GENETICS OF ANTIBODY PRODUCTION
Antibody production is unusual in the following ways:
1 The molecule is encoded within three separate chromosomes:
(a) Chromosome 14 for heavy chain
(b) Chromosome 2 for K light chain
(c) Chromosome 22 for ,\ light chain
2 Rearrangement of the multiple elements of germline DNA leads to production of antibodies with many different antigen-binding sites (clonal diversity of Fab)
3 Successive recombinations of VDJ to CIL (IgM), Cll (IgD), C’Y3(IgG), C’Yl, Cat (IgA), C’Y2.C’Y4.CE (IgE), or Ca2 cause progressive switching in the isotype of the antibody but as the Fab gene is not altered the sameantigen-binding region is maintained.
This explains why the primary immune response is of the IgM isotype, as this is the first to be translocated. Switching to subsequent isotype requires T lymphocyte help. IgG and other isotype responses therefore develop later. However, once the switch has occurred, memory B cells remain. These react rapidly to any further challenge and the IgG of the secondary response is produced. The extensive variability of antibody molecules is
explained by the following factors:
MULTIPLICITY OF V (there are 25-100 genes), D (10 genes) and J (5–6 genes) within the DNA.
COMBINATIONAL FREEDOM of VJ and VDJ genes and light and heavy genes, i.e. any of the multiple genes above can join each other.
JUNCTIONAL DIVERSITY. Splicing of the genes together is frequently inaccurate and ‘frame-shift’ in base-pairs leads to misreading and production of the ‘wrong’ amino acid.
SOMATIC MUTATION in V genes.
IMMUNOGLOBULIN ISOTYPES AND THEIR FUNCTIONS
The main biological features of the human isotypes are summarized in Table 2.16. Different classes of antibody tend to predominate at different sites. The major effector functions of antibody are:
1 Antigen elimination
(a) Binding to prevent adhesion and invasion of organisms
(b) Opsonization of particles for phagocytosis
2 Antitoxin activity
3 Immune regulation, acting as the antigen receptor on B cells
4 Sensitization of cells for antibody-dependent cell cytotoxicity (ADCC)
This is the most abundant immunoglobulin in serum, present as a monomer. IgG is the antibody of secondary response, but has high antigen affinity. It is the only antibody to cross the placenta in significant quantities. There are four subclasses: IgGl, IgG2, IgG3 and IgG•. IgGl and IgG3 are produced mainly in response to protein antigens, such as tetanus toxin and many viruses. These subclasses are good opsonins, binding Fc receptors on neutrophils, and having some complement activating activity. IgG2 and IgG4 are produced in response to polysaccharide antigen, for example the capsule of bacteria such as pneumococcus and Haemophilus.
This antibody is mainly confined to the intravascular pool. It is a pentameric molecule, the single IgM molecules being bound together by the joining T chain. It is the major antibody of the primary immune response. It does not cross the placenta, and is not normally produced until after birth. Therefore antigen-specific IgM is a good marker for intrauterine infection, if present in the newborn infant.
There are two subclasses, IgAl and IgA2′ and their functions appear to be similar. IgAl predominates in the serum, but the subclasses are present in equal amounts in secretions. IgA is mainly monomeric in the serum, but dimeric in secretions, the two molecules complexed by a J chain. IgA in serum binds to a poly Fc receptor for IgA and 19M on the basal surface of enterocytes and hepatocytes.
Transcellular transport delivers the immunoglobulin to the luminal surface where it is secreted still bound to the receptor which is termed the secretory component (SC). The most important function of 19A appears to be in the protection of mucosal surfaces (gut, respiratory tract, urinary tract). Within GALT or BALT there are specialized cells that transport antigen from the lumen to the follicle. 19A precursor B cells in the follicle journey to local, e.g. mesenteric, lymph nodes and to the systemic circulation via the thoracic duct. They then circulate back to settle in the lamina propria of the gut. This homing is a generalized phenomenon to all the mucosal surfaces of the body. Therefore localized antigen exposure gives rise to generalized mucosal immunity, which is of importance in vaccination.
19A in secretions may be important in binding enterotoxins such as that of cholera, preventing the attachment of viruses such as polio and other enteroviruses, and in prevention of invasion by bacteria.
Serum levels are very low and its function at this site is uncertain. 19D is present on the surface of B lymphocytes, and may have an immunoregulatory role. Levels are high in conditions with B-cell activation such as systemic lupus erythematosus (SLE), AIDS and Hodgkin’s disease.
IgE is a monomer that is normally present in very low levels in serum as most is membrane bound on mast cells. Its main physiological role is its anti-nematode activity, but its most common clinical relevance is in the pathogenesis of type 1 hypersensitivity, atopic or allergic disease.