All immunoglobulins have two heavy polypeptide chains and two light polypeptide chains. The heavy chains but not the light chains are glycosylated. Disulfide bonds link heavy chains together and heavy chains to light chains. The hinge region linking the heavy chains to the light chains is flexible and confers certain properties to the immunoglobulin. So-called 'constant' regions are invariable in amino acid sequence. Antigen binding specificity occurs in the variable and hypervariable regions.
The light chains are ~25 kDa each while the heavy chains are 50 kDa each. The amino ends of the heavy chains form the Y-arm while the carboxy terminal forms the stem. Light chain structure includes a constant beta-sheet domain at the carboxy end, and this region occurs in two types, kappa and lambda. Each lambda gene has five different versions of the constant region. The variable region features 3 loops that stick out to form the hyper variable region. The heavy chain in the same area also has 3 hyper variable loops, and the six loops form the CDR or complimentarity-determining regions.
As alluded, the heavy chain structure shows variability in the amino-terminus progressing to a first constant region, then a 'hinge' region. The hinge region is rich in proline and has one or more disulfide bridges between the two heavy chains. For the D, G, and A classes, (with corresponding delta, gamma, and alpha heavy chains) there is flexibility. The M-class and E-class (mu and epsilon heavy chains) forms a rigid bend at C2 between two constant stem domains (C3 and C4).
The carbohydrate attachments occur in the C2 region of the D, G, and A immunoglobulins and in C3 of the M and E classes. The oligosaccharides are added post-transcriptionally in the stem opens the Fc stem. The carbohydrates are important for complement interactions. The attachment is an N-linkage to the glycosyl chain, and in the example below, the oligosaccharide shows 13 sugar residues including GlcNAc (N-acetyl glucosamine), mannose, fucose, galactose, and sialic acid. There is diversity in the glycosylation. It seems the glycosylation pattern is important in immunoglobulin interactions with viruses and bacteria.
The carboxy terminus (C3 of the D, G, and A classes and C4 for the M and E classes) determine whether or not the immunoglobulin is secreted or is membrane bound.
- Naive cells and memory cells feature membrane-bound immunoglobulins, the sequences at the terminus being hydrophobic followed by hydrophilic.
- The secreted versions are expressed in plasma cells have a short hydrophilic sequence at the carboxy-terminus.
IgA: These are the only dimerized class, and there are two types. They are found in mucosal tissues (e.g., gut, urogenital, and respiratory tract) as well as saliva, tears, and breast milk. Their main function is thought to be prevention of pathogen colonization.
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Functions at epithelial barrier to prevent colonization.
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Monomer can be found in serum but,
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The secreted form occurs as dimer, looking like 2 IgG's stuck together, stems in,
4 antigen-binding sites out, and may occur as trimer or even tetramers
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Two subclasses (1 and 2)
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Also held together by an additional peptide, the J chain (binds secretory peptide)
which is identical to the one in IgM
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Secreted into mucus, tears, saliva, and breast milk- up to 15 grams per day!
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Plasma cells that secrete this tend to home in on various epithelial linings.
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Pathogen proteases can inactivate IgA by cleaving at the hinge region
IgD: Monomeric in structure like IgG and IgE, this class functions as a B-cell antigen receptor that have not been exposed to antigens. It activates basophils and mast cells.
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Function- aids recognition by naïve B cell.
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Primarily found (with IgM) as a membrane-bound receptor in naïve B cells. While
M class antibodies also function in plasma, D class rarely does.
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Rarely found in plasma (0.2% of total serum immunoglobulins)
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superficially resembles IgG (different amino acid sequence).
IgE: Monomeric in structure, functioning to protect against parasites. It binds to basophils and mast cells, causing release of histamine. It is the main immunoglobulin involved in allergies.
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Function – defense again worm parasites.
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Monomer superficially resembles IgM (somewhat different amino acid sequence)
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rare, but potent
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involved in allergic response
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binds to FC (stem) receptors on mast cells and basophils, which causes them to
trigger the allergic reaction.
IgG: Monomeric in structure with four forms, these provide the major mechanism of adaptive immunity. It is the sole class able to cross the plancenta and give passive immunity to the fetus.
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flexible hinge, 3 constant domains
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standard secreted antibody defending against bacterial and viral pathogens
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comes in four versions, numbered 1 to 4, varying in biological specificity:
IgG1 – activates complement, Fc receptors bind tightly
IgG2 – weakly activates complement, Fc receptors bind weakly
IgG3- strongly activates complement and binds tightly to Fc (lots disulfides) IgG4 – does not activate complement, binds weakly to Fc.
IgM: Is pentameric in structure in secreted form but monomeric when expressed on the B cell surface. IgM is the first responder to eliminate pathogens before there is sufficient IgG.
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rigid bend – 4 constant domains
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Function- general purpose - First class expressed in plasma.
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Monomeric form (actually 2H +2L) expressed as a membrane-bound antibody on
the naïve B cell.
- Secreted form occurs as pentamer, looking like 5 IgG's stuck together, stems in, 10 antigen-binding sites out.
- Held together by an additional peptide, the J chain. The J chain binds to a secretory component, a peptide that allows structure to be secreted into mucus, etc. (Figure 4.23)
- Very good at binding large complex structures and activating complement (to kill foreign cells).
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