricade, then active innate and acquired immune reactions mount a defense.

Innate immune responses employ phagocytic cells that are circulating or tissue emplaced – granulocytes, monocytes, dendritic cells, macrophages, and B lymphocytes. The early, innate response also employs chemical responses – chemical-mediated inflammation; the complement cascade; antimicrobial peptides; and, pattern-recognition receptors (PRR), including Toll-like receptors. The innate system is considered to constitute an evolutionarily older defense strategy, and it is the predominant immune system exhibited by plants, fungi, insects, and primitive metazoa.

An induced, acquired, adaptive response begins when foreign or pathogenic substances (antigens) are 'recognized' by cells of the lymphoid system, stimulating a co-ordinated cellular/humoral response depending upon the nature of the pathogen. Antigen recognition relies on a random and highly diversified repertoire of receptors for antigens (TCR, BCR) and antigen stimulation is followed by clonal selection and expansion of cells expressing receptors with relevant specificities, accounting for immunological memory. Adaptive immune responses are typically delayed for 4 to 7 days because specific clones must expand and differentiate into effector cells before participating in host defense.

Surfaces of cells of the immune system are coated with proteins and receptors that participate in cellular signal transduction, enabling regulatory interaction:
● clusters of differentiation – a defined subset of cellular surface receptors (epitopes) on B and T lymphocytes that identify cell type and stage of differentiation, and which are recognized by antibodies.
● B cell receptors (BCR) comprising one of thousands of distinct immunoglobulin superfamily molecules generated through VDJ recombination.
● T cell receptors (TCR) with heterodimers of α and β chains or γ and δ chains with Ig-like domains. Each TCR originates in a single allele and binding with a single specificity (CDR3 for antigens and CDR1-2 for MHCs).
● pattern-recognition receptors, including Toll-like receptors, which participate in the innate immune response by responding to pathogen-associated molecular patterns (PAMP) and endogenous stress signals termed danger-associated molecular patterns (DAMP).
● major histocompatibility complex (MHC) molecules of classes I, II, and III, participate in lymphocyte recognition and antigen presentation.

B lymphocytes perform the humoral immune response, and are activated when naïve B cells encounter their specific, cognate antigen. Secreted cytokines promote the proliferation of single clones of B cells that express that immunoglobulin surface receptor (BCR) which already possesses VDJ recombination-generated affinity for the antigen. Assisted by costimulation from helper T cells, B cells may undergo differentiation into plasma cells, which secrete copious quantities of the monoclonal antibody, or into memory B cells, which are primed for rapid, amplified secondary response to a repeated exposure of the priming antigen.

T lymphocytes participate in the cellular immune response, and are activated by engagement of their surface receptor (TCR), which ensures antigen specificity and MHC restriction of the response. As for B cells, costimulatory, synergistic second signaling by costimulatory molecules is also necessary to sustain and integrate TCR signaling in order to stimulate optimal T cell proliferation and differentiation. T cells include cytotoxic T cells, helper T cells, regulatory T cells, natural killer T cells, and γδ T cells.

A ф activation ф affinity maturation ф anergy ф antibodies ф antigen ф APCs ф autoimmunity B ф B cells ф basophils ф blood C ф cancer and immune system ф cancers of immune system ф CD ф cellular response ф class-switch recombination ф clonal selection ф complement system ф costimulation ф cytolysis ф cytotoxicity D ф dendritic cells E ф eosinophils ф evolution of immune and coagulation systems G ф gene conversion ф granulocytes H ф helper T cell ф hematopoiesis ф humoral immunity ф HIV/AIDs I ф immune cytokines ф immune response ф immune tolerance ф inflammatory response ф interferons ф isotype switching K ф killer T cells L ф leukocytes ф leukocyte adhesion cascade ф lymphocytes ф lymphokines ф lymphoid system M ф macrophages ф MHC ф migration ф monocytes N ф neutrophils P ф pathogens ф pattern-recognition receptors ф phagocyte ф plasma cells R ф receptors S ф secondary antibody diversification ф signaling ф somatic hypermutation, somatic mutation ф surface receptors T ф T cells ф thymus ф (tolerance) V ф vaccines ф VDJ recombination

Tables Complement Receptors Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

tags [Immunology] [Overview]

activation

2007-12-22T04:15:00.000-08:00

Activation of cells of the immune system variably induces proliferation, differentiation, production, and maturation. Some activated cells of the immune system are involved in activation (costimulation) of other cell types. Likewise, some activated cells express molecules involved in activation.

▼ activating agents : B cell activation : costimulatory agents : costimulatory cells : complement activation pathways : dendritic cell activation : granulocyte activation : lymphocyte activation : macrophage alternative : macrophage classical : markers : mediators : monocyte-macrophage : pDC : phagocyte activation : precursor dendritic cells : signaling/receptors : T cell activation : Tc activation : Th activation ▼

Activating agents
_ ● antigen
___ ● pathogens
___ ● pathogen-associated molecular patterns (PAMP)
___ ● danger-associated molecular patterns (DAMP)

Markers
___ ● major histocompatibility complex (MHC) molecules

Costimulatory agents
___ ● CD28
___ ● SLAM (signaling lymphocytic activation molecule), a 70-kDa costimulatory molecule belonging to the Ig superfamily
___ ● ICOS (inducible costimulator) molecules
___ ● TNFR: CD40, CD30, CD27, OX-40, 4-1BB
___ ● negative regulators of costimulation: CTLA-4, PD-1

Costimulatory cells
● helper T cells (Th) for activation of B cells, and APCs for activation of T cells
_ ● Antigen presenting cells display epitope proteins – exogenous antigen or fragmented antigen from phagocytosed cells – on their surfaces. APCs include:
___ ● phagocytic cells – dendritic cells, macrophages
___ ● B cells (B lymphocytes)

Signaling / receptors
_ ● pattern recognition receptors
_____ ● complement receptors (table)
_____ ● Fc receptors (table)
_____ ● scavenger receptors (table)
_____ ● Toll-like receptors (table)
_ ● TNFR
_ ● B cell receptors (BCR)
___ ● immunoglobulin - antibodies (table)
_ ● T cell receptors (TCR)
_____ ● clusters of differentiation
_____ ● major histocompatibility complex (MHC) molecules

Mediators
_ ● immune cytokines (table)

Phagocytes

Dendritic cells
Dendritic cells and their immature counterparts, Langerhans cells (LC), are highly specialized, professional antigen-presenting cells (APC). Immature dendritic cells are called 'veiled cells' because they display large cytoplasmic 'veils' rather than the long dendritic projections of mature cells. As key regulators of immune responses, dendritic cells (DC) stimulate lymphocytes to perform cell-mediated and humoral immune responses against pathogens and tumor cells.

Immature, precursor dendritic cells (pDC) circulate throughout the body, migrating to lymphocyte rich tissues (such as spleen and lymph nodes) upon stimulating encounter with antigen. The dendritic cells internalize the antigen then externalize (fragmented) antigen that they present to lymphocytes in MHC-peptide complexes, expressing markers that stimulate lymphocyte activation.

Monocyte → macrophage activation
Production of the macrophage lineage from progenitors in the bone marrow is typically controlled by M-CSF, which is constitutively expressed by many cell types. Serum levels of M-CSF and GM-CSF increase in response to invasive stimuli and inflammation, and monocyte numbers increase dramatically. M-CSF-derived macrophages are larger, and have a higher phagocytic capacity, while GM-CSF-derived macrophages are more cytotoxic against TNF-α-resistant tumour targets, express more MHC class II antigen, and constitutively secrete more PGE-2.

Classically activated macrophages are associated with chronic inflammation and tissue injury wherein classically activated macrophages exhibit a Th1-like phenotype, promoting inflammation, destruction of the extracellular matrix (ECM), and apoptosis. Classical macrophage activation proceeds in two stages.
1. IFN-γ-primed stage in which macrophages exhibit enhanced MHC class II expression, antigen presentation, but reduced proliferative capacity. (IFN-α, IFN-β, IL-3, M-CSF, GM-CSF and TNF-α can also prime macrophages for selected functions.)
2. Secondary stimuli operated to fully activate primed macrophages. Diverse agents provide secondary signals (including LPS (CD14), bacteria, yeast glucans, GM-CSF and phorbol esters). Macrophages stimulated for tumoricidal activity secrete IL-1, display decreased MHC class II gene transcription, and are generally poor antigen presenters of antigen.[r]

Alternatively activated macrophages typically resolve inflammation and facilitate wound healing wherein they display a Th2-like phenotype, promoting construction of ECM, cell proliferation, and angiogenesis. Alternative macrophage activation does not require a priming stage and IL-42 and/or IL-1326 can act as sufficient stimuli.[r2]

Granulocyte activation
The hematopoietic cytokines, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have pleiotropic activating effects on mature leukocytes, which can improve leukocyte function, facilitating eradication of microbial infections. G-CSF activates neutrophils, while GM-CSF activates neutrophils, eosinophils, and monocyte/macrophages.

Lymphocytes
B cell activation: naïve B cells → plasma cells
Activation of naïve B cells occurs when a BCR (antibody) encounters and ligates its cognate antigen. B cells are coated in immunoglobulin receptors and are able to recognize intact antigen, which they engulf, digest, and subsequently present in complex with surface MHC class II molecules. The MHC-peptide complex binds CD4 + helper T cells (Th), inducing secretion of cytokines that stimulate B cell proliferation and their differentiation into plasma cells, which secrete specific antibodies that bind with the cognate antigen. These antigen-antibody complexes are subsequently cleared by liver and spleen cells and the classical complement cascade.

T cell activation:
Activation of T cells requires a first signal of TCR engagement, which ensures antigen specificity and MHC restriction of the response. The second signal comprises synergistic costimulatory signaling by professional antigen presenting cells. The costimulatory second signal is necessary to sustain and integrate TCR signaling to stimulate optimal T cell proliferation and differentiation. The level of activation of T cells is closely related to their state of differentiation.

Activation of the resting Tc cell involves two steps: 1) TCR on the CD8+ cell interacts with antigen-class I MHC complex on the surface of a target cell. 2) CD8+ Tc cell is stimulated by cytokines, particularly IL-2, which have been secreted predominantly by activated Th cells. Resting Tc do not express IL-2 receptors until antigen stimulation increases the expression of Tc IL-2 receptors, ensuring that activation is confined to Tc cells that ligate cognate antigen. Activated Tc cells become CTLs.

