Chella S. David

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.

Genetic nomenclature for new lymphocyte antigens controlled by the I region of the H-2 complex

Several laboratories have recently reported studies of new alloantigenic specificities preferentially expressed on lymphocytes and apparently controlled by genes in the Ir region [hereafter designated the I region (Klein et al. 1974)] of the H-2 gene complex (Hauptfeld et al. 1973, David et al. 1973, Sachs and Cone 1973, G~Jtze et al. 1973, Hammerling et al. 1973). These antigens have been designated by various laboratories as Ir-l.1 (Hauptfeld et al. 1973), Lna (David et al. 1973b) and ~ (Sachs and Cone 1973). To avoid confusion in the literature and to establish a standard nomenclature for these new antigens, representatives of the laboratories concerned met during the H-2 workshop in Bar Harbor, Maine, October 8-10, 1973, and agreed upon the following notation: 1) The system of antigens and the controlling genetic element(s) will be provisionally designated Ia (I-region-associated antigens). This symbol was chosen as a general, descriptive term having no specific connotations with regard to possible relationships of these antigens with It-1 or Lad genes or the tissue or cellular distribution of these antigens. When further information on these questions becomes available, the notation can be modified as necessary. 2) If it is found that these antigens are controlled by more than one genetic locus in the I region, the separate loci will be designated by numbers, Ia-1, Ia-2, Ia-3, etc. 3) If it is found that there are multipe Ia loci, some of which control antigens specific for B lymphocytes (bursa-equivalent lymphocytes) and some of which control antigens specific for T lymphocytes (thymusderived lymphocytes), those loci may be distinguished by the symbols Iab and Iat respectively. Multiple loci of each type would be denoted Iab-1, Iab-2, etc. and Iat-1, Iat-2, etc. 4) Alleles at the Ia loci should be designated by a superscript which

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.

Lymphocyte antigens controlled by the ir region of the mouse h-2 complex. Detection of new specificities with anti-h-2 reagents.

SUMMARY Several anti-H-2Kk(Irk) reagents were analyzed for antibodies directed against lymphocyte antigens (Lnk) controlled by the Irk region. Most of the antisera contained anti-Lna antibodies. On the basis of the reactivity of these antisera and the anti-Lna sera previously reported, tentative Lna specificities, Lna 1,2,3,4,5, and 6, have been assigned. Antiserum-target cell combinations to define each specificity are presented.

I region-associated antigen system (ia) of the mouse h-2 gene complex. Further definition of ia specificities with restricted anti-ia antisera.

Restricted anti-Ia antisera were produced by immunizing the following F1 mice with A.TL (,Ik) tissues: (A.TH × B10)F1; (A.TH × 129)F1; (A.TH × C3H.Q)F1; (A.TH × B10.D2)F1, (A.TH × B10.M),F1 Analyses of these antisera suggested that specificity Ia.3 (Lna.3) should be subdivided into three specificities, Ia.1, Ia.3, and Ia.7, associated with the, Ib,, Id and, If regions, respectively. Immunization of (A.TL × B10.M)F1 and (A.TL × A.TB)F1 with A.TH tissue produced anti-Ia.4 antibodies which were specific for, Is strains. These suggested that a single specificity, Ia.5, is shared by the, Is and the, If,, IP, and, Iq regions. The current view of the Ia antigenic makeup of various inbred and recombinant H-2 haplotypes and postulated I region map positions of their determinants are summarized.

Immune response to calf collagen type I in mice: A combined control of Ir-1A and non H-2 linked genes

The genetically controlled immune response to calf skin collagen type I in mice could be demonstrated to be governed by at least two genes. One is linked to theH-2 complex and located within theIA subregion. High-responder alleles areH-2b,H-2f, andH-2s. The other gene(s) is not linked to theH-2 complex and high-responder allele(s) are found in the genome of B10 mice but not in the genome of DBA mice. There are strong indications that theIr-1A gene controls the response at the T-cell level, whereas it is assumed that the background gene(s) control the immune response at a different level.

The specificity and significance of the inhibition of Fc receptor binding by anti H 2 sera

The possibility that Ia antigens are unique among H-2 antigens in their relationship to the Fc receptor was investigated in an EA rosette assay. Antibody specific for antigens in various regions of theH-2 complex was incubated with mouse cells, and the ability of the cells to form rosettes with antibody-coated chicken erythrocytes was tested. Antibody raised against the H-2 antigens of Ia-negative tumor cells was highly effective in inhibiting rosette formation. A variety of antisera againstK-, I-, andD-region antigens tested in recombinant mice inhibited EA rosette formation, suggesting that antigens in each of these regions could be detected in rosette inhibition. The F(ab′)2 fragments of all antisera tested also produced specific EA rosette inhibition. Finally, antibody against Ia antigens failed to inhibit bone marrow RFCs, although antibody against H-2K and H-2D antigens did inhibit. Although H-2 serology is in a state of rapid change at present, it must be concluded that in this assay, antibody against antigens in theK andD regions as well as theI region can inhibit EA rosette formation. Inhibition of these rosettes by anti H-2 sera is therefore not due to a special association of Ia antigens with Fc receptors.

Murine Ia Antigens. Expression On T and B Cells and Their Role In Immune Response

Publisher Summary The H-2 gene complex is a part of the IXth linkage group on the 17th chromosome of the mouse. The complex is comprised of five regions, denoted in order from the centromeric end, K, I, S, G, and D. Cell-bound and soluble molecules reactive directly or indirectly with anti-Ia-sera involved in a number of immune phenomena. The function of the I region is very complex. This complexity reflects either multiple products of multiple I region genes, each with a distinct role and reactive with a distinct population of anti-la antibodies, or diverse manifestations of a very few Ia-reactive gene products, which play a very central role in immune processes. Ia antigens are predominantly expressed on lymphoid cells. Among the lymphoid cells, Ia antigens are most readily detected on B cells. The chapter discusses the ability of anti-la sera to block the mitogenic responses of lymphocytes or to eliminate mitogen-sensitive lymphoid cell populations.