Complexity in the major histocompatibility complex.

The human major histocompatibility complex (MHC) is one of the most intensively studied regions of the human genome, containing over 70 known genes and spanning about 4 million base pairs (4 Mbp) of DNA on chromosome 6p21.3 (Klein, 1986). It can be divided up into three regions: the class I region (telomeric), the class II region (centromeric), and the class III region (between class I and II), which includes the complement component genes C2, C4, and Bf (Trowsdale & Campbell, 1988). The MHC has been mapped in detail using pulse field gel electrophoresis (PFGE) and by cloning in yeast artificial chromosome (YAC) and cosmid vectors, revealing long stretches of DNA between the regions as well as between individual class I and class II genes. Novel genes, that have no sequence relationships with class I, class II or complement components, have recently been found in these areas, and we will present an update on these after reviewing the more established loci.     

Rabbit major histocompatibility complex. IV. Expression of major histocompatibility complex class II genes

The rabbit MHC class II DP, DQ, and DR alpha and beta chain genes were transfected into murine B lymphoma cells. The transfected cells expressed R-DQ and R-DR molecules on the cell surface but they did not express the R-DP genes either on the cell surface or at the level of mRNA. Northern blot analyses showed that the R-DP genes were expressed, albeit at low levels, in rabbit spleen. Similar analyses showed that the R-DQ and R-DR genes were expressed at high levels in rabbit spleen. A new monoclonal anti-rabbit class II antibody, RDR34, has been developed and shown to react with the R-DR transfected cells and not with the R-DQ transfected cells. The previously described monoclonal anti-rabbit class II antibody, 2C4, reacted with the R-DQ transfected cells and not with the R-DR transfected cells. Thus, 2C4 and RDR34 MAb's are specific for the R-DQ and R-DR molecules, respectively. Each of the antibodies reacted with approximately 50% of rabbit spleen cells as shown by immunofluorescent antibody studies.     

Genetics of rheumatoid arthritis (RA): two separate regions in the major histocompatibility complex contribute to susceptibility to RA.

We analyzed HLA-DR antigens and microsatellite Bat2 alleles in 97 adult caucasian patients with classical seropositive rheumatoid arthritis (RA) and 95 normal healthy controls. The results demonstrate that the prevalence of microsatellite Bat2 138 allele was significantly higher in RA-susceptibility DRB1 QKRAA/QRRAA epitope-negative patients as compared with normal controls. Analysis of the data suggested that Bat2 138 allele has primary association with RA-susceptibility in QKRAA/QRRAA epitope-negative patients. The Bat2 138 allele thus provides an additional risk in RA-susceptibility. In addition, microsatellite Bat2 138 allele showed a highly significant positive association with microsatellite D6S273 138 allele, which has similar (identical) association with RA development in DRB1 QKRAA/QRRAA epitope-negative patients. The present data demonstrate that DRB1 QKRAA/QRRAA epitope and microsatellite Bat2 138/D6S273 138 alleles more completely define the risk for development of RA. The results in the present study therefore suggest that two regions in MHC, class II (DRB1) and class III (Bat2 and D6S273 in HSP70-Bat2 region), contribute to susceptibility to RA.     

The major histocompatibility complex in swine

Summary: In swine, the major histocompatibility complex ( Mhc ) or swine leukocyte antigen ( SLA ) is located on chromosome 7 and divided by the centromere. Thus, the telomeric class I and more centromeric class III regions are located on the p arm and the class II region is located on the q arm. The SLA region spans about 2 Mb, in which more than 70 genes have so far been characterized. Despite its division by the centromere, the spatial relationships between the genes in the class II and class III regions, and between the well-conserved non-class I genes of the class I region, are similar to those found in the human HLA complex. On the other hand, no orthologous relationships have been found between the Mhc class I genes in man and swine. In swine, the 12 SLA class I sequences constitute two distinct clusters. One chister comprises six classical class 1-related sequences, while the other comprises five class I-distantly related sequences including two swine homologous genes of the HLA Mhc class I chain-related gene ( MIC ) sequence family. The number of functional SLA classical class I genes, as defined by serology, probably varies from one to four, depending on the haplotype. Some of the SLA class I-distantly related sequences are clearly transcribed. As regards the SLA class II genes, some of them clearly code for at least one functional SLA-DR and one SLA-DQ heterodimer product, but none code for any DP product. The amino acid alignment of the variable domains of 33 SLA classical class I chains, and 62 DRβ and 20 DQβ chains confirmed the exceptionally polymorphic pattern of these polypeptides. Among the class II genes, the genes are either monomorphic, like the DRA gene, or oligomorphic, like the DQA genes. In contrast, the DRB and DQB genes display considerable polymorphism, which seems more marked in DRB than DQB genes.     