The first signal for helper T cell (Th) activation is interaction of the TcR-CD3 complex with antigen-MHC class II molecules on the surface of an antigen presenting cell. Stimulation is aided by the CD4 molecule on Th cells, with or without assistance from other accessory molecules, such as CD45, CD28 and CD2. Increased IL-2 secretion by the T cell and an increase in IL-2 receptors on the T cell surface trigger a cascade of biochemical events.

Three pathways are involved in complement activation:
● classical pathway (binding of an antibody to its cognate antigen)
● alternative pathway (relies upon spontaneous conversion of C3 to C3b)
● mannose-binding lectin pathway (MBL -MAPS) (homologous to the classical pathway, but utilizes opsonin, mannan-binding lectin (MBL) and ficolins rather than C1q)

▲ф A activating agents § adaptor protein ~ adhesion molecules ф affinity maturation ♦ AID ф anergy ф antibodies ф antigen ф APCs סּ apoptosis ф autoimmunity B : B cell activation ф B cells ọ blood ọ bone marrow C סּ caspases ф CD סּ cell-cycle control ₪ cellular fate ф cellular response סּ cellular signal transduction סּ chemotaxis ф class-switch recombination ф clonal selection ф complement system : complement activation pathways : costimulatory agents : costimulatory cells ~ cytokines ~ cytokine receptors D סּ death receptor : dendritic cell activation ф dendritic cells ₪ differentiation E סּ ECM F ♦ Fyn G ф gene conversion ọ germinal centers : granulocyte activation ф granulocytes H ф helper T cell ф hematopoiesis ф humoral immunity I ф immune cytokines ф immune response ф immune tolerance ~ immunoglobulins § immunoglobulin isotypes ф inflammatory response ф interferons ф isotype switching L ф leukocytes ф leukocyte adhesion cascade : lymphocyte activation ф lymphocytes ọ lymphoid system ф lymphokines ф lymphoid system M : macrophage alternative : macrophage classical ф macrophages ф MHC ф migration ¤ mitogens ф monocytes : markers : mediators : monocyte-macrophage N § NF-κB P ф pathogens ф pattern-recognition receptors : pDC : phagocyte activation ф phagocyte ф plasma cells : precursor dendritic cells ¤ proliferation R ф receptors S ф secondary antibody diversification ф signaling ¤ signaling molecules : signaling/receptors סּ signal transduction ф somatic hypermutation, somatic mutation ф surface receptors T : T cell activation ф T cells : Tc activation : Th activation ф thymus ọ thymus ф (tolerance) ▲ф

Complement Receptors Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

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tags [Immunology] [activation]

affinity maturation

2007-12-19T18:11:00.000-08:00

Affinity maturation is a process of affinity-selected differentiation of activated B cells. Repeated exposures to the same antigen provokes greater antibody ligating affinity in the antibody secreted by successive generations of plasma cells.

The mechanisms by which affinity maturation is achieved are somatic hypermutation and clonal selection. Somatic hypermutation (SHM) is a diversity generating, regulated cellular mechanism through which antibodies are produced against an enormous variety of different potential antigens. The binding affinities of the variable regions of immunoglobulins are altered by AID-enzyme-promoted mutations during antigen-stimulated proliferation of B cells. These somatic hypermutations are transcribed and translated into thousands of slightly different immunoglobulins coded by the hypermutated V regions. The complementarity determining regions of these antibodies possess different affinities for the encountered antigen, and clonal selection will favor cells equipped with highest affinity antibodies because these B cells are favoured in terms of activation and co-operation with T cells.

Clonal selection is the phenomenon whereby a previously unencountered cognate antigen (epitope) can stimulate naïve B lymphocytes to proliferate and differentiate into clones of memory B cells and plasma cells that produce antibodies with the highest affinity for the antigen. Those B cells that have highest affinity BCR against the encountered antigen will be selected for proliferation, antibody production, and committment to an antigen-specific memory lineage.

Thus, SHM prepares a spectrum of antibodies with different affinities for the antigen, while clonal selection ensures that the immune system will react increasingly effectively (highest affinity) to an encountered antigen and will be ready for rapid response to subsequent encounters with the antigen.

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

tags [Immunology] [affinity maturation]

anergy

2007-12-11T19:08:00.000-08:00

Anergy (immunologic tolerance) refers to the failure to mount a full immune response against a target.

Anergy toward self-targets operates as one self-tolerance mechanism to control the autoreactive cells found in autoimmunity. Clonal deletion in which lymphocytes are killed if they recognize a self-antigen during their maturation in the thymus gland or bone marrow is a major mechanism for the prevention of autoimmunity. However, not all human self-antigens are expressed in the central lymphoid organs where the lymphocytes are developing. Thus, self-tolerance to an individual's own antigens must also depend on mechanisms such as clonal anergy. Theoretically, recognition of a self-antigen eliminates the proliferative capacity of autoreactive lymphocytes in the peripheral immune system. Another process, immunoregulation, utilizes regulatory T cells that weaken harmful or inappropriate lymphocyte responses.

In B cell anergy, self-reactive B cells persist in the periphery yet remain unresponsive to immunogen. Research findings indicate that continuous binding of antigen and subsequent receptor signaling are essential for the maintenance of anergy.[n]

T cell anergy is induced when TCR stimulation "freezes" T cell responses until they receive an adequate subsequent antigenic signal from an antigen-presenting cell. Such APC signals can rescue T cells from anergy, stimulating them to produce the lymphokines necessary for the growth of additional T cells.

During a productive immune response, CD4+ T cells respond to effective signals by producing interleukin 2 (IL-2) and by proliferating. Effective signals stimulate require both ligation of TCRs with cognate antigens presented by class II MHC molecules on the surface of APCs and activation of costimulatory receptors, such as CD28, which recognize ligands such as B7 proteins expressed on the surface of APCs.

When T cells receive stimulus only TCR signals in the absence of engagement of costimulatory receptors, they enter a state of anergic unresponsiveness characterized by an inability to produce IL-2 or to proliferate upon re-stimulation. Such anergic T cells show a profound block in Ras/MAPK pathway that prevents activation of the AP-1 family of transcription factors (Fos/Jun).

GRAIL (gene related to anergy in lymphocytes) is GRAIL is an E3 ubiquitin ligase that is necessary for the induction of CD4+ T cell anergy in vivo. It is upregulated in naturally occurring (thymically derived) CD4+ and CD25+ cells [a] and anergized T cells [1]. Both GRAIL and Foxp3 are genotypic marker for CD25+ Treg cells. T cell activation appears to be controlled by Foxp3 through transcriptional regulation of early growth response (Egr) genes Egr-2 and Egr-3, and E3 ubiquitin (Ub) ligase genes Cblb [?], Itch [?] and GRAIL, subsequently affecting degradation of two key signaling proteins, PLCgamma1 and PKC-theta. [a]

It is believed that GRAIL could induce anergy through ubiquitylation of membrane-associated targets required for T-cell activation. It has been demonstrated that two isoforms of otubain-1, in conjunction with the deubiquitylating enzyme USP8, produce opposing effects on the expression and function of GRAIL in the induction of anergy.[2] GRAIL is differentially expressed in naturally occurring and peripherally induced CD25+ Treg cells where the expression of GRAIL has been suggested is linked to their functional "regulatory" activity.

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

tags [Immunology] [anergy]

antibodies

2007-12-11T04:19:00.000-08:00

Antibodies are glycoproteins of the immunoglobulin superfamily, and are adhesion-signaling molecules that recognize (bind to) specific antigens. Antibodies are synthesized by B cell-derived plasma cells.

▼: adhesion molecules : antigen binding site : C : CH1-4 : cellular adhesion molecules : complement fixation : complementarity determining regions : constant domains : domains : evolution of immunoglobulins : Fab : Fc : heavy chain : hinge region : Ig supergene family : isotypes : kinase activation : light chain : location of Ig classes : membrane-bound Igs : multimeric structures : tissue location : V : VDJ recombination : VH, VL : variable domains :▼

Immunoglobulins (left - click to enlarge) comprise two heavy (h) and two light-chain (l) protein subunits, each of which folds into domains (4 on heavy, 2 on light). These adhesion sites or domains contain one or more folds of 60 to 100 amino acids.

Depending upon the character of the heavy chain, immunoglobulins are divided into five classes – IgG, IgD, IgE, IgA, IgM – that are expressed in different tissues. The classes are further subdivided into isotypes, which have different properties in terms of complement fixation and binding to immunoglobulin (Ig) receptors.

Members of the immunoglobulin supergene family are found as:
● membrane-bound surface receptors of immune-system cells,
● cellular adhesion molecules, or
● soluble antibodies (γ-globulins) synthesized by activated B cells.

Membrane-bound Igs have a transmembrane segment and a cytoplasmic C-terminal tail. The 2 β- chains are stabilized into sandwiched β sheets that are adherent by virtue of hydrophobic interactions between disulphide bonds. Igs assume a Y-shaped structure "topped" at the extracellular N-terminals by variable domains (red), with a variable domain at the tip of the heavy chain (1) and the light chain (2), between which lies an antigen binding site (3). The variable regions are coded by pluripotential DNA sequences that can generate thousands of polypeptide sequences capable of adhering to millions of different ligands. Binding is homophilic or heterophilic, including binding to different Igs and to integrins. Both light and heavy chains contain constant domains (white, 4).

Right - click to enlarge - the heavy chains of IgA, IgD and IgG each have four domains, where those at the N-terminal are variable (VH) and the other three are constant (CH1-3). IgE and IgM have one variable and four constant domains (CH1-4) on the heavy chain. The variable domains are termed Fab, while the constant domains are termed Fc.

The light chains have two domains, one variable domain (VL) at the N-terminal, and one constant (CL) domain.

The antigen binding site lies between VH and VL (shaded lavendar). Most variability is found in three superficial-loop forming regions in the VH and VL domains, which are the complementarity determining regions or CDRs. CDR3 binds antigens and CDR1-2 bind MHCs. CDR3 shows more variation that do either CDR1 or 2.

