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103 Silent

GL, simultaneous gain and loss of antigenic determinants; L, loss of antigenic determinants.

aReferences: Mclntyre KR and Seidman JG (1984) Nature 308: 551-553; Nathenson SG, Geliebter J, Pfaffenbach GM and Zeff HA (1986) Annual Review of Immunology 4: 471-502; Hemmi S, Geliebter J, Zeff RA, Melvold RW and Nathenson SG (1988) Journal of Experimental Medicine 168: 2319-2335; Pfaffenbach GM, Melvold RW and Nathenson SG (1990) Biochemical Genetics 28: 433-411; Pease LR, Horton RM, Pullen JK and Cai Z (1991) Critical Reviews in Immunology 11: 1-32; Horton RM, Loveland BE, Parwani A, Pease LR and Fischer Lindahl K (1991) Journal of Immunology 147: 3180-3184; Pease LR, Horton RM, Pullen JK and Yun TJ (1993) Molecular and Cellular Biology 13: 4374 4381; Yun TJ, Melvold RW and Pease LR (in press; for bm28).

GL, simultaneous gain and loss of antigenic determinants; L, loss of antigenic determinants.

aReferences: Mclntyre KR and Seidman JG (1984) Nature 308: 551-553; Nathenson SG, Geliebter J, Pfaffenbach GM and Zeff HA (1986) Annual Review of Immunology 4: 471-502; Hemmi S, Geliebter J, Zeff RA, Melvold RW and Nathenson SG (1988) Journal of Experimental Medicine 168: 2319-2335; Pfaffenbach GM, Melvold RW and Nathenson SG (1990) Biochemical Genetics 28: 433-411; Pease LR, Horton RM, Pullen JK and Cai Z (1991) Critical Reviews in Immunology 11: 1-32; Horton RM, Loveland BE, Parwani A, Pease LR and Fischer Lindahl K (1991) Journal of Immunology 147: 3180-3184; Pease LR, Horton RM, Pullen JK and Yun TJ (1993) Molecular and Cellular Biology 13: 4374 4381; Yun TJ, Melvold RW and Pease LR (in press; for bm28).

are specialized so that they bind only to a specific combination of [antigen + class I molecule] on a cell surface. The amino acid sequence of the peptide-binding region(s) of a major histocompatibility complex (MHC) class I molecule imparts an affinity for preferential binding of particular peptides. Thus changes in the amino acid sequence of a class I molecule can alter the subset of peptides which are displayed on the cell surface, and this in turn determines which subset(s) of CD8+ T cells are able to bind and become activated. Therefore, changes in MHC class I molecules can alter the immune repertoire. The bm mutations, by altering only one or a few amino acids at various sites in the H-2K and H-2D gene products have been crucial in identifying which portions of these molecules are important sites for the associations between class I molecule and peptide and between class I molecule and T cell receptor. Small changes, even only a single amino acid, can completely alter the ability of some individuals to respond to particular antigens. While all of the class I bm mutants affect cell-mediated functions, their effects on serologic functions are somewhat less consistent and dramatic, and many of them fail to stimulate antibody production when mutant and parental mice are immunized against one another.

Only a single spontaneous in vivo mutation of an H-2 class II gene has been recovered, and it too is a bm mutant (H-2bm'2). CD4+ T lymphocytes recognize combinations of [peptide + class II molecule] on cell surfaces. The bml2 mutation, which involves a change in only three amino acids, has profound effects on the immunobiology of the mutant animal by altering the way in which the class II molecule interacts with antigenic peptide or with T cell receptors on CD4+ lymphocytes. For example, the mutant is unable to respond to some antigens to which the parental strain responds well. On the other hand, the mutant has gained the ability to respond to certain antigens to which the parental strain is unable to respond. The mutation is also able to confer resistance to the development of an autoimmune disease, experimental myasthenia gravis, to which the parental strain is susceptible.

In summary, the bm mutants have provided exquisitely subtle genetic tools for the fine-detail analysis of H-2 gene structure and the relationship of that structure to the function of the resultant gene products, and are particularly valuable where whole, intact animals are required to study a particular process. They have been instrumental in the assignment of diverse biological and immunologic functions to single H-2 genes, and have even been shown to influence mating preferences, in that mice can distinguish parental animals from those carrying bm mutations by urine-associated odors. The bm mutations, and those derived from other haplotypes as well, will undoubtedly continue to demonstrate their value in immunogenetic research.

See also: Cell-mediated immunity; Congenic mice; Cytotoxic T lymphocytes; Gene conversion; H2 class I; H2 class II; Immune response (Ir) genes; Inbred strains; Mouse inbred strains.

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