Roger L. Dawkins

Nomenclature for the major histocompatibility complexes of different species: a proposal.

The major histocompatibility complex (MHC) has been given different names in different species (Klein 1986). It is designatedH-2 in the mouse, HLA in humans, B in the domestic fowl, RT1 in the rat, and Smh in the mole rat. In most other species that have been studied, the MHC is referred to by the LA symbol (for lymphocyte or leukocyte antigen), prefixed by an abbreviation of the species’ common name. Thus, it is called ChLa in the chimpanzee, GoLA in the gorilla, RhLA in the rhesus macaque, RLA in the rabbit, BoLA in the domestic cattle, SLA in the pig, and so on. This practice has two problems associated with it. First, MHC products are expressed on many other tissues in addition to lymphocyte or leukocyte (and lymphocytes express many other antigens in addition to those controlled by the MHC) and their antigenicity is secondary to their biological function. Second, the use of common names to identify a species is a potential source of confusion. Common names are notoriously vague and imprecise. The designation “lemur”, for example, can refer to any of the genera Lemur, Hapalemur, Varecia, Lepilemur; Avahi, Propithecus, and Indri, of which only the first four belong to the family Lemuridae; the last three are members of the family Indriidae. A “bushbaby” can be a Galago, Otolemur, or Euoticus. A “mouse” could be a Notomys, ylcomys, Uranomys, Pogomys, Chiruromys, Chiropodomys, Neohydromys, and so on. Obviously, common names not only fail to identify the species appropriately, they often do not even identify the genes or the family. If the trend in choosing common names for MHC symbols were to continue, chaos would soon ensue because we can expect MHCs in many different species to be identified in the future.

Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease

Summary: The genomic region encompassing the Major Histocompatibility Complex (MHC) contains polymorphic frozen blocks which have developed by local imperfect sequential duplication associated with insertion and deletion (indels), In the alpha block surrounding HLA‐A, there are ten duplication units or beads on the 62,1 ancestral haplotype. Each bead contains or contained sequences representing Class 1, PERB11 (MHC Class I chain related (MIC)) and human endogenous retrovirus (HERV) 16, Here we consider explanations for co‐occurrence of genomic polymorphism, duplication and HERVs and we ask how these features encode susceptibility to numerous and very diverse diseases. Ancestral haplotypes differ in their copy number and indels in addition to their coding regions. Disease susceptibility could be a function of all of these differences. We propose a model of the evolution of the human MHC. Population‐specific integration of retroviral sequences could explain rapid diversification through duplication and differential disease susceptibility. If HERV sequences can be protective, there are exciting prospects for manipulation. In the mean‐while, it will be necessary to understand the function of MHC genes such as PEKB11 (MIC) and many others discovered by genomic sequencing.

Ancestral haplotypes: conserved population MHC haplotypes

We describe here a number of Caucasoid MHC haplotypes that extend from HLA-B to DR and that have been conserved en bloc. These haplotypes and recombinants between any two of them account for 73% of unselected haplotypes in our Caucasoid population. The existence of ancestral haplotypes implies conservation of large chromosomal segments. Irrespective of the mechanisms involved in preservation of ancestral haplotypes, it is clear that these haplotypes carry several MHC genes, other than HLA, which may be relevant to antigen presentation, autoimmune responses, and transplantation rejection. In light of the existence of ancestral haplotypes, it is critical to evaluate MHC associations with disease and transplantation outcome in terms of associations with ancestral haplotypes rather than individual alleles.

Polymorphic MHC ancestral haplotypes affect the activity of tumour necrosis factor‐alpha

It remains unclear which MHC loci are involved in susceptibility to autoimmune diseases and immune deficiencies. We have chosen to evaluate whether different alleles of tumour necrosis factor‐alpha (TNF‐α) are important, as TNF has been implicated in the etiology of many immunological disorders. We have shown previously that a restriction fragment length polymorphism in the TNF region correlates with MHC ancestral haplotypes. We therefore examined the effect of ancestral haplotype on the activity of TNF‐α in culture supernatants of lymphoblastoid cell lines. The results demonstrate that TNF‐α activity in supernatants of 8.1 (A1, B8, DR3) cell lines was higher than that present in the supernatants from cells homozygous for eight different MHC ancestral haplotypes, and indicate that polymorphisms in TNF‐α, or in other MHC genes that regulate TNF, may be responsible for the 8.1 phenotype.

An approach to the localization of the susceptibility genes for generalized myasthenia gravis by mapping recombinant ancestral haplotypes

The association of HLA A1, B8, and DR3 with generalized myasthenia gravis (GMG) ini Caucasoids is well established, but no particular gene has been implicated and there is still no adequate explanation in functional terms. In study we have taken advantage of sequential genomic markers between B8 and DR3 so as to map the location of susceptibility gene(s) on the A1, B8, DR3 (8.1) ancestral haplotype. By studying 51 patients, we have delineated a region between HLA B and TNF which is shared by 29/29 patients with B8 and DR3, 19/19 patients with B8 but not DR3 and 2/3 patients with DR3 but not B8. The potential importance of this region was confirmed by examining a similar disease induced by D-Penicillamine (D-PenMG) and associated with different HLA class II alleles (DR1 and/or DR7). Among these patients, 7/16 (44%) have B8, often with other markers of 8.1. These results implicate at least two categories of genes in determining susceptibility to MG; one located in the region between HLA B and TNF may be immunoregulatory, whereas the second, located in the class II region, may relate to the inducing factor (e. g., DR1 or DR7 in D-PenMG).