The domains have related amino acid sequences that possess a common secondary and tertiary structure. This conserved structure is found frequently in proteins involved in cell-cell interactions and is particularly important in immunology. The constant (Fc) regions have complement fixing and Ig receptor binding activity. The hinge region, in IgG, IgA and IgD, is an important sequence of 10-60 amino acids between CH1 and CH2 that confers flexibility on the molecule.

animations Џ B cell selection Џ ELISA test +ve, -ve Џ IgG rotating x- y- axes Џ Rotating mouse IgG2a Molecule (y-axis) Џ somatic recombination of Ig gene Џ spinning IgG1 Kol Џ unfolding (small) IgG . unfolding (large) IgG .

Immunoglobulins attain their enormous variability by splicing components (VDJ recombination) coded in widely scattered sequences of DNA that are located in two different chromosomes. Antigen binding takes place at the heavy chain, which displays enormous variation by virtue of combining 1 of 400 possible variable gene segments with 1 out of 15 diversity segments and 1 out of 4 joining segments. This alternative splicing generates 24,000 possible combinations for the DNA encoding the heavy chain alone. The variable coding segments are assembled together with those for the constant-C segments of the heavy-chain molecule.

Tissue location:
IgA – mucus – gut, respiratory tract
IgD – antigen receptor on B cells
IgE – mast cells – releases histamines in response to allergens
IgG – primary immunity against invading pathogens
IgM – early B cell-mediated response to invading pathogens

Some antibody classes form multimeric structures – pentamers (IgM) and dimers or trimers (IgA). These two isotypes also associate with a small protein called the joining (J) chain required for stabilisation of the complexes.

The immunoglobulin superfamily is evolutionarily ancient, is widely expressed, and is constitutive or long-term up-regulated. Immunoglobulin antibodies are released by activated B cells of the immune system, on which they also act as surface marker proteins. Adherence of immunoglobilins to foreign substances or to cellular invaders may be sufficient to disarm the invader, or the attached antibodies function as attack signal to macrophages and natural killer cells. Adhesion molecules of the immunoglobulin supergene family, activate specific kinases through phosphorylation, resulting in activation of transcription factors, increased cytokine production, increased cell membrane protein expression, production of reactive oxygen species, and cell proliferation.

▲: adhesion molecules ~ adhesion molecules ф antigen : antigen binding site ф APCs ф B cells : C : CH1-4 : cellular adhesion molecules : complement fixation ф complement system : complementarity determining regions : constant domains : domains : evolution of immunoglobulins : Fab : Fc : heavy chain : hinge region ф humoral immunity : Ig supergene family ~ immunoglobulins : isotypes : kinase activation ♦ kinases : light chain : location of Ig classes : membrane-bound Igs : multimeric structures ф receptors ф signaling ф surface receptors ф T cells : tissue location ~ tyrosine kinases : V : VDJ recombination ф VDJ recombination : VH, VL : variable domains :▲

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

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tags [Immunology]
[antibodies]

antigen

2007-12-11T04:18:00.000-08:00

An antigen is any molecule that stimulates an immune response. Most antigens are proteins or polysaccharides, though small molecules coupled to carrier proteins (haptens) can also be antigenic. The segment of an antigenic molecule to which its cognate antibody binds is termed an epitope or antigenic determinant.

▼ allergen : allergic reactions : antigenic determinant : autoantigenic : autoimmune disorders : class I histocompatibility molecule (MHC I) : class II histocompatibility molecule (MHC II) : immunogen : endogenous : epitope : exogenous : lipid Ag : pathogen-associated molecular pattern (PAMP) : pattern-recognition receptor (PRR) : polysaccharide Ag : T-dependent : T-independent : tolerogen : Toll-like receptor (TLR) : tumor antigens : tumor-associated antigen (TAA) : tumor-specific antigen (TSA) ▼

Antigens are classified by immune activity as immunogens, tolerogens, or allergens according to whether the molecule in question activates the immune response, is tolerated by the immune system, or elicits an allergic response, respectively. Allergic reactions are exaggerated immune responses to molecules (allergens) that would otherwise not prove harmful. Antigens may also be classified according to their source as exogenous, endogenous, autoantigenic, or tumor antigens.

Exogenous antigens are foreign molecules that are ingested (endo-, phagocytosis) by antigen presenting cells on which the fragmented and extruded antigens are then carried on class II histocompatibility molecules (MHC II) for presentation to CD4+ Th cells. Pathogen-associated molecular patterns (PAMPs ) are small molecular sequences consistently found on pathogens that are recognized by Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs). Pattern recognition receptors (PRR) are a class of innate immune response-expressed protein receptors that respond to PAMPs.

Endogenous antigens are internally generated molecules that become presented on the cell surface in the complex with class I histocompatibility molecules (MHC I). Endogenous antigens may result from exogeneous viral or bacterial infections that have altered the host cell.

In autoimmune disorders, endogenous, self-molecules induce autimmune attack by CD8+ Tc/CTLs that have escaped negative selection in the thymus.

Tumor-specific antigens (TSAs) typically result from a tumor specific mutation and are targetted for non-self attack when displayed on class I histocompatibility molecules. Tumor-associated antigens (TAAs) are more common than TSAs, and are presented both by tumor cells and by normal cells. Tumor antigens may elicit targetting by CTLs before the tumor cells can successfully proliferate and metastasize. Unfortunately, tumors employ a variety of mechanisms to evade the immune system.

Protein antigens are T dependent in that they require T cell co-operation to induce antibody responses in B cells. Non-protein antigens, such as polysaccharides and lipids can elicit T-independent antibody responses. Such T-independent antigens are typically polymeric, so it is believed that they are able to cross-link BCR-surface-Ig sufficiently strongly to activate B cells without T cell costimulation. These T-independent polymeric antigens elicit IgM antibodies and do not demonstrate affinity maturation. However, a subclass of T cells are specialized to present lipid and glycolipid antigens – γδ T cells recognize foreign nonpeptide antigens presented by CD1 proteins, which are MHC-like-molecules specialized for the presentation of lipids.

ф activation ф anergy ф antibodies ф antigen presenting cells (APCs) ф autoimmunity ф basophils ¤ cancer סּ cell-cycle control ф class-switch recombination ф clonal selection ф dendritic cells o-o endogenous vs exogenous ф eosinophils ф granulocytes ~ growth factors ф immune cytokines ф immune response ф immune tolerance ф inflammatory response ф interferons ф isotype switching ф leukocytes ф lymphocytes ф lymphokines ф lymphoid system ф macrophages ф MHC ф monocytes ф pathogens ф pattern-recognition receptors ф phagocyte ф plasma cells ¤ proliferation ф receptors ₪ regulation of gene expression ф secondary antibody diversification ф signaling ф surface receptors ф vaccines

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

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tags [Immunology] [antigen] [pathogen] [autoimmune]

APCs

2007-12-09T21:59:00.000-08:00

APCs are antigen presenting cells, which display epitope proteins – exogenous antigen or fragmented antigen from phagocytosed cells – on their surfaces.

▼ APC types : B cells : BCRs : CD1 family : CD1 proteins : CD4+ : class II MHC : dendritic cells : endocytosis : exocytosis : fragmented antigen peptides : histocompatibility molecules : γδ T cells : intact antigen : lipid antigen : macrophages : mycobacterial cell wall components : peptide antigen : phagocytic presenting cells : T cells and fragmented peptides, T cells and lipid antigens ▼

Antigen presenting cells include:
● phagocytic cells – dendritic cells, macrophages
● B cells (B lymphocytes)
● γδ T cells

Fragmented antigen – APCs engulf the antigen through endocytosis, then the endosome fuses with a lysosome where the antigen is digested into fragments such as short peptides. Following, exocytosis, a class II histocompatibility molecule holds the fragmented antigenic peptides at the surface of the cell, where they may be recognized by CD4+ T cells.

Intact antigen – dendritic cells can present intact antigen to B cells (not fragmented in lysosomes) by presenting the antigen on the cell surface. This antigen can bind to BCRs of the appropriate specificity, and can stimulate the B cells.

Presentation of peptide antigens for activation of naïve T cells does not reside solely in dendritic cells. A population of γδ T cells can efficiently present peptide antigens to αβT cells, and γδ T cells of the major tissue subset recognize self and foreign nonpeptide, lipid antigens presented by CD1 proteins. γδ T cells carry TCRs encoded by different gene segments than those of αβ T cells.

CD1 proteins are a family (CD1a-e) of cluster of differentiation glycoproteins related to the class I MHC molecules. CD1 are involved in the presentation of lipid and glycolipid antigens, particularly self, microbial, and mycobacterial cell wall components, to CD1-specific T cells.

The human CD1 family of transmembrane glycoproteins are encoded by five CD1 family genes organized in a cluster on chromosome 1. CD1 glycoproteins form heterodimers with beta-2-microglobulin. CD1 family members are considered to differ in cellular localization and specificity for particular lipid ligands. The CD1a protein (R4, T6, CD1, FCB6, HTA1) localizes to the plasma membrane and to recycling vesicles of the early endocytic system. Alternatively spliced transcript variants have been observed.[e]

ф activation ₪ alternative splicing ф antibodies ф antigen ф B cells cell membranes ф costimulation ф dendritic cells סּ endosomes סּ exosome ф helper T cell ф killer T cells סּ lysosome ф macrophages ф MHC ф pathogens ф pattern-recognition receptors ф phagocyte סּ phagocytosis סּ receptor-mediated endocytosis ф surface receptors ф γδ T cells ф T cells

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

tags [Immunology][APC]

autoimmunity

2007-12-04T04:09:00.000-08:00

Autoimmune responses involve immune responses directed at self, and are operative in the development of immunological tolerance to self. Autoimmune diseases arise when the immune system targets the organism's tissues because of a failure of tolerance.

Several hypotheses have been proposed to explain mechanisms of immumological tolerance:
● Clonal Deletion theory – proposal that self-reactive lymphoid cells are destroyed during the development of the immune system in an individual.
● Clonal Anergy theory – proposal that self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.
● Idiotype Network theory – proposal that a network of antibodies capable of neutralising self-reactive antibodies exists naturally within the body.
● Suppressor population or Regulatory T cell theories – proposal that regulatory T-lymphocytes (commonly including CD4+FoxP3+ cells) function to prevent, downregulate, or limit autoaggressive immune responses.
● Clonal Ignorance theory – proposal that host immune responses are directed to ignore self-antigens

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

tags [Immunology][autoimmunity]

basophils

2007-11-24T05:09:00.000-08:00

Basophils are granulocytes packed with granules that stain basic (purple with H&E).

