IMMUNOLOGY - Roit I. - Mir 2000

Chapter 8. Sources of Diversity in Antigen-Recognizing Structures

THE SCALE OF DIVERSITY

The repertoire of TCR Specificity is generated through simple combinations of V, D, and J segments, the insertion of additional NUCLEOTIDES ("N-region Variability"), variations in the joining positions of Gene segments, and shifts in the reading frames of D segments. Specifically, the number of nucleotides separating the germline V and J segments after recombination is variable, corresponding to roughly 6–15 amino acid residues in the V region of β chains and 3–7 residues in the V region of α chains. Hunkapiller and Hood calculated that this mechanism can generate up to 4.4 · 10¹³ different forms of Vβ genes and 8.5 · 10¹² Vα genes. If only 1% of these encode viable Proteins, the same calculations suggest that 2.9 · 10²² receptors of varying specificity could theoretically emerge. Let us assume that 99% of these must be eliminated due to complementarity with autoantigens or other defects. Even so, the number of potential TCRs in a mouse remains approximately equal to 2.9 · 10²⁰. Given that no more than 10⁹ T Cells leave the Thymus during an individual's lifetime, the question arises: how random is the specificity of their receptors? The specificity repertoire of IMMUNOGLOBULINS is equally enigmatic, as its calculated diversity exceeds the total number of generated B cells by many orders of magnitude.

Questions for Consideration

■ How can a limited number of genes encode Antibodies and receptors for an almost infinite array of Antigens?

■ What are somatic Mutations, and how can they either promote or hinder the Immune Response?

■ Compare individual and population polymorphism in antibodies and MHC products.

■ How might microbes have influenced the evolution of The Immune System?

■ If an animal lacks recombination-activating genes (RAG-1 and RAG-2), how does this affect the immune system as a whole and the generation of antibody diversity?

■ What changes occur in Ig genes following antigenic stimulation that lead to increased antibody affinity (affinity maturation)? What is the mechanism for selecting genes carrying beneficial mutations? What happens to Cell clones whose genes harbor useless mutations?

Introduction/47.html">Further Reading

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Berens S.J., Wylie D.E., Lopez O.J. 1997. Use of a single Vh family and long CDR3s in the variable region of cattle Ig heavy chains, internat. Immunol. 9 189-199.

Blackwell T.K., Alt F.W. 1989 Mechanism and developmental program of immunoglobulin gene rearrangement in mammals. Annu. Rev. Genet. 23: 605-636.

Brack C., Hirama M., Lenhard-Schuller R. et al. 1978. A complete immunoglobulin gene is created by somatic recombination. Cell 15: 1-14.

Chang B., Casali P. 1994. The CDR-1 sequences of major proportion of human germline Ig Vh genes are inherently susceptible to amino acid replacement. Immunol. Today 15:367-373.

Davis M.M., Bjorkman P.J. 1988. T-cell antigen receptor genes and T-Cell Recognition. Nature 334: 395-402.

Difippantonio M.J., McMahan C.J., Eastman Q.M. et al. 1996. Schatz D.G, RAG-1 mediates signal sequence recognition and recruitment of RAG-2 in V(D)J recombination. Cell 87: 253-262

Haas W., Pereira P., Tonegawa S. 1993. Gamma/Delta cells. Annu. Rev. Immunol. 11: 637-685.

Harriman W., Volk H., Defanoux N. et al. 1993. Immunoglobulin Class switch recombinations. Annu. Rev. Immunol. 11: 361-384.

Hiom K., Gellert M. 1997. A stable RAG1-RAG2-DNA complex that is active in V(D)J Cleavage. Cell 88: 65-72.

Honjo T., Alt F.W. Immunoglobulin Genes. London; Academic Press, 1995.

Hunkapiller T., Hood L. 1990. Water/126.html">Diversity of the immunoglobulin gene superfamily. Adv. Immunol. 44. 1-63.

Leiden J.M. 1993. Transcriptional Regulation of T cell receptor genes. Annu. Rev. Immunol. 11: 539-570

Lewis S.M. 1994. The Mechanism of V(D)J joining: lessons from molecular, immunological and comparative analyses. Adv. Immunol. 56: 27-150.

Owen M.J., Lamb JR. Immune Recognition. Oxford. IRL Press, 1988.

Pascual V., Capra J.D. 1991. Human immunoglobulin heavy-chain variable region genes: Organization, polymorphism and expression. Adv. Immunol. 49. 1-74.

Rast J.P., Anderson M.R., Strong S J et al. 1997. α, β, γ and δ T CELL ANTIGEN receptor genes arose early in vertebrate phylogeny. Immunity 6: 1-11.

Spanopoulou E., Zaitseva F., Wang F. et al. 1996. The homeodomain region of Rag-1 reveals the parallel mechanisms of bacterial and V(D)J recombination. Cell 87: 263-276.

Wu T.T., Kabat E.A. 1970. An Analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J. Exp. Med. 132: 211-250.