Cell-Mediated Cytotoxicity to Muscle in Polymyositis

Abstract Immunologic injury to cultures of skeletal muscle was studied in patients with polymyositis by means of a 51Cr release method that allows quantitation of myocyte injury. Lymphocyte-mediated myotoxicity was elevated in a group of nine patients with active disease (p<0.001) but was normal in four patients with inactive disease. There was no evidence of antibody-mediated cytotoxicity. Lymphocyte-mediated myotoxicity in the active group was analyzed in relation to treatment and immunosuppression in six of the nine patients. Seven tests on patients on immunosuppressive therapy gave normal lymphocyte-mediated myotoxicity values of 1.0 ± 4.2 per cent (mean ± S.D.), whereas eight tests on patients who were on less than immunosuppressive therapy yielded elevated lymphocyte-mediated myotoxicity: 24.4 ± 10.6 per cent, with a significant difference between these two groups (p < 0.001). These data suggest that the pathogenesis of polymyositis involves a cell-mediated immunologic reaction directed against skel...

A new polymorphic and multicopy MHC gene family related to nonmammalian class I

We have used genomic analysis to characterize a region of the central major histocompatibility complex (MHC) spanning ∼ 300 kilobases (kb) betweenTNF andHLA-B. This region has been suggested to carry genetic factors relevant to the development of autoimmune diseases such as myasthenia gravis (MG) and insulin dependent diabetes mellitus (IDDM). Genomic sequence was analyzed for coding potential, using two neural network programs, GRAIL and GeneParser. A genomic probe, JAB, containing putative coding sequences (PERB11) located 60 kb centromeric ofHLA-B, was used for northern analysis of human tissues. Multiple transcripts were detected. Southern analysis of genomic DNA and overlapping YAC clones, covering the region fromBAT1 toHLA-F, indicated that there are at least five copies of PERB11, four of which are located within this region of the MHC. The partial cDNA sequence ofPERB11 was obtained from poly-A RNA derived from skeletal muscle. The putative amino acid sequence ofPERB11 shares ∼ 30%o identity to MHC class I molecules from various species, including reptiles, chickens, and frogs, as well as to other MHC class I-like molecules, such as the IgG FeR of the mouse and rat and the human Zn-α2-glycoprotein. From direct comparison of amino acid sequences, it is concluded thatPERB11 is a distinct molecule more closely related to nonmammalian than known mammalian MHC class I molecules. Genomic sequence analysis ofPERB11 from five MHC ancestral haplotypes (AH) indicated that the gene is polymorphic at both DNA and protein level. The results suggest thet we have identified a novel polymorphic gene family with multiple copies within the MHC.

Serum exchange and use of dilutions have improved precision of measurement of islet cell antibodies

In an attempt to improve the diagnostic value of measuring antibodies to islet cell cytoplasmic antigen, coded sera were distributed to 38 laboratories and results were returned for analysis. Comparison between laboratories revealed that results for some individual sera differed by up to nine doubling dilutions and even within laboratories duplicate samples could differ by six doubling dilutions. By including dilutions of sera it was possible to draw a standard curve for each laboratory and this revealed major variations in shape, slope and intercept. However, using each laboratorys standard curve and converting results to units, a substantial improvement was obtained. The approach described improves standardisation and will permit laboratories to identify poor precision and/or any systematic change in assay performance.

Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM

The major histocompatibility complex (MHC) contains multiple and diverse genes which may be relevant to the induction adn regulation of autoimmune responses in insulin dependent diabetes mellitus (IDDM). In addition to HLA class I and II, the possible candidates include TNF, C4, and several other poorly defined polymorphic genes in the central MHC region. This study describes two approaches which take advantage of the fact that the relevant genes are carried by highly conserved ancestral haplotypes such as 8.1 (HLA-B8, TNFS, C4AQO, C4B1, DR3, DQ2). First, three “diabetogenic” haplotypes (two Caucasoid and one Mongoloid) have been compared and it has been shown that all three share a rare allele of BAT3 as well as sharing DR3, DQ2. In 43 sequential patients with IDDM the cross product ration for BAT3S was 4.8 (p<0.01) and 6.9 for HLA-B8 plus BAT3S (p<0.001). Second, partial or recombinant ancestral haplotypes with either HLA class I (HLA-B8) or II (HLA-DR3, DQ2) alleles were identified. Third, using haplotypic polymorphisms such as the one in BAT3, we have shown that all the patients carrying recombinants of the 8.1 ancestral haplotype share the central region adjacent to HLA-B. These findings suggest that both HLA and non-HLA genes are involved in conferring susceptibility to IDDM, and that the region between HLA-B and BAT3 contains some of the relevant genes. By contrast, similar approaches suggest that protective genes map to the HLA class II region.

Central MHC genes, IgA deficiency and autoimmune disease.

IgA deficiency is a common immunological disorder that is sometimes associated with an immunodeficiency syndrome, allergic disease, autoimmune disease and gluten enteropathy. Many subjects with this deficiency, however, are healthy, at least for many decades. Analysis of the immunological and genetic abnormalities found in IgA deficiency and in some of the associated disorders has led to the postulate that a genetically determined defect of immunoregulation underlies all of these diseases. Here, Martyn French and Roger Dawkins propose that the products of genes located within the central region of the major histocompatibility complex (MHC) regulate B cells and/or antibody production. Particular MHC ancestral haplotypes contain specific alleles and arrangements of these genes, thereby explaining associations with either increased or decreased production of immunoglobulin isotypes by B cells.