The nucleus is bilobed, and the metachromatic granules contain sulfated glycosaminoglycans as well as vasoactive compounds – histamine and proteoglycans. Lysosomal arylsulfatase is found in granules of developing basophils in bone marrow.

Basophil granules are surrounded by a unit membrane and contain particles which are uniform in size across the same granule yet vary in size in different granules within the same cell. Some granules reveal a homogeneous texture and/or "myelin" figures. [s] Though basophils and mast cells share morphological features, the appearance of most basophil granules differs from the ultrastructure of human mast cell granules.

Activated basophils release proinflammatory histamine and proteoglycans from granules, and synthesize then secrete leukotrienes and cytokines (particularly IL-4). Histamine and IL-4, which is associated with production of IgE, are involved in allergic reactions.

Basophils are the least common granulocyte, representing about 0.5% to 1% of circulating leukocytes. A low basophil count combined with a low neutrophil count almost always portends leukemia.

Tables Fc receptors Immune Cytokines Immunoglobulins .

tags [Immunology][leukocytes]

B cells

2007-11-22T19:12:00.000-08:00

B cells are lymphocytes (WBCs) that participate in humoral immunity by producing antibodies in response to antigen stimulation.

▼ activation : B-1 : B-2 : BCRs : CDRs : granzymes : helper T cells : life-span B cells : lymphopoiesis : memory B : naïve B cells : NK cells : NK receptors : NK cells attack viral infected cells : perforin : plasma B : stimulation : surface-immunoglobulins : surface receptors : VDJ recombination ▼

Surface membrane-associated immunoglobulins (IgD and IgM) act as B cell receptors (BCRs), and the enormous variety of antigen recognition sites is attributable to VDJ recombination (alternative splicing) of peptide sequences encoded by V, D, and J genes. The variable region of immunoglobulins includes the recognition sites or complementarity determining regions (CDRs).
Lymphopoiesis, which takes place in the bone marrow of almost all mammals, produces small lymphocytes, large granular lymphocytes (NK) cells, B lymphocytes (precursors of plasma cells, T lymphocytes, and lymphoid dendritic cell. Recognition of self during lymphopoiesis permits anergy (suppression of self-attack).

Naïve B cells each have one of millions of distinct surface antigen-specific receptors, yet have not encountered their specific, cognate antigen. With a life-span of only a few days, many B cells die without ever encountering their cognate antigen. Naïve B cells are activated when the BCR binds to its cognate antigen. This antigen-Ig binding must be coupled with a signal from a helper T cell in order to activate the B cell.

Once activated, B lymphocytes:
● differentiate into one of the B cell types (directly or through intermediate, germinal center reactions)
● plasma cells produce antibodies against the antigenic stimulus, or memory cells are primed for subsequent activation by the antigen

Types of B cell:
● B-1
● B-2
● Plasma B cells
● Memory B cells

After newly formed B cells exit generative sites in fetal liver or adult bone marrow they undergo selection events that may involve interactions with self or with external antigens. Selective events can influence the phenotype and functional characteristics of B cells. B cell receptor-mediated events also influence lymphoid organs localization as marginal zone B cells in the spleen, as follicular (B-2 cells), as well as B-1 cells in the peritoneal and pleural cavities. [] fluorescence micrograph spleen, fm high power in which T cells form periarteriolar lymphocyte sheath (PALS) (red) and B-2 cell follicles (green) []

B-1 cells are the first B cells produced in the fetus, and in adults are located primarily in the peritoneal and pleural cavities. B1 cells are believed to operate in the innate response to infection by viruses and bacteria, and usually show preferential responses to T cell-independent antigens. The diversity of B-1 lymphocytes is attributed to their recombinatorial recombination, in which there is a preferential recombination between D-proximal VH gene segments. B-1 lymphocytes express (polyspecific) IgM in greater quantities than they express IgG, and the ability of B1 cells to respond to isotype switch commitment factors such as interleukin-4 may be secondary to their production of IgM. B-1 cells express CD5, which binds to CD72 to mediate B cell-B cell interactions.

B-2 cells are conventional B lymphocytes that are produced postnatally (unlike fetal B-1 cells) and are replaced from the bone marrow.

Plasma B lymphocytes are committed to production of copious amounts of monoclonal antibodies.

Memory B lymphocytes are long-lived, stimulated B lymphocytes that are primed for rapid response to a repeated exposure of the priming antigen. Memory B cells are generated in lymphoid tissue after B cell activation/proliferation and reside in the bone marrow, lymph nodes, and spleen. High affinity surface immunoglobulins enable their activation by lower levels of cognate antigen than are naïve B cells.

NK cells are differentiated from killer T cells. NK, natural killer cells constitute a corps of circulating lymphocytes that are constitutively specialized to attack cancerous cells and virus infected cells. Preprogramming for target recognition, coupled with the absense of need for backup by a clone of identical cells, renders NK cells capable of rapid (innate) response to pathogens. NK attack involves the exocytosis of cytoplasmic granules containing perforin and granzymes. Perforin forms pores in the plasma membrane of attacked cells through which serine-protease granzymes enter, cleaving caspase precursors and triggering apoptosis.

Individuals inherit multiple, polymorphic genes for NK receptors, so the assemblage of NK receptors differs between individuals. NK cells carry two forms of surface receptors:
● killer inhibitory receptors (KIRs) transmit an inhibitory signal when they encounter class I MHC molecules on a cell surface. (By contrast, T cells only recognize antigens that are presented by a MHC molecule.)
● activating receptors, which activate the NK cell upon binding to a target cell

Viral infection often causes suppression of MHC expresion, leading to a reduction of inhibition of NKs by its killer inhibitory receptors. This double negative renders the virus infected cell a target for killing by NK cells.

"About 85% of peripheral B cells are phenotypically mature and display first-order exponential kinetics defined by a half-life of 5-6 weeks, whilst the remainder are short-lived with a life span of several days."[s]

[] tem plasma cell [] micrograph macrophage surrounded by normal plasma cells [] micrograph macrophage & plasma cells []

▼ activation : BCRs : CDRs : helper T cells : life-span B cells : lymphopoiesis : naïve B cells : surface-immunoglobulins : surface receptors : VDJ recombination ▼

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

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tags [Immunology][lymphocyte]

blood

2007-11-13T09:09:00.000-08:00

Blood is a highly specialized tissue produced in the bone marrow in a process called hematopoiesis. Blood contains red blood cells (erythrocytes) and white cells (leukocytes) circulating in plasma accompanied by platelets, plasma proteins, and other dissolved substances.

[] Hemopoiesis [] Hematopoiesis - high-resolution version (837 KB) [] tem basophil [] tem eosinophil [] tem eosinophil [] tem small lymphocyte [] tem monocyte [] tem neutrophil engulfing Candida []

tags [Immunology][hematology]

cancer and immune system

2007-10-24T09:34:00.000-07:00

The immune system plays a role in surveillance of neoplastic cells that have escaped controls on proliferation. In their turn, tumors employ a variety of mechanisms to evade the immune system.

Some tumors have tumor-specific antigens on their surfaces. (These antigens are also called TSA, tumor-specific transplantation antigens, TSTA, tumor rejection antigens, or TRA.) TSA are absent on non-tumor cells, and typically appear after an infecting virus has caused the cell to express viral antigens and to become immortal. Some TSAs are not induced by viruses, are are the idiotypes of BCR on B cell lymphomas or TCR on T cell lymphomas. [table]

Tumor-associated antigens (TAA) are more common than TSA. These T antigens are found on tumor cells and on normal cells during fetal life (onco-fetal antigens), after birth in selected organs, or in many cells at a considerably lower concentration than on tumor cells. Because of the presence of these antigens on various normal cells, the immune responses to TAA may be suppressed because they are tolerated as "self".

Evasive mechanisms range from a passive failure to express major histocompatibility complexes (MHC) and co-stimulatory molecules 4,5 to active strategies such as the production of immunosuppressive cytokines and other factors 6,7 . Passive and active processes are also involved in the Fas counterattack.[s]

Tumor cells can present only self peptides or can downregulate Class I MHC expression. Tumor cells often fail to express co-stimulatory molecules such as B7, or do not produce adhesion molecules that are necessary for interaction with CD8 T cells.

Tumors can also avoid immune system attack by down-regulating expression of their tumor antigens or by spontaneously alter their structure (antigenic variation).

Ironically, antibodies to tumor surface antigens could promote tumor survival (enhancing antibodies) should the antibodies bind without eliciting cytotoxicity – by masking the tumor antigens from T cells while inducing tumor cells to down-regulate expression of tumor antigen.

Some tumors actively suppress the immune response by producing TGFβ, which is a suppressive cytokine that inhibits cellular immunity. Some tumors, including myeloma and HTLV-1 T cell leukemia, also produce cytokines that stimulate their own proliferation.

The Fas ligand (FasL, C95L) is expressed by cells of the lymphoid/myeloid series and by non-lymphoid cells, where it contributes to the 'immune privilege' of cancer cells by inducing apoptosis in infiltrating proinflammatory immunocytes 9,10 . Simultaneously, many cancer cells are relatively resistant to Fas-mediated apoptosis.