The major histocompatibility complex origin

Summary: The present review focuses on the history of genes involved in the major histocompatibility complex (MHC), with a special emphasis on class I function in peptide presentation. The MHC class II story is covered in less detail, as it does not have a major impact on the general understanding of the MHC evolution. We first redefine the MHC as the definition evolved over time. We then use phylogenetic analysis to investigate the history of genes involved in the MHC class I process. As not all the genes involved in this process have been phylogenetically analyzed and because new sequences have been recently released in biological databases, we have re‐investigated this matter. In the light of the phylogenetic analysis, the functions of the orthologs of the genes involved in MHC processes are examined in species not having an MHC system. We then demonstrate that the emergence of this new function is due to various levels of co‐option.     

The canine major histocompatibility complex

The frequencies of 12 DLA-D alleles in a random canine population were determined in one-way mixed lymphocyte cultures using a panel of homozygous typing cells established in this laboratory. The homozygous typing cells served as stimulators for responder lymphocytes obtained from 160 random dogs. The results of these studies were compared to those with lymphocytes from 75 dogs in our research laboratory. DLA-D allelic frequencies were estimated by maximum likelihood techniques. The use of a relative response (RR) ≫5% as a definition of a typing response resulted in the recognition of a total allele frequency of 59% in dogs from the research laboratory. Three of the 12 DLA-D alleles were not detected. Typing responses of cells from random dogs to the 12 DLA-D alleles were determined using RRs °5%, °10%, °15%, and °20%. With RRs of °5%, °10%, and °15%, the total allele frequencies recognized were 39%, 47%, and 55%, respectively. Within each of these %RR ranges all but one of the DLA-D alleles were detected. With an RR °20% the total allele frequency recognized was 58% and all 12 alleles were detected. Our results indicate that an RR of °10% could be used to define a phenotypic DLA-D typing response in the dog. The level of allelic frequencies detected in both the research and random canine populations indicates the need to identify additional DLA-D alleles through expanded family studies using mixed lymphocyte culture and homozygous cell typing.     

Signal transduction by the major histocompatibility complex class I molecule.

Ligation of cell surface major histocompatibility class I (MHC-I) proteins by antibodies, or by their native counter receptor, the CD8 molecule, mediates transduction of signals into the cells. MHC-I-mediated signaling can lead to both increased and decreased activity of the MHC-I-expressing cell depending on the fine specificity of the anti-MHC-I antibodies, the context of CD8 ligation, the nature and cell cycle state of the MHC-I-expressing cell and the presence or absence of additional cellular or humoral stimulation. This paper reviews the biochemical, physiological and cellular events immediately after and at later intervals following MHC-I ligation. It is hypothesized that MHC-I expression, both ontogenically and in evolution, is driven by a cell-mediated selection pressure advantageous to the MHC-I-expressing cell. Accordingly, in addition to their role in T-cell selection and functioning, MHC-I molecules might be of importance for the maintenance of cellular homeostasis not only within the immune system, but also in the interplay between the immune system and other organ systems.     

Regulatory noncoding RNAs and the major histocompatibility complex

The Major Histocompatibility Complex (MHC) is a 4 Mbp genomic region located on the short arm of chromosome 6. The MHC region contains many key immune-related genes such as Human Leukocyte Antigens (HLAs). There has been a growing realization that, apart from MHC encoded proteins, RNAs derived from noncoding regions of the MHC—specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)—play a significant role in cellular regulation. Furthermore, regulatory noncoding RNAs (ncRNAs) derived from other parts of the genome fine-tune the expression of many immune-related MHC proteins. Although the field of ncRNAs of the MHC is a research area that is still in its infancy, ncRNA regulation of MHC genes has already been shown to be vital for immune function, healthy pregnancy and cellular homeostasis. Dysregulation of this intricate network of ncRNAs can lead to serious perturbations in homeostasis and subsequent disease.     

The Muckle-Wells syndrome and the major histocompatibility complex

The members of a family affected by the Muckle Wells syndrome were typed for HLA-A, B antigens. No close linkage was found with the major histocompatibility complex.     

Different staphylococcal enterotoxins bind preferentially to distinct major histocompatibility complex class II isotypes

The stimulation of T cells by staphylococcal enterotoxins (SE) is strictly dependent on major histocompatibility complex (MHC) class II-bearing cells. The interaction between SE and MHC class II molecules was studied on the human B cell lymphoma Raji and its MHC class II-negative variant RJ 2.2.5. Affinity purification with SEA and SEB matrix allowed the isolation of HLA-DR-like molecules from detergent lysates of 125I surface-labeled Raji cells, but not from RJ 2.2.5 cells. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis also revealed preferences in the binding of other SE such as SED, SEE and toxic shock syndrome toxin 1 to DR-like molecules, SEC2 to HLA-DQ-like molecules and SEC3 to DR- and DQ-like molecules. Preadsorption of the different MHC class II MHC isotypes confirmed the preferential binding of SEA to DR and of SEC2 to DQ. The implications of these findings for the understanding of SE-induced T cell activation and the potency of SE as a tool in the study of MHC class II antigens are discussed.     

