affinity maturation

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

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]

APCs

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]

CD

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]