This resistance to Fas-mediated apoptosis might be a result of downregulation of Fas, or release of soluble Fas, or of abnormalities in the level of several signal transduction cascade proteins. Neoplastic Fas resistance might also result from downregulation of caspase 1, Bax or Bak, and upregulation of FLIP, FAP-1 or Bcl2. Further, some components of the pathway exhibit mutations, including Fas itself and caspase 8. Some mutations of oncogenes and tumor suppressor genes, which are commonly found in tumors, could impair Fas signaling (p53 and Ras) or could cooperate with Fas resistance (c-Myc) in certain tumor cells. Many cancer cells express FasL, so are able to counterattack and kill Fas-sensitive tumor- infiltrating lymphocytes (TILs).[s]

¤ carcinogenesis ¤ immune evasion ¤ malignant transformation ¤ metastasis ¤ oncogenes ¤ p53 ¤ proliferation ¤ proto-oncogenes ¤ Ras ¤ signaling molecules ¤

Malignant Transformation Oncogenes Proto-oncogenes Regulatory Proteins Sequences Apoptosis vs Necrosis Apoptosis Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

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tags [Immunology][cancer]

cancers of immune system

2007-10-24T09:33:00.000-07:00

Cancers of the hematologic/immune system most commonly include:
● Leukemias
● Lymphomas
● Multiple Myeloma
● Myeloproliferative Disorders and Myelodysplastic Syndrome

Disorders of the immune system include:
● autoimmune disorders
● immune deficiency disorders

Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

tags [Immunology] [cancer]

CD

2007-10-21T23:59:00.000-07:00

CD stands for cluster of differentiation, which indicates a defined subset of cellular surface receptors (epitopes) that identify cell type and stage of differentiation, and which are recognized by antibodies.

There are more than 250 identified clusters, each a different molecule, coating the surface of B lymphocytes and T lymphocytes.

All T and B cells have about 10⁵ = 100,000 molecules on their surface. B cells are coated with CD21, CD35, CD40, and CD45 together with non-CD molecules, while T cells express CD2, CD3, CD4, CD8, CD28, CD45R, and other non-CD molecules. Many CDs are expressed on both B and T cells, including CD5, CD6, CD23, CD27, CD28, CD84. Dendritic cells also express CD4 and CD8.

▼ B lymphocyte CDs : B and T lymphocyte CDs : T lymphocyte CDs : TNFRs : CD1 : CD2 : CD3 : CD4 : CD5 : CD6 : CD8 : CD14 : CD23 : CD25 : CD27 : CD28 : CD30 : CD31 : CD36 : CD40 : CD45 : CD45 isoforms : CD55 : CD58 : CD72 : CD84 : complement CÆ : costimulatory : ITAMs : LFA : lymphocyte function associated antigen : glycoproteins : Ig superfamily : Macrophages/Monocytes : migration : pattern recognition receptors : platelets : scavenger receptors : SLAM (signaling lymphocyte activation molecule) : TNFR▼

T cell CDs:

CD2 family receptors are immunoglobulin (Ig) superfamily type I transmembrane, glycosylated proteins characterized by an N-terminal variable (V) domain that lacks disulfide bonds and a truncated Ig constant 2 (C2) domain that has two disulfide bonds in the extracellular region.

CD3 family receptors comprise three distinct chains – CD3γ, CD3δ and CD3ε in mammals – which are closely related proteins of the immunoglobulin superfamily, each containing a single extracellular immunoglobulin domain. The CD3 chains associate with TCRs and the ζ-chain to activate T lymphocytes. Together the TCR, ζ-chain, and CD3 molecules consitute the TCR complex.

The transmembrane region of the CD3 chains is negatively charged, enabling these chains to associate with the positively charged TCR chains (TCRα and TCRβ). The intracellular tails of the CD3 molecules contain a single conserved motif termed the immunoreceptor tyrosine-based activation motif (ITAM) that is essential for TCR signaling. Phosphorylation of CD3's ITAM enables the CD3 chain to bind Fyn, a membrane-associated protein tyrosine kinase important in the T cell's signaling cascade.

CD4 is notorious because of its importance in HIV/AIDs. It is an approximately 55 kDa type I membrane glycoprotein expressed predominantly on T cell precursors and a subset of mature T cells, providing the surface protein to which HIV attaches itself in order to invade the cell. CD4 is also found on the surface of monocytes, macrophages, Langerhans cells, astrocytes, keratinocytes and glial cells. The number of serum T4 cells is employed to measure the health of the immune system in people infected with HIV.[R&D]

CD8 (T8) is a protein embedded in the cell surface of 'suppressor' or regulatory T lymphocytes (Treg).

The CD31 adhesion molecule (PECAM-1) is expressed in large amounts at intercellular junctions of endothelial cells, subsets of T cells, platelets, and most other leukocytes including monocytes and neutrophils. CD31 is required for the trans-endothelial migration – extravasation – of leukocytes through intercellular junctions of vascular endothelial cells.

CD58 is also known as lymphocyte function-associated antigen (LFA-3). CD58 is a cell-bound immunoglobulin superfamily receptor with only one known ligand, which is CD2. CD58 is widely expressed on human hematopoietic and non-hematopoietic tissues, leukocytes, erythrocytes, endothelial and epithelial cells, and fibroblasts. The receptor-ligand pair, CD58 plus CD2, optimizes immune recognition and initiates T cell expansion and activation. Such contact activities can occur between helper T cells and antigen-presenting cells and between cytolytic effectors and target cells.

B and T cell CDs:

C5 is a 67 kDa surface glycoprotein of the scavenger receptor cysteine-rich (SRCR) superfamily that appears on thymocytes, mature T cells, and B cells. CD5 is important for the apoptosis of antigen-receptor induced B lymphocytes and for the maintenance of tolerance by anergic B cells. CD5 crosslinking induces extracellular mobilization of calcium ions, tyrosine phosphorylation of intracellular proteins, and production of diacylglycerol. Infection by EBV downregulates CD5 expression, while the glycoprotein is expressed in many T-cell leukemias and lymphomas.

CD6 is a member of the group B scavenger receptor cysteine-rich (SRCR) superfamily, which is expressed at low levels on immature thymocytes, at high levels on mature thymocytes, on the majority of peripheral blood T cells, a subset of B cells, and a subset of neuronal cells. Human and mouse CD6 proteins share 70% amino acid sequence identity over their full lengths.

CD23 is the receptor for the Fc portion of IgE.

CD27 Ligand/TNFSF7 is also known as CD70, and is a type II transmembrane glycoprotein belonging to the TNF superfamily (TNFSF). The expression of CD27 Ligand is induced by antigen-receptor activation in B cells. CD27/TNFRSF7 is a lymphocyte-specific member of the TNF receptor superfamily, which is expressed on a subset of human T cell precursors (thymocytes), on the majority of mature T cells, on natural killer (NK) cells, and subsets of B cells. CD27 ligation on NK cells induces proliferation and production of IFN-γ. CD27 binding (ligation) to T cells provides a co-stimulatory signal required for T cell proliferation, the promotion of effector T cell formation, and clonal expansion. The binding of CD27 to B cells inhibits the terminal differentiation of activated B cells into plasma cells and instead enhances commitment to memory B cell responses.

CD28 and CTLA-4, together with their ligands, B7-1 and B7-2, constitute one of the dominant B and T cell costimulatory pathways. CD28 and CTLA-4 are structurally homologous molecules of the immunoglobulin (Ig) gene superfamily. Mouse CD28 is expressed constitutively on almost all mouse T cells and on developing thymocytes.

CD45 is a protein tyrosine phosphatase (PTP) that regulates Src kinases required for T and B cell receptor signal transduction. CD45 dephosphorylates a negative regulatory residues on one or more of the protein tyrosine kinases that are involved in receptor-mediated second messenger formation. CD45 is located in all hematopoietic cells except erythrocytes and platelets, so it is also called the common leukocyte antigen.[]rotatable im[]

The CD45-regulated Src kinases are Lyn and Blk in B cells, and Lck and Fyn in T cells. ITAMs are immunocreceptor tyrosine bases motifs comprising two tyrosine residues separated by amino acids. RTK-phosphorylation of ITAMS enables them to bind to second family protein tyrosine kinases such as CD45, for which their SH2 domains have high binding affinity. In T cells, CD45 phosphorylates Csk, which is an inhibitory protein tyrosine kinase that controls tyrosine activity in lymphocytes. In B cells, calcium ions are transduced by the BCR, inducing CD45 expression. CD45RO, CD45RA, and CD45RB are isoforms of CD45.

CD84 is also known as Ly-9B, and is a member of the CD150/SLAM (signaling lymphocyte activation molecule) subfamily of the CD2 family (designated SLAMF5). CD84 is expressed on B cells, T cells, monocytes and platelets and acts as a self-ligand. Human and mouse CD84 share approximately 57% amino acid sequence identity.

B cell CDs:

CD40 is a type I transmembrane glycoprotein belonging to the TNF receptor superfamily. CD40 is expressed on B cells, follicular dendritic cells, dendritic cells, activated monocytes, macrophages, endothelial cells, vascular smooth muscle cells and several tumor cell lines. Human and mouse CD40s have 64% identity of amino acid sequence identity.

CD72 is a 39-43 kDa type II membrane glycoprotein of the C-type lectin family. CD72 is a pan-B cell marker that is expressed throughout the B lymphocytes differentiation (except plasma cells). CD72 is also present on follicular dendritic cells.

Monocytes/Macrophages

CD14 is a 55 kDa cell surface glycoprotein that is preferentially expressed on monocytes and macrophages. The amino acid sequence of human CD14 is approximately 65% identical to mouse CD14, and 82% identical to rat proteins.

Also: CD4, CD31 adhesion molecule (PECAM-1), CD40, CD84

Platelets:

CD36 is also known as scavenger receptor class B member 3 (SR-B3), GPIIIb, platelet membrane glycoprotein IV (GPIV), collagen receptor, thrombospondin receptor, and fatty acid translocase (FAT). CD36 is a broadly-expressed integral membrane glycoprotein with multiple physiological functions. As a member of the scavenger receptor family, CD36 is a multi-ligand pattern-recognition receptor that interacts with a large number of structurally dissimilar ligands. Upon ligand binding, CD36 transduces signals that mediate a wide range of pro-inflammatory cellular responses.

Complement CÆ activation family (RCA):

CD55, also known as decay-accelerating factor (DAF), is a 70 to 75 kDa member of the regulators of complement/CÆ activation (RCA) family of proteins. It is ubiquitously expressed on cells that are exposed to plasma complement proteins. Human CD55 is synthesized as a 381 amino acid precursor that comprises a 34 aa signal sequence, a 319 aa mature region and a 28 aa C-terminal prosegment.

Costimulatory:

CD28 and CTLA-4, together with their ligands, B7-1 and B7-2.

Pattern-recognition receptors :

CD36

Glycoproteins:

CD4, CD5, CD14, CD27, CD30, CD36, CD40, CD72

Immunoglobulin superfamily:

CD2, CD58, CD28 and CTLA-4,
CD23 is the receptor for the Fc portion of IgE.

