IMMUNOLOGY - Roit A. - Mir 2000

Chapter 12. Ontogeny of the Immune System

ANTIBODY SPECIFICITY DIVERSITY

Antibody diversity (repertoire) is generated through Gene rearrangement. In any somatic Cell, the variable gene regions, comprising V, D, and J segments, are in the germline configuration (see Chapter 8). Early in B-cell development, intervening sequences between the D and J segments are deleted, bringing these segments into close proximity. At the pro-B-cell stage, further rearrangement of the V, D, and J segments of the heavy-chain variable region (Vh) takes place (Fig. 12.14). The recombined gene of the large pre-B cell is expressed to form a cytoplasmic p-chain. These actively proliferating pro-B Cells subsequently rearrange their Vk genes or, if this rearrangement proves unproductive, their Vλ genes. Upon productive rearrangement of the light-chain genes, the immature B cell expresses surface μ-chains combined with the available light chain (k or λ). Cells that undergo unproductive gene rearrangement die via apoptosis, which accounts for the loss of a significant proportion of pre-B cells during maturation (see above). If immature B cells express receptors with light chains specific for self-Antigens following gene rearrangement, the light chains may undergo further rearrangement, a process known as receptor editing. The expression of μ-chains with surrogate light chains prior to the appearance of k and λ chains (at the pre-B-cell stage) is likely crucial for the Selection of B cells at early developmental stages (see above).

Antibody diversity is generated in a somewhat non-random manner. Once k- or λ-chains begin to be produced, surface IgM on immature B cells acquires The properties of a functional antigen receptor. It is generally believed that the V, D, and J segments for heavy chains, as well as the V and J segments for light chains in B cells, undergo random rearrangement. However, data obtained from mice, rats, and chickens indicate that The Development of antibody specificities follows a programmed sequence (Fig. 12.17). Unlike B-cell antigen recognition, antibody production is dependent on both T cells and APCs. The molecular mechanism underlying this programmed GENERATION OF B-cell specificities remains elusive; it may involve either the preferential use of V-gene segments closest to the D and J segments with progressive movement of recombinases toward the 3' end, or the negative selection of specific clones (potentially autoreactive ones), or perhaps a combination of both pathways.

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Fig. 12.17. Rats of various ages were immunized with one of 5 different antigenic preparations — Brucella abortus, sheep red Blood Cells (SRBC), donkey red blood cells (DRBC), KLH, and type III pneumococcal polysaccharide (SSS_III) — after which antibody production was measured. Responses to the first four preparations are expressed as log₂ antibody titers, and those to SSS_III as the percentage of responding individuals. Blank cells indicate a lack of data. Note that the capacity to respond to different antigens emerges at distinct times, suggesting a programmed sequence in the appearance of Antibodies with diverse specificities.

CD5⁺ B lymphocytes represent a distinct subpopulation. Many B cells appearing during early ontogeny express CD5. The IMMUNOGLOBULINS of these cells are encoded by unmutated or minimally mutated germline genes. Although CD5⁺ B cells predominantly produce IgM, they also synthesize small amounts of IgG and IgA. These so-called natural antibodies exhibit low avidity, though they are occasionally polyreactive, and are present at high concentrations in the serum of mature individuals. CD5⁺ cells mount robust responses to T-independent antigens, may participate in ANTIGEN Processing AND presentation by B cells, and likely play a role in tolerance and the development of humoral immune responses (antibody production). It is hypothesized that natural antibodies constitute the first line of defense against microbes, clear the body of damaged self-components, and participate in shaping the idiotypic networks of The Immune System.