Publisher Summary One of the most rapidly developing areas of immunologic research deals with the H-2 gene complex, a tightly linked series of genes controlling a variety of immunologic traits, including histocompatibility and immune responsiveness. This chapter summarizes the varieties of phenotypic traits associated with differences in the H-2 complex. The mapping of the H-2 complex into four major regions marked by H-2K, Ir-1, Ss-Slp, and H-2D genes plus the associated Tla gene is discussed in the chapter, along with the phenotypic traits associated with these regions. The chapter discusses the immune response region, the genes of which appear to control a variety of immune phenomena—including antibody response to many antigens, susceptibility to tumor viruses, and graft-versus-host (GVH), and mixed lymphocyte culture (MLC) reactions. The H-2 complex consists of many genes with diverse functions, most of which control cell membrane structures and/or processes. The fact that lymphocytes are particularly affected by H-2 genes has important implications for immunology. However, some of the genes also affect other cell types, implying a still larger role for the H-2 complex, perhaps in development or in cell regulation. Because the H-2 complex is the most thoroughly characterized segment of a mammalian chromosome, it is also an important model for the studies of gene action, organization, and evolution in mammals.

The H-2 major histocompatibility complex and the I immune response region: genetic variation, function, and organization.

Human fourth component of complement (C4) was found to be highly polymorphic by agarose gel electrophoresis of neuraminidase-treated plasma. The system allows clear-cut separation of the products of the two C4 genetic loci, C4A (acidic or Rodgers) and C4B (basic or Chido). There are at least six structural variants and a deletion allele at the C4A locus and two structural variants and a deletion allele at the C4B locus. Close linkage with no crossovers was found between the two C4 loci, allowing the definition of C4AB haplotypes, and between C4 haplotypes and the C2 and BF loci of the human histocompatibility complex. Nine C4 haplotypes, each with a frequency of 0.005 or more in Caucasians, were found. These studies provide direct evidence for two distinct but closely linked genetic loci for human C4 in the major histocompatibility complex on the short arm of chromosome 6.

Inherited structural polymorphism of the fourth component of human complement.

The cell-mediated lympholytic capability of mouse spleen cells stimulated in mixed lymphocyte culture is related to the major histocompatibility complex genotype on target lymphocytes. The strain combinations AQR-B10. T(6R) and B10.A(4R)-B10.A(2R) that result in significant mixed lymphocyte culture activation do not mediate cell-mediated lympholysis on sensitizing target lymphocytes; serologically defined regions (H-2K and H-2D) are identical within each combination. H-2K or H-2D region disparity alone does not cause cell-mediated lympholysis. However after mixed lymphocyte culture activation as seen with B10.A-B10.T(6R), a target cell bearing only an H-2K region difference from the effector cell is sensitive to cell-mediated lympholysis. Likewise an H-2D region difference is an adequate target after mixed lymphocyte culture activation of the effector cell in the combination B10.A(2R)-B10.D2.

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Cell-mediated lympholysis importance of serologically defined h-2 regions

Publisher Summary This chapter discusses the use of H-2 mutations to study functions of the murine major histocompatibility complex. A single H-2 locus can control a variety of immunologic phenomena, and strong MLC reactions can occur to H-2K and D antigens as well as to I region antigens. Histogenetically and serologically detectable antigens are of comparable complexity and small changes in the H-2 molecule—a single amino acid substitution—can have drastic effects on phenotype. The chapter describes methods of detection and analysis of histocompatibility mutations in general and H-2 mutations in particular. The knowledge of H-2 mutations is related to the perennial problem of polymorphism. The individual immune functions are discussed, and data are presented on the way mutations change these functions. In the allograft reaction—the reaction on which the detection of H-2 mutations is based—antigens carried by the transplant are recognized by specific receptors on T lymphocytes. In vitro studies indicate that the H-2 antigens recognized by T cells are complex in the sense that different T cells presumably recognize different portions of the H-2 molecule.

H-2 mutations: their genetics and effect on immune functions.

The downpour of information about the H-2 complex has hit immunology with the force of a tropical rainstorm. It is flooding whole fields, uprooting carefully cultivated orchards, displacing cottages, houses, and palaces, threatening to drown their inhabitants. This and the following article (Klein et al. 1982) are meant to serve as kinds of life-savers for those who have not learned how to swim in the rapid and murky waters. The First Listing, published four years ago (Klein et al. 1978), consisted only of tables; to this Second Listing we have added a brief description of all the loci residing, or thought to be residing, on the mouse chromosome 17, the chromosome carrying the H-2 complex. This arrangement necessitated the division of the Second Listing into two parts, the first part concerned with loci on chromosome 17 outside of the H-2 complex and the second part dealing with the complex itself. The discussion of the individual loci is prefaced by a description of the chromosome.

H-2 haplotypes, genes, and antigens: second listing. I. Non-H-2 loci on chromosome 17.

An alloantiserum produced in the mouse has been used to detect an antigen which is present only in male serum from certain inbred strains of mice, e.g., DBA/2J, A/J, and BALB/c. Genetic tests reveal that the presence of this antigen is controlled by a dominant autosomal gene which is expressed only in males of the proper genotype. Test crosses and analysis of congenic resistant strains indicate close linkage between the sex-limited protein (Slp) and the histocompatibility-2 (H-2) region of linkage group IX. Analysis of seven intra-H-2 recombinant strains is consistent with the placement of the genetic determinant for Slp within the H-2 region in the same position as the Ss (serum substance) determinant. Immunological evidence suggests that the Slp antigenic sites reflect structural variation in the Ss component of mouse serum.

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A sex-limited serum protein variant in the mouse: inheritance and association with the H-2 region.

The sex-limited protein (Slp) antigen of the mouse is first detected in the serum of strain DBA/2J males at 5–6 weeks of age and reaches full adult levels by 10 weeks. This antigen is normally absent in females. Immature DBA/2J males castrated at 3 1/2 weeks of age failed to develop Slp antigen, while DBA/2J females treated with testosterone propionate starting at 3 1/2 weeks developed normal adult male levels of Slp antigen. Similar hormone-influenced effects were demonstrated in adult males and females of the same strain. Experiments indicated that testosterone does not act directly in the serum to expose Slp antigenic sites. Testosterone treatment of both males and females of strain C57BL/10JSf, which does not carry the gene for the presence of the Slp antigen, failed to stimulate the appearance of the antigen. Thus, the presence of Slp antigen in the serum is dependent on both the proper genotype and the presence of male hormone.

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Howard C. Passmore

Papers

A sex-limited serum protein variant in the mouse: inheritance and association with the H-2 region.

A Sex-Limited Serum Protein Variant in the Mouse: Hormonal Control of Phenotypic Expression