LFA (lymphocyte function associated antigen):

CD58

migration:

CD31 adhesion molecule (PECAM-1)

Scavenger receptor (SRCR) family:

CD5, CD6, CD36

SLAM (signaling lymphocyte activation molecule) subfamily:

CD84 (Ly-9B), CD2 family (SLAMF5)

TNFRs :

CD30/TNFRSF8 is a type I transmembrane glycoprotein belonging to the TNF receptor superfamily, where the the ligand for CD30 is CD30L (CD153, TNFSF8), which is a member of the TNF superfamily. CD30 binding by CD30L mediates pleiotropic effects, including cellular proliferation, activation, differentiation, and apoptosis.

Other TNFRs are CD40 and CD27.

Miscellaneous CDs
CD9 is a member of the tetraspanin transmembrane receptor family. CD9 contains four putative transmembrane domains and two extracellular loops, and is thought to be involved in egg-sperm fusion. Several reports indicate that CD9 associates with integrins and affects cell behavior on fibronectin surfaces (ref).[s]

▲ B lymphocyte CDs : B and T lymphocyte CDs : T lymphocyte CDs : TNFRs : CD2 : CD3 : CD4 : CD5 : CD6 : CD8 : CD14 : CD23 : CD27 : CD28 : CD30 : CD31 : CD36 : CD40 : CD45 : CD45 isoforms : CD55 : CD58 : CD72 : CD84 : complement CÆ : costimulatory : ITAMs : LFA : lymphocyte function associated antigen : glycoproteins : Ig superfamily : Macrophages/Monocytes : migration : pattern recognition receptors : platelets : scavenger receptors : SLAM (signaling lymphocyte activation molecule) : TNFR ▲

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[C][CD5][CD72] Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology][cluster+differentiation][receptor]

cellular response

2007-10-20T12:08:00.000-07:00

Cellular responses to invading pathogens utilize phagocytic and cytotoxic cells of the innate and adaptive immune responses.

The immune system is intimately connected with the hematologic system since white blood cells (leukocytes, including B- and T-lymphocytes) are key players in the lymphoid system.
Cellular participants in the immune and inflammatory responses include :
● phagocytic cells (dendritic cells, monocytes and macrophages, and granulocytes)
● antigen presenting cells (dendritic cells, macrophages, B lymphocytes, helper T cells, γδ T cells)
● antibody producing cells (plasma cells)
● cytotoxic cells (CTL, NK)
● regulatory cells (APCs, helper T cells, regulatory T cells)
● cells-in-waiting (memory B cells, monocytes)
● chemical releasing cells (basophils, eosinophils, neutrophils; mast cells - histamine, cytokines; hepatocytes - complement proteins)

Innate responses solely comprise cellular immune responses employ phagocytic cells that are circulating or tissue emplaced – granulocytes, monocytes, dendritic cells, macrophages, natural killer T cells, and B lymphocytes. The innate response induces (triggers) the adaptive system, the cellular component of which relies upon activated macrophages, T-lymphocytes – cytotoxic T lymphocytes (killer T cells).

Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology][cellular+immunity]

class-switch recombination

2007-10-13T23:05:00.000-07:00

Class-switch recombination involves isotype switching between immunoglobulin classes and isotypes.

Small resting B lymphocytes initially producing IgM antibodies. The diverse antibody repertoire achieved early in B-lymphocyte development results from VDJ recombination of gene segments to produce unique heavy- and light-chain variable (V) Ig regions. The variable regions encode the antigen binding sites of antibody receptors expressed on the surface of naïve B lymphocytes and their clonal progeny. The low affinity of naïve VDJ generated antibodies is compensated for by the high affinity of secreted IgM, in which the prototypical four-chain Ig structure is combined into pentamers or hexamers. Following encounter with antigen, B cells become activated to isotype switch from IgM to other Ig classes, including high-affinity IgG and IgA antibodies required to inactivate toxins, neutralize viruses, and promote the clearance of microorganisms.

Ligation of antigen by cognate B lymphocytes accompanied by costimulation by helper T lymphocytes, activates B lymphocytes, which enter the germinal centers of peripheral lymphoid organs to become centroblast B cells. Within the germinal center, secondary antibody diversification is brought about through somatic hypermutation (SHM) and/or gene conversion (GC) of the V region to generate high-affinity antigen binding sites. (SHM is the predominant mechanism in mice and humans, whereas GC occurs in chickens and some other species.)

Within a particular centroblast B cell in the germinal center, the heavy-chain variable (V) regions encoding the antigen binding sites are rearranged down the chromosome through class-switch recombination (CSR). Then they can be expressed with one of the constant (C) region genes to perform many different effector functions having been released into the circulation.

This isotype class switch distributes a particular variable region to different constant immunoglobulin regions. Each constant region mediates a specialized effector function, and switching permits adaptive guidance of antibodies. Creating a new heavy chain requires loop-out and deletion of DNA between switch regions, employing transcription of the switch regions. Requisite switching factors include activation-induced cytidine deaminase and components of general DNA repair, including base excision repair (UNG2), mismatch repair, and double-strand break repair.[r1]

'Individuals, such as those with hyper-IgM syndrome (HIGM), who lack the ability to make such high-affinity IgG and IgA antibodies, are unable to combat bacterial and viral infections and usually die at a young age.[s]

Tables Fc receptors Immune Cytokines Immunoglobulins

[r1] DNA acrobats of the Ig class switch. Wang CL, Wabl M. J Immunol. 2004 May 15;172(10):5815-21. [Free Full Text Article]

[s] The generation of antibody diversity through somatic hypermutation and class switch recombination. Li Z, Woo CJ, Iglesias-Ussel MD, Ronai D, Scharff MD. Genes Dev. 2004 Jan 1;18(1):1-11. [Free Full Text Article]

tags [Immunology][recombination]

clonal selection

2007-10-13T09:05:00.000-07:00

Clonal selection is the phenomenon whereby the antigenic determinant (epitope) of a previously unencountered cognate antigen can stimulate naïve B lymphocytes to proliferate (clonal expansion) and differentiate into memory B cells and plasma cells that produce antibodies against the antigen (primary response). That is, the antigen itself determines (selects) the characteristics of clones of B cells that expand (multiply and specialize) after encounter with the antigen.

Should the epitope be encountered again, the memory B cell-conducted secondary response will be specific, more rapid, and elicit a greater production of antibodies than was the first-encounter, primary response. Vaccination takes advantage of immunological memory in that the individual is primed for efficient, rapid response to epitopes associated with disease producing organisms.

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

tags [Immunology] [clone]

complement system

2007-10-10T11:08:00.000-07:00

The complement system comprises an assembly of liver-manufactured, soluble and cell-bound proteins that participate in innate and adaptive immunity. Activation of the complement cascade by protease cleavage leads to chemotaxis (C5a), inflammation and increased capillary permeability (C3a, C5a), opsonization (C3b), and cytolysis.

▼activation : alternative pathway : amplification by C3 : anaphylatoxins C3a, C5a : antigen uptake : C1 : C2 : C3 : C4 : C5 : C6 : C7 : C8 : C9 : C1INH : CD59 : chemotaxis : classical pathway : complement cascade : complement control proteins : convertases C3, C3/C5, C5 : disorders : evolution : Factor B : Factor H : Factor I : ficolins : immunoglobulins and complement activation : inhibitory proteins : lectin pathway : MBL -MAPS : mannose-binding lectin pathway : membrane attack complex : opsonin : pathways : perforin : phagocytosis : pore : proteases : regulation : serine proteases : sialic acid ▼

Sequential activation of the protein components of the complement cascade upon cleavage by a protease, leads to each component's becoming, in its turn, a protease. Three pathways are involved in complement attack upon pathogens:
● classical pathway
● alternative pathway
● mannose-binding lectin pathway (MBL -MAPS)

The classical pathway utilizes C1, which is activated by binding of an antibody to its cognate antigen.

Inactive C1 circulates as a serum molecular complex comprising 6 C1q molecules, 2 C1r molecules, and 2 C1s molecules. Constant regions in some immunoglobulins specifically bind C1q, activating C1r and C1s. The mu chains of IgM and some gamma chains of IgG contain specific binding sites, though IgM is far more effective than IgG.

Activated C1s is a serine protease that cleaves C4 and C2 into small inactive fragments (C4a, C2a) and larger active fragments, C4b and C2b. The active component C4b binds to the sugar moieties of surface glycoproteins and binds noncovalently to C2b, forming another serine protease C4b•C2b, which is called C3 convertase because it cleaves C3, releasing an active C3b opsonin fragment.

Macrophages and neutrophils possess receptors for C3b, so cells coated with C3b are targetted for phagocytosis (opsonization). The small C3a fragment is released into solution where it can bind to basophils and mast cells, triggering histamine release and, as an anaphylatoxin, potentially participating in anaphylaxis.

C3 amplifies the humoral response because of its abundance and its ability to auto-activate (as a C3 convertase). Breakdown of C3b generates an antigen-binding C3d fragment that enhances antigen uptake by dendritic cells and B cells .

Binding of C3b to C5 induces an allosteric change that exposes C3b•C5 to cleavage by C4b•C2b, which is now acting as C3/C5 convertase. The alternative pathway possesses a distinct C5 convertase, so the two pathways converge through C5.

Cleavage of C5 by the C3/C5 convertase releases:
● anaphylotoxic C5a, which promotes chemotaxis of neutrophils
● C5b, which complexes with one molecule of each of C6, C7, and C8. The resultant C5b•6•7•8 complex assists polymerization of as many as 18 C9 molecules to form a cytolysis-promoting pore (membrane attack complex, tem) through the plasma membrane of the target cell, which then suffers osmosis-induced cytolysis.

Another cytolytic mediator utilized by CTLs and NK cells is perforin, which is a 534 aa glycoprotein with sequence homology to the membrane attack component of complement C9. Like C9, perforin integrates into the target cell membrane, forming polyprotein pores up to 20nm in diameter comprising 12—18 perforin monomers, which breach membrane integrity and permit cytolytic cell death.

