antibodies

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]

evolution of immune and coagulation systems

Immune system
The innate immune system is ancient and displays roots roughly one billion years old, deep in the deuterostome branch of the bilaterians (pre-Cambrian). The lectin pathway (MBL - MASP) is homologous to the classical complement pathway, but utilizes opsonin, mannan-binding lectin (MBL, MBP) and ficolins rather than C1q. Diversified ficolins are of particular importance in invertebrates, which lack the adaptive immune response that evolved some 500 million years ago in jawed vertebrates.

Macrophage scavenger receptors appear to mediate important, conserved functions, so it was likely pattern-recognition receptors that arose early in the evolution of host-defense mechanisms. Eicosanoids play a prominent role in inflammatory/immune responses and the evolution of eicosanoid receptors has been analyzed on the basis of amino acid sequences. Eiconasoid receptors are located on a variety of cells, tissues, and organs and can be activated by either non-selective or selective ligands.

The more specific, versatile, memory-capable adaptive immune response evolved more recently, roughly 450 million years ago, and is found in the jawed vertebrates (gnathostomes) but not in invertebrates.

Although the B cells of higher vertebrates lack phagocytic capabilities, it has recently been demonstrated that B cells from teleost (bony) fish and amphibians display potent phagocytic activities. Particle uptake by B cells induced activation of 'downstream' degradative pathways, leading to 'phagolysosome' formation and intracellular killing of ingested microbes. It is most probable that the less-elaborated, restrictive adaptive immune response of fish and amphibians makes the preservation of phagocytosis an evolutionary advantage to B cells in their defence against pathogens. These findings support the idea that B cells evolved from an ancestral phagocytic cell type, providing an evolutionary framework for understanding the close relationship between mammalian B lymphocytes and macrophages.[a, n]

Mast cell degranulation releases histamine and other vasoactive mediators in response to allergens. Although this reaction is most often encountered in allergic reactions, it apparently evolved as a defense system against intestinal parasitism, such as tapeworm infestations.

The versatile 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. The enormous diversity of antibodies is attributable to the alternative splicing of VDJ recombination.

RAG1 and RAG2, the proteins that mediate VDJ recombination, are closely related to transposases, and it is believed that evolution of the vertebrate genome includes their entry as part of a Transib superfamily transposon.

Blood coagulation employs the same fundamental mechanism in all vertebrates, from the early diverging jawless fishes to mammals.[1]. It has been amply demonstrated that all groups of fish generate thrombin through pathways that:
● utilize vitamin K-dependent factors
● exhibit factor XIII-dependent fibrin cross-linking, and
● manifest a fibrinolysis inhibited by the same antifibrinolytic agents as mammals (1–3).

(Thrombin-generated fibrin coagulation has not been observed in nonvertebrate chordates or in other invertebrate animals.)

Such a convoluted pathway as the clotting cascade could not have evolved as a single event. Proponents of "intelligent design theory" attempted to monopolize on this fact in order to promote their claims that an intelligent designer (God) must be responsible for the so-called "irreducible complexity" of the coagulation cascade. (Behe is a little more cautious in his wording, but the implied argument is as stated above.) Just as for the claims of irreducible complexity for evolution of the eye and the bacterial flagellum, the argument has been both logically and scientifically refuted.

Scientists realized some time ago that a series of gene duplications must be responsible for the complex set of interactions observed in mammalian clotting. Sequence comparisons of serine proteases led to the suggestion that the contact system of clotting factors ( factors XI and XII, and prekallikrein) must have evolved more recently than some of the other clotting factors and thus would likely be absent in lower vertebrates (4).

The genome sequences (5) for the puffer fish, Fugu rubripes, along with that for the urochordate (sea squirt) Ciona intes (6) have enabled a direct comparison of two early diverging chordates. The genomes confirm that the main lines of the vertebrate clotting pathway were evolved during the less than a hundred million years between the last common ancestor of these two creatures. It is currently believed that 50–100 million years separate the appearances of urochordates (including the sea squirt) and vertebrates. During this interval, the machinery for thrombin-catalyzed fibrin formation was presumably 'concocted by gene duplication and the shuffling about of key modular domains'.[adapted from article]

Talk Origins Evolving Immunity . Evolution of the Immune System, Spring 2005 .

Sequence comparisons of the three homologous polypeptide chains that compose vertebrate fibrinogens (acute phase proteins) imply that the molecule evolved before the divergence of vertebrates and invertebrates. Computer comparisons of various fibrinogen-related sequences indicate that the sea cucumber proteins diverged before the beta-gamma gene duplication.
Presence of a vertebrate fibrinogen-like sequence in an echinoderm. [Proc Natl Acad Sci U S A. 1990]

Coelomocytes increased expression of ferritin mRNA after stimulation. In vertebrates, cytokines can cause changes in iron levels in macrophages. Similarly, echinoderm macrokines produced decreases in iron levels in coelomocyte supernatant fluids. These results suggest that echinoderm ferritin is an acute phase protein and suggest that sequestration of iron is an ancient host defense response in animals.
Evolution of the acute phase response: iron release by echinoderm (Asterias forbesi) coelomocytes, and cloning of an echinoderm ferritin molecule.[Dev Comp Immunol. 2002 Jan;26(1):11-26.]

tags [Immunology] [evolution] [immune system] [coagulation cascade] ["irreducible complexity"]