Donald C. Shreffler

The H-2 Major Histocompatibility Complex and the/Immune Response Region: Genetic Variation, Function, and Organization

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.

H-2 haplotypes, genes, regions, and antigens: First listing

H-2, the major his tocompatibi l i ty complex of the mouse, is a cluster of loci posit ioned in the middle por t ion of ch romosome 17 (Fig. 1). Present da t a indicate that the cluster is composed of ten loci grouped into regions and subregions (Fig. 2). Tradit ionally, the borders of the H-2 complex are thought to lie in the K region at the centromeric end of the cluster and the D region at the telomeric end. At the lat ter portion of chromosome 17 lies another cluster of seven loci compris ing the T region, originally identified by the Tla locus. The loci in the T region show certain similarities to some of the tl-2 loci, and it is possible that , genetically, the region is, in fact, par t of the H-2 complex. Fur ther down at the telomeric por t ion o f ch romosome 17 is a group of i sozyme loci, which are becoming useful markers in his tocompatibility studies. The H-2 loci occur in many v a r i a n t s a l l e l e s a n d the combinat ions of certain [1-2 alleles in a single ch romosome form many different haplotypes . F o r example,

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

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.

The firstH- 2 mutant workshop.

ConclusionThe major accomplishment of the Workshop was probably the realization of many of its participants that most of the 21 availableH- 2 variants aretrue mutations very likely derived from single nucleotide substitutions. Any theory of the pleiotropic effect of theH- 2 genes must now take this fact into account; such theories must also consider the observation that a wide variety of immunological phenomena are affected byH- 2 mutations and thus, apparently, are controlled by a single gene.

Genetic nomenclature for the H-2 complex of the mouse

The H-2 complex (system, Snell and Stimpfling 1966) represents a segment of chromosome 17 delimited by the H-2K and H-2D loci (Table 1). The complex is split by the Ss locus into two ends, the K end between H-2K and Ss, and the D end between Ss and H-2D. The term end can also be used to indicate the direction; thus the K end could mean the direction from the Ss locus toward the centromere, and the D end the direction from the Ss locus toward the telomere. The H-2 complex is composed of regions, subregions and loci. An H-2 region is a segment of the H-2 complex delimited by recombination and consisting of a marker gene and an undeterminate number of neighboring loci. The H-2 complex is to be divided into four regions, K, /, S and D, defined by marker genes H-2K, Ir-lA, Ss and H-2D, respectively. Subregions of a given region are segments identified by distinct but functionally related marker genes and separated from each other and the other regions by recombination. The I region is to be divided into two subregions, Ir-lA and Ir-lB, formerly termed Ir-1 and Ir-IgG, respectively. It is assumed that each region or subregion contains at least one locus,

A sex-limited serum protein variant in the mouse: Hormonal control of phenotypic expression

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.

Homozygous Hb J Tongariki: Evidence for Only One Alpha Chain Structural Locus in Melanesians

A high frequency of Hb J Tongariki (α 115 Ala → Asp) was found in a Kilenge village in New Britain. Heterozygotes had 45 to 50 percent of the Hb J component (determined by cellulose acetate electrophoresis). Two homozygotes for Hb J had no Hb A, suggesting that in this family only one Hbα structural locus is present.

The H-2 Model for the Major Histocompatibility Systems

Thirty-five years ago, Gorer (1936), working with inbred strains of mice, discovered four blood group antigens and showed (Gorer 1937) that one of them, antigen II, was also present in fixed tissues and played a decisive role in determining susceptibility or resistance to tumor transplants. Following the suggestion of Snell (1948) that antigens concerned in transplantation reactions should be called histocompatibility (H) antigens, the designation antigen II was changed to H-2. The gene controlling the H-2 antigen was shown to be linked with Fused (a gene for a tail anomaly) in the 9th linkage group (Gorer et cd. 1948). It soon became apparent through histogenetical studies by Snell and his coworkers (for a review, see Snell 1953) that what looked at first like a simple biaJlelic locus was actually a multiallelic system with many different H-2 alleles present in different inbred strains. At the same time, serological studies by Gorer, Amos, Hoecker, and others (for a review, see Gorer 1959) revealed that the H-2 antigen was not simple, but consisted of increasing numbers of antigenic components. In 1951, Snell showed that Fl hybrids between inbred strains BALB/c {H-2^) and CBA {H-2^) were susceptible to an A strain tumor and suggested that the H-2^ allele of strain A was actually composed of two components, d and k, and should be therefore written as H-2^^, This was the first indication of a bipartite structure of the H~2 locus. The bipartity was further supported by detection of crossingover between the d and k components (Allen 1955), but was later obscured by discoveries of additional recombinants and an increasing serological complexity. The idea re-emerged in 1965 when it was discovered that the Ss (serum protein) locus was located within the complex chromosomal region controlling H-2 antigens (Shreffler 1965).

Genetic analysis of an H-2 mutant, B6.C-H-2 ba , using cell-mediated lympholysis: T- and B-cell dictionaries for histocompatibility determinants are different

B6.C-H-2ba [H (z1)] is a mutant derived from C57BL/6. The two strains mutually reject their skingrafts and are incompatible in the mixed leucocyte reaction (MLR) and in cell-mediated lympholysis (CML) assays. They are serologically indistinguishable.This report shows that H(z1) carries a new, privateK end CML specificity clearly distinguishable from that of B6 by a third party strain, HTG. Antisera directed against the private H-2K specificity of B6 present on H(z1) cells) can block CML between the two strains in either direction. The new CML specificities of H(z1) cross-react with (public) CML specificities controlled by bothK andD regions of other unrelated haplotypes. The results suggest that H(z1) carries a mutation in theH-2K locus itself or in a closely linked gene, the product of which is also physically associated with the H-2K molecule corresponding to the cis-configuration of the alleles in both loci.These findings indicate that T- and B-cell dictionaries for histocompatibility determinants are different.

Identification of Specificity H-2.7 as an Erythrocyte Antigen : Control by an Independent Locus, H-2G, between the S and D Regions

SpecificityH-2.7 is expressed predominantly on erythrocytes and controlled by a gene that maps within theH-2 gene complex at a locus, designated asH-2G, which apparently lies between regionsS andD. Three phenotypes have been observed with respect to this antigen: a) positive by direct test and absorption (haplotypesH-2f,H-2j,H-2p,H-2s); b) positive only by absorption (H-2k); and c) negative (H-2b,H-2d,H-2q). New crossover positions have been established for severalH-2 recombinants based on classifications for theH-2G locus.