The alternative pathway is not activated by antigen-antibody binding, but instead relies upon spontaneous conversion of C3 to C3b, which is rapidly inactivated by its binding to inhibitory proteins and sialic acid on the cell's surface. Because bacteria and other foreign materials lack these inhibitory proteins and sialic acid, the C3b is not inactivated and it forms the C3b•Bb complex with Factor B. The C3b.Bb complex acts as a C3 convertase, forming C3b•Bb•C3b, which acts as a C5 convertase that can ititiate assembly of the membrane attack complex. C3b•Bb, acting as a C3 convertase, provides a positive feedback loop that amplifies production of C3.

The lectin pathway (MBL - MASP) is homologous to the classical pathway, but utilizes opsonin, mannan-binding lectin (MBL, MBP) and ficolins rather than C1q. Binding of mannan-binding lectin to mannose residues on the pathogen surface activates the MBL-associated serine proteases, MASP-1, MASP-2, MASP-3, which cleave C4 into C4b and C2 into C2b. As in the classical pathway, C4b and C2b bind to form the C4b•C2b C3 convertase. Ficolins are homologous to MBL and function through MASPs. Diversified ficolins are of particular importance in invertebrates, which lack the adaptive immune response that evolved some 500 million years ago in jawed vertebrates.

Several complement control proteins regulate activity of the complement system, including:
● C1 inhibitor (C1INH), which eliminates the proteolytic activity of activated C1r and C1s. Following C1 activation by antigen-antibody complexes, C1INH permits only a brief interval during which activated C1 can cleave C4 and C2.
● Factor I, which inactivates C3b
● Factor H, which removes Bb, thus interrupting the C3 convertase feedback loop within the alternative pathway
● CD59, which inhibits C9 polymerization during assembly of the membrane attack complex.

Dysregulation of the complement system manifests variously as immune complex disorders (C2 deficiency), susceptibility to bacterial infections (C3 deficiency), the autoimmune disorder SLE (early component or C2 deficiency), hereditary angioneurotic edema (HANE) (C1INH deficiency).

▲ activation : alternative pathway : amplification by C3 : anaphylotoxins C3a, C5a ф antibodies ф antigen : antigen uptake : C1 : C2 : C3 : C4 : C5 : C6 : C7 : C8 : C9 : C1INH : CD59 : chemotaxis : classical pathway : complement cascade : complement control proteins : convertases C3, C3/C5, C5 : disorders : evolution : Factor B : Factor H : Factor I : ficolins : immunoglobulins and complement activation : inhibitory proteins : lectin pathway : MBL -MAPS : mannose-binding lectin pathway : membrane attack complex : opsonin : pathways : perforin : phagocytosis : pore : proteases : regulation : serine proteases : sialic acid ▲

Tables Fc receptors Immune Cytokines Immunoglobulins

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tags [Immunology][complement]

co-stimulation

2007-10-10T05:04:00.000-07:00

Co-stimulation, or costimulation, involves ligand-receptor interactions at the surfaces of a responder lymphocyte and an "accessory" cell – APCs for activation of T cells, and helper T cells for activation of B cells.

▼activation B : activation T : anergy : CD28 receptor : CD28RE : CDC42 : costimulatory molecules : first/second signals : helper T cell : IL-2 : MAPK cascade : MHC class II : negative regulators : Rac : regulatory mechanisms : Rel-NFkB : Rho GTPases : TCR engagement : TCR threshold reduction : transcription factors : WASP ▼

Activation of B cells occurs when a BCR (antibody) encounters and ligates its cognate antigen. Naïve B cells each have one of millions of distinct surface antigen-specific receptors, yet have not encountered their specific, cognate antigen. With a life-span of only a few days, many B cells die without ever encountering their cognate antigen. In most cases, B-cell activation is dependent upon costimulation by an activated helper T cell that has itself been activated by the same antigen. (click images to enlarge)

Unlike T cells, B cells are coated in immunoglobulin receptors and are able to recognize intact antigen, which they engulf, digest, and subsequently present in complex with surface MHC class II molecules. The MHC-peptide complex binds CD4 + helper T cells (Th), inducing secretion of cytokines that stimulate B cell proliferation and their differentiation into plasma cells, which secrete specific antibodies that bind with the cognate antigen. These antigen-antibody complexes are subsequently cleared by liver and spleen cells and the classical complement cascade.

Activation of T cells requires (1) TCR engagement, which ensures antigen specificity and MHC restriction of the response. However, synergistic signaling by (2) costimulatory molecules is also necessary to sustain and integrate TCR signaling to stimulate optimal T cell proliferation and differentiation.

Delivery of first signal (TCR engagement) in the absence of costimulation by a second signal(s) results in apoptosis or anergy. Anergic T cells neither produce IL-2 nor proliferate upon restimulation. This requirement of naïve T cell activation for delivery of both antigen-specific and costimulatory signals implies that only professional antigen presenting cells can initiate T cell responses.

Activation-regulatory mechanisms:
● increasing TCR avidity (adhesion molecules)
● enhancing recruitment of tyrosine kinases to the TCR complex coreceptors (CD4 and CD8)
● costimulation involving reciprocal and sequential signals between cells

Negative regulators of costimulation include receptors that bind B7 family members:
● CTLA-4
● PD-1

Molecules involved in costimulation include:
1. Disulfide-linked homodimers that bind to distinct members of the B7 family of surface proteins
---● CD28 ↓
---● ICOS (inducible costimulator) molecules
2. Members of the TNF receptor (TNFR) family
---● CD40, the major B cell costimulatory molecule
---● CD30
---● CD27
---● OX-40
---● 4-1BB

The CD28 receptor is involved in the best characterized costimulatory pathway. CD28 is the primary costimulatory molecule for naïve T cells, although CD4+ helper T cells are more dependent than are CD8+ killer T cells on CD28 costimulation. CD28 binds the CD80 (B7-1) and CD86 (B7-2) ligands that are expressed on antigen presenting cells (APCs). CD28 costimulation increases T cell responses in naïve cells by increasing cytokine (mainly IL-2) production, which results from an increase in both cytokine gene transcription and mRNA stabilization.

CD28 signaling involves the activation of the small Rho family GTPases Rac and CDC42, which activate p21-activated kinase. This may link them to the mitogen-activated protein kinase cascades and the subsequent induction of IL-2 synthesis. Rac and CDC42 are also important in CD28-mediated cytoskeletal rearrangements, through the action of the Wiscott-Aldrich syndrome protein (WASP).

CD28 costimulation increases the activity of nuclear transcription factors of the Rel/NFkB family, whose members bind the CD28-responsive element (CD28RE) present in several cytokine gene promoters.

CD28 triggering reduces the number of engaged TCRs necessary to induce cytokine production and cell proliferation. This threshold reduction for T-cell activation is attributed to CD28-induced recruitment of lipid rafts to the immunological synapse, which promotes recruitment of raft-associated kinase and adapter molecules.

▲ activation B : activation T : anergy : CD28 receptor : CD28RE : CDC42 : costimulatory molecules : first/second signals : helper T cell : IL-2 : MHC class II : negative regulators : plasma cells : Rac : regulatory mechanisms : Rel-NFkB : Rho GTPases : TCR engagement : TCR threshold reduction : WASP ▲

Tables Fc receptors Immune Cytokines Immunoglobulins

▲ Top ▲

tags [Immunology][costimulation][activation]

cytolysis

2007-10-02T04:09:00.000-07:00

Cytolysis (cell lysis) results when the plasma membrane is ruptured, resulting in osmosis-induced swelling and cell death. (see cytotoxicity)

Cytotoxic lymphocytes (CTLs) are important agents of cytolysis. Cytotoxic cells are considered essential for the elimination of oncogenically or virally transformed cells, but they are detrimental when mediating autoimmune disease or graft rejection.

Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology][cytolysis][cell+death]

cytotoxicity

2007-10-02T04:01:00.000-07:00

Cytotoxic agents are toxic to cells:
● Cytotoxic physical agents
___ ● thermal (excessive heat or cold)
___ ● irradiation

● Cytotoxic drugs and chemicals have cytolytic, carcinogenic, mutagenic and/or teratogenic potential. Direct contact may cause tissue irritation, ulceration, and necrosis.
___ ● antineoplastic and immunosuppressive therapeutic agents
___ ● free radicals
___ ● strong acids and alkalis
___ ● secreted digestive enzymes and antimicrobials – lysozyme, phospholipase, defensins
___ ● secreted cytolytic molecules • FasL, granzymes, granulysin, perforin
___ ● phagocytosis-promoting opsonins – C3b of complement cascade, pulmonary surfactants

● Cytotoxic cellular immune responses
_ ● Antibody-dependent cell-mediated cytotoxicity (ADCC) is mediated by antibody-marking
_ ● Complement-dependent cytotoxicity (CDC) is mediated by the complement system (opsonin-induced phagocytosis performed by macrophages and neutrophils, anaphylatoxin induced histamine release by basophils and mast cells).
_ ● Lymphocyte-mediated cytotoxicity ('LMC') requires is independent of antibody-marking and the complement system

__ ● killer cells
___ ● non-specific 'attack' cells – eosinophils (IgE, CD67), macrophages (IgG, CD14), K cells (IgG), LAK cells (IL-2 activated cytolysis cells, lymphokine-activated killer cells), NK cells (CD16, CD56)
___ ● natural killers cells (NK) of innate immune system – have activating receptors and killer inhibitory receptors (KIR) – secrete cytolytic granzymes and perforin ('LMC')
___ ● natural killer T cells (NKT) – have αβ TCR plus some of the cell-surface molecules of NK cells – respond to glycolipid antigens presented by the cell-surface molecule CD1d (ADCC) – secrete IFN-γ (Th1 cytokine) plus IL-4 and IL-13 (Th2 cytokines)
___ ● cytotoxic T cells • (CD8 +) Tc matures into CTL (killer T cells) following activation (ADCC)
___ ● phagocytic cells engulf pathogens, often after pathogen coating by opsonins (CDC)

Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology] [cytotoxicity] [cell death]

dendritic cells

2007-09-20T10:41:00.000-07:00

Dendritic cells and their immature counterparts, Langerhans cells (LC), are highly specialized, professional antigen-presenting cells (APC) located in the skin, mucosa, and lymphoid tissues.