Gene complex controlling growth and fertility linked to the major histocompatibility complex in the rat.

The B1 strain of rats carries a unique mutation which causes defects in growth and reproduction: the males and females are small, the testes are hypoplastic and aspermatic, and the females have a reduced reproductive capacity. The loci controlling these defects are linked to the major histocompatibility complex (MHC) as determined by segregation studies in backcross and F2 hybrid populations. The levels of pituitary hormones and somatomedin C in the B1 strain are elevated or normal, and the testosterone level is elevated relative to the size of the testes. These findings suggest that hormone deficiencies are not the cause of these defects. The genes governing these defects have been designated the growth and reproduction complex (Grc). The recessive gene regulating small body size has been designated dw-3 (dwarf-3), and the recessive gene influencing reproductive capacity has been designated f. The Grc and MHC are separable by recombination, and the dw-3 and f genes are also separable by recombination. Studies in the (B1 X DA)F2 hybrid indicate that the map distance between the Grc and the MHC is 0.6 cM. Segregation distortion due to a deficiency of RT11 homozygotes is seen in some F2 hybrid populations derived from the B1 strain. Litter size data suggest that the loss of the RT11 homozygotes is due to intrauterine death. There is no apparent sex influence on the inheritance of the Grc, at least as it is presently understood, since it can be transmitted by either females or males. The growth and reproduction complex in the rat may be the analog of the T/t complex in the mouse, and the importance of the region of the chromosome adjacent to the major histocompatibility complex in the control of developmental processes may be a general phenomenon in mammals.     

Novel major histocompatibility complex class I alleles extracted from two rhesus macaque populations

We report here the novel Mamu-A and -B alleles that were detected in two groups of rhesus monkeys.     

Genes in two major histocompatibility complex class I regions control selection, phenotype, and function of a rat Ly-49 natural killer cell subset.

We have generated a monoclonal antibody (STOK2) which reacts with an inhibitory MHC receptor on a subset of alloreactive NK cells in the rat. This receptor, termed the STOK2 antigen (Ag), belongs to the Ly-49 family of lectin-like molecules and displays specificity for the classical MHC class I molecule RT1-A1c of PVG rats. Here, we have investigated the influence of the MHC on the selection, phenotype and function of the STOK2+ NK subset in a panel of MHC congenic and intra-MHC recombinant strains. STOK2 receptor density was influenced by the presence of its classical MHC I ligand RT1-A1c, as evidenced by a reduction of STOK2 Ag on the surface of NK cells from RT1-A1c+, as compared with RT1-A1c-, strains. In addition, a role for nonclassical MHC I RT1-C/E/M alleles in the selection of the STOK2 Ag was demonstrated. The relative number of STOK2+ NK cells was fivefold higher in rats expressing the RT1-C/E/M(av1) as compared with those expressing the RT1-C/E/M(u) class Ib haplotype. The STOK2 ligand RT1-A1c inhibited cytotoxicity of STOK2+ NK cells regardless of effector cell MHC haplotype. Allospecificity of STOK2+ NK cells varied markedly with effector cell MHC, however, and suggested that inhibitory MHC I receptors apart from STOK2 were variably co-expressed by these cells. These data provide evidence for the MHC-dependent regulation of the allospecific repertoire within a subset of potentially autoreactive Ly-49+ rat NK cells.     

The chromosomal duplication model of the major histocompatibility complex

Summary: The major histocompatibility complex (MHC) is a genetic region that has been extensively studied by immunologists, molecular biologists, and evolutionary biologists. Nevertheless, our knowledge of how the MHC acquired its present-day organization is quite limited. The recent discovery that the mammalian genome contains regions paralogous to the MHC has led us to the proposal that the MHC region of jawed vertebrates arose as a result of ancient chromosomal duplications. Here, I review the current status of this proposal.     

Genetic divergence of the rhesus macaque major histocompatibility complex

The major histocompatibility complex (MHC) is comprised of the class I, class II, and class III regions, including the MHC class I and class II genes that play a primary role in the immune response and serve as an important model in studies of primate evolution. Although nonhuman primates contribute significantly to comparative human studies, relatively little is known about the genetic diversity and genomics underlying nonhuman primate immunity. To address this issue, we sequenced a complete rhesus macaque MHC spanning over 5.3 Mb, and obtained an additional 2.3 Mb from a second haplotype, including class II and portions of class I and class III. A major expansion of from six class I genes in humans to as many as 22 active MHC class I genes in rhesus and levels of sequence divergence some 10-fold higher than a similar human comparison were found, averaging from 2% to 6% throughout extended portions of class I and class II. These data pose new interpretations of the evolutionary constraints operating between MHC diversity and T-cell selection by contrasting with models predicting an optimal number of antigen presenting genes. For the clinical model, these data and derivative genetic tools can be implemented in ongoing genetic and disease studies that involve the rhesus macaque.