▼ adhesion : APC activities : clonal expansion B cells : cytokines : DC types : disorders : ectopic FDC-formation : follicular dendritic cells (FDC) : FDC networks : generating germinal centers : germinal centers : immature dendritic cells : immune regulators : immunological synapse : interferon producing cells : lymphoid dendritic cells : maturation : morphology : myeloid dendritic cells : pDC : plasmacytoid dendritic cells (PDC, IPC) : precursor dendritic cells : regulators : Th1 and Th2 stimulation : TLRs : types of DC : veiled cells ▼

Immune dendritic cells are named for their morphology (long surface projections), and bear no relationship to neurons. Immature dendritic cells are also called 'veiled cells' because they display large cytoplasmic 'veils' rather than dendrites. DC and LC play a key role in the induction phase of contact allergenicity.

As key regulators of immune responses, dendritic cells (DC) stimulate lymphocytes to perform cell-mediated and humoral immune responses against pathogens and tumor cells. DCs can also educate T cells to tolerate self-antigens, thereby minimizing autoimmune reactions.

Types of dendritic cell
● follicular dendritic cells (origin?) – FDC
● lymphoid dendritic cells (lymphopoiesis) –
● myeloid dendritic cells (monocytopoiesis) – MDC1, MDC2
● plasmacytoid dendritic cells – PDC, IPC – the major producers of type I interferon (IFN)

Immature, precursor dendritic cells (pDC) circulate throughout the body, migrating to lymphocyte rich tissues (such as spleen and lymph nodes) upon stimulating encounter with antigen. The dendritic cells internalize the antigen, then digest, and externalize the fragmented antigen that they present to lymphocytes in MHC-peptide complexes, expressing markers that stimulate lymphocyte activation. Dendritic cells are the most effective antigen presenting cells. Follicular dendritic cells stimulate differentiation of B cells, monocytopoietic lineages (pDC1) stimulate differentiation of Th1 cells, lymphopoietic dendritic cells (pDC2) induce differentiation of Th2 cells. Plasmacytoid cells produce type 1 interferon (IFN-α, β, Ω) and can mature into dendritic cells that link innate and adaptive immune responses.

A variety of factors operate in antigen recognition and processing by immature (precursor) dendritic cells and in the maturation of immature cells. Toll-like receptors on the surfaces of precurson dendritic cells recognize microbial components and induce the differentiation of dendritic cell precursors. GM-CSF and IL-4 stimulate the maturation of monocytopoietic pDC1, while IL-3 stimulates the differentiation of pDC2. The transition to mature dendritic cells down-regulates those factors that were involved in antigen internalization, while up-regulating the expression of MHC, costimulatory molecules that participate in lymphocyte activation, adhesion molecules, and specific cytokines and chemokines.

Adhesion molecules enhance direct interactions between T cells and dendritic cells (immunological synapse). Dendritic cell stimulation of formation of Th1 and Th2 cells appears to be regulated by negative feedback. Th1 production of interferon-γ blocks the further stimulation of Th1 differentiation by DC1 cells. Th2 production of IL-4 kills the dendritic cell precursors that contribute to Th2 cell creation. Thus, although IL-4 stimulates Th2 differentiation, the promotion of Th2 cell formation by DC2 cells does not appear to involve IL-4. Costimulatory receptors CD80 and CD86 expressed by mature dendritic cells activate T cells in concert with the recognition of antigen/MHC by the T cell receptor. The secretion of IL-12 by dendritic cells stimulates T cell responses, in particular the differentiation of Th1 cells, which produce interferon-γ and other inflammatory cytokines.

Follicular dendritic cells are stromal cells unique to primary and secondary lymphoid follicles. FDCs express all three types of complement receptors as well as Ig-Fc receptors, through which antigen-antibody immune complexes are retained. FDCs present native antigens to potential memory B cells, of which only those coated with high affinity B cell receptors (BCR) are able to bind.

Recirculating resting B cells migrate through the FDC networks. Antigen-activated B cells undergo clonal expansion within the FDC networks in a T cell-dependent fashion, generating germinal centers. Evidence suggests the presence of two types of dendritic cells within human germinal centers: (i) the classic FDCs that express DRC-1, KiM4, and 7D6 antigens represent stromal cells; and (ii) the newly identified CD3-CD4-CD11c- germinal center dendritic cells (GCDC) represent hematopoietic cells that may be analogous to antigen-transporting cells of mice.

Within germinal centers, B cells undergo somatic hypermutation, positive and negative clonal selection, isotype switching and differentiation into high-affinity plasma cells and memory B cells. Adhesion between FDCs and B cells is mediated by ICAM-1 (CD54)-LFA-1(CD11a) and VCAM-VLA-4. T cells may interact with FDCs in a CD40/CD40-ligand-dependent fashion.

Ectopic FDC-formation is found in a number of autoimmune diseases and/or chronic inflammatory situations, suggesting that FDC development is not restricted to secondary lymphoid organs, but rather that local conditions drives a precursor cell type into FDC-maturation. The precursor of FDCs has presently not been identified, but data suggests a close relation to fibroblast-like cells. [s] It was initially believed that all DCs were of myeloid origin until several recent studies demonstrated that some DCs could also be efficiently generated from lymphoid-restricted precursors. FDCs appear to be involved in the growth of follicular lymphomas and in the pathogenesis of HIV infection.[pm]

Lymphoid dendritic cells are of lymphopoietic origin, and IL-3 stimulates the differentiation of pDC2 cells into DC2 cells, which stimulates differentiation of Th2 cells, which secrete the lymphokine interleukins 4, 5, 10, and 13. (IL-4, IL-5, IL-10, IL-13)

Myeloid dendritic cells are of monocytopoietic origin, and the maturation of precursor cells (pDC1) is stimulated by GM-CSF, and IL-4. Mature DC1 cells secrete interleukin 12 (IL-12), which acts through the JAK-STAT pathway to induce Th1 cells to secrete TNF-β (lymphotoxin) and IFN-γ. MDC-1 is the more common subtype, and is a major stimulator of Th1 cell differentiation. MDC-2 is rare, and may function in response to wound infection.

Plasmacytoid dendritic cells (pDC=IPC) are the major producers of type I interferon (IFN) and exhibit the unique ability to link innate and adaptive immune responses, by differentiating into DC capable of stimulating naive T cells and modulating the adaptive immune response. Human plasmacytoid DCs (PDCs) can induce either Th1- or Th2-type immune responses upon exposure to viruses or IL-3, respectively.

Plasmacytoid dendritic cell precursors (pDC) are type 1 interferon-(α, β, Ω)-producing cells (IPCs) that comprise 0.2%-0.8% of peripheral blood mononuclear cells (humans, mice). IPCs display plasma cell morphology, selectively express Toll-like receptor (TLR)-7 and TLR9, and rapidly secrete massive amounts of type 1 interferon following viral stimulation. IPCs promote the function of natural killer cells, B cells, T cells, and myeloid DCs through type 1 interferons (IFN) during an antiviral immune response. Later in viral infection, IPCs differentiate into a unique type of mature dendritic cell, which directly regulates the function of T cells and thus links innate and adaptive immune responses. [s, ↓] [fft]

images [] sem dendritic cell and T cell [] micrograph Langerhans cells [] PKC bII signaling in dendritic cells [] micrograph gallery dendritic cells [] photomicrograph dendritic cells interacting with yeast (lilac) [] photomicrograph Human Dendritic cell (labelled with anti MHC class-I FITC) presenting Influenza antigens to T-lymphocytes.
videos Џ Nature video library index Q Џ

ф activation ф affinity maturation ф anergy ф antibodies ф antigen ф APCs ф autoimmunity ф B cells ф blood ọ bone marrow ф CD ф cellular response ф class-switch recombination ф clonal selection ф complement system ф costimulation ф helper T cell ф hematopoiesis ф humoral immunity ф immune cytokines ф immune response ф immune tolerance ф inflammatory response ф interferons ф isotype switching ф killer T cells ф lymphocytes ф lymphokines ф lymphoid system ф lymphopoiesis ф macrophages ф MHC ф monocytopoiesis ф pattern-recognition receptors ф phagocyte ф plasma cells ф receptors ф signaling ф somatic hypermutation ф surface receptors ф T cells ф thymus

Tables Complement Receptors Cytokines Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors

IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. [Annu Rev Immunol. 2005]
Plasmacytoid dendritic cell precursors/type I interferon-producing cells sense viral infection by Toll-like receptor (TLR) 7 and TLR9. [Springer Semin Immunopathol. 2005] PMID: 15592841 [Free Full Text]
Natural type I interferon-producing cells as a link between innate and adaptive immunity. [Hum Immunol. 2002] PMID: 12480256
Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors. [Blood. 2004] PMID: 14670916
Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation. [J Exp Med. 2003] PMID: 12515817
Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance. [Hum Immunol. 2002]

tags [Immunology]
[dendritic+cell][APC][cytokine]
[Toll-like+receptor]

Rationality

2007-09-14T13:25:00.000-07:00

Gray Matters
Adeistic
Avidity
Eine Kleine Nattermusing
eMusings
eVolition
Galaria
Godspell Follies
MetaThoughts
Mimble Wimble
Naturalism
Neologisms
palimpsest
Sechuam
Sintheist
Tabula Flexuosa
Weltschauung

eosinophils

2007-08-10T05:16:00.000-07:00

Eosinophils (acidophils) are granulocytes packed with granules that stain acidic (red with H&E). Eosinophils combat parasitic infection, and have diverse immune responsibilities.

Eosinophils play roles in:
● combatting viral infections (RNAses)
● allergic response
● fibrinolysis (following inflammation).
● pathogenesis of asthma
● combatting helminthic colonization, other parasites.

The acidophilic granules contain proteolytic enzymes that are toxic to parasite and elicit allergic symptoms in the host. The enzymes include histaminase, peroxidase, RNase, DNases, lipase, plasminogen, and Major Basic Protein. Eosinophils also secrete IL-5.

Eosinophils normally comprises about 2.3% of leukocytes, and elevations (eosinophilia) are associated with parasitic infestation, collagen vascular diseases (such as rheumatoid arthritis), malignancies such as Hodgkin's lymphoma, allergic skin conditions (such as exfoliative dermatitis), Addison's Disease, and hypersensitivity to drugs such as penicillin.

Tables Fc receptors Immune Cytokines Immunoglobulins

tags [Immunology] [leukocyte]