Molecular genetics of the swine major histocompatibility complex, the SLA complex

The swine major histocompatibility complex (MHC) or swine leukocyte antigen (SLA) complex is one of the most gene-dense regions in the swine genome. It consists of three major gene clusters, the SLA class I, class III and class II regions, that span approximately 1.1, 0.7 and 0.5Mb, respectively, making the swine MHC the smallest among mammalian MHC so far examined and the only one known to span the centromere. This review summarizes recent updates to the Immuno Polymorphism Database-MHC (IPD-MHC) website (http://www.ebi.ac.uk/ipd/mhc/sla/) which serves as the repository for maintaining a list of all SLA recognized genes and their allelic sequences. It reviews the expression of SLA proteins on cell subsets and their role in antigen presentation and regulating immune responses. It concludes by discussing the role of SLA genes in swine models of transplantation, xenotransplantation, cancer and allergy and in swine production traits and responses to infectious disease and vaccines.     

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.     

The major histocompatibility complex as self-referential]

In order to effectively perceive the huge diversity of antigenic determinants to which it is confronted, the immune system uses referring internal images from self. The major histocompatibility complex constitutes the main reference to self, essential to the operating system of T and NK lymphocytes. It is involved in shaping the T operating repertoire in the thymus, where each differentiating thymocyte, with its TCR interacting with the MHC-peptide self complexes exposed by thymic presenting cells, should answer to both questions: Is it really necessary (positive selection) Is not dangerous (negative selection)? Once in periphery, naive T lymphocytes will undergo an homeostatic control helping their survival through the same contacts between TCR and MHC-peptide self complex than those which allowed the thymic positive selection. In a more hypothetic way, it is possible that contact between a T lymphocyte and the rare foreign MHC-peptide complexes spread at the surface of antigen presenting cell, is not sufficient to initiate its activation. Some arguments exist to involve the MHC-peptide self complexes themselves in the activation process.Finally, the MHC also constitutes a quality referential for the NK lymphocytes. When a somatic cell, infected by a virus or transformed, repress the expression of one or more of its class I HLA alleles, this absence of the self is perceived by the NK lymphocytes which proceed to its elimination through cytolysis. This disposition to sanction the non-self is also used for therapeutic purpose in the case of a non HLA identical allogenic hematopo?etic stem cells graft.     

The major histocompatibility complex and diseases in farm animals

Breeding for genetic resistance to disease and development of veterinary vaccines are major stimuli for research of the major histocompatibility complex (MHC) in farm animals. Genetically determined resistance is an attractive preventive measure because it precludes veterinary services, and is consistent over generations. Also many infectious diseases in farm animals cannot be prevented by vaccination. In a recent seminar sponsored by the European Community, the MHC of farm animals was discussed, its association with diseases was assessed, and other means of selection for disease resistance were evaluated.     

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.     

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.     

Sequence of the swine major histocompatibility complex region containing all non-classical class I genes

A segment of 158,063 nucleotides of the pig major histocompatibility complex (SLA) and corresponding to the junction of the class I and class III regions was sequenced entirely. The centromeric part of the segment contained six class III genes including the three tumor necrosis factor genes, while the telomeric part contained three genes belonging to the class I region. The order and the molecular organization of these genes were exactly conserved in the SLA and HLA complexes, except for the SC1 gene which displayed a shift of the reading frame in swine. The cluster of the three SLA class I-related genes (Ib) and the MIC1 and MIC2 genes were located in the middle of the segment, in the following order from the centromeric side onwards, SLA-6, SLA-7, SLA-8, MIC-1 and MIC-2. All three SLA Ib genes displayed an overall molecular structure compatible with the expression of membrane-anchored glycoproteins. The SLA-7 and SLA-8 genes bear greater resemblance than to the SLA-6 gene. Six SLA-6 alleles have been previously defined differing each from the other by unique point mutations. One of them, appeared to have arisen through the occurrence of a gene conversion event in which the SLA-7 gene served as template. Only MIC-2 gene might be functional, the second MIC-1 gene being truncated. In all, the 14 genes characterized spans 37% of the total sequence. The remaining 63% nucleotides comprised a number of repeat DNA motives, including LINE fragments, SINEs, microsatellites, and also numerous nucleotide stretches not yet defined in swine.     

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.     

The haplotype structure of the human major histocompatibility complex

There is great interest in the use of single-nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) analysis to localize human disease genes. The results suggest that the human genome, including the major histocompatibility complex (MHC), consists largely of 5- to 200-kb blocks of sequence fixity between which random recombination occurs. Direct determination of MHC haplotypes from family studies also demonstrates similar-sized blocks, but otherwise gives a very different picture, with a third to a half of Caucasian haplotypes fixed from HLA-B to HLA-DR/DQ (at least 1 Mb) as conserved extended haplotypes (CEHs), some of which encompass more than 3 Mb. These fixed haplotypes differ in frequency both in different Caucasian subpopulations and in Caucasian patients with HLA-associated diseases, complicating disease susceptibility gene localization. The inherent inability of LD analysis to "see" DNA fixity beyond three markers contributes to the failure of SNP/LD analysis to define in detail or even detect CEHs in the MHC and probably elsewhere in the genome. More importantly, the use of statistical analysis, rather than direct haplotype determination and counting, fails to reveal the details of haplotype structure essential for gene localization. Given the oversimplified picture of the MHC (and probably the rest of the genome) provided only by SNP/LD-defined blocks, it is questionable whether this approach will be of great help in disease susceptibility gene localization or identification.     

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.     

The mouse major histocompatibility complex: some assembly required

Summary: We have assembled a contig of 81 yeast artificial chromosome clones that spans 8 Mb and contains the entire major histocompatibility complex (Mhc) from mouse strain C57BL/6 (H2^b), and we are in the process of assembling an Mhc contig of bacterial artificial chromosome (BAC) clones from strain 129 (H2^bc), which differs from C57BL/6 in the H2-Q and H2-T regions. The current BAC contig extends from Tapasin to D17Leh89 with gaps in the class II, H2-Q. and distal H2-M regions. Only four BAC clones were required to link the class I genes of the H2-Q and H2-T regions, and no new class I gene was found in the previous gap. The proximal 1 Mb of the H2-M region has been analyzed in detail and is ready for sequencing; it includes 21 class I genes or fragments, at least 14 olfactory receptor-like genes, and a number of non-class I genes that clearly establish a conserved synteny with the class I regions of the human and rat Mhc.     

Expressed major histocompatibility complex class II loci in fishes

Summary: Peptides derived from parasites are presented to T helper cells by major histocompatibility complex (MHC) class II αβ heterotrimeric cell-surface molecules. In mice and humans, the genes encoding these antigen-presenting molecules are known to be polymorphic and poly-genic. Multiple loci for MHC class II A and E genes are proposed to allow for an increased peptide-binding repertoire. The multigenic nature of expressed MHC class II loci and the differences between these loci in fishes are the focus of this review, Particular emphasis is placed on an evolutionary comparison of class II B loci, especially two class 11 B loci that have undergone dramatic changes from one another suggesting an ancestral gene duplication event that took place at an early stage in the evolution of teleosts, The number of functional class II αβ loci heterotrimers may have a profound impact on the organisms ability to battle constantly evolving parasitic infections.     

Roles for major histocompatibility complex glycosylation in immune function

The major histocompatibility complex (MHC) glycoprotein family, also referred to as human leukocyte antigens, present endogenous and exogenous antigens to T lymphocytes for recognition and response. These molecules play a central role in enabling the immune system to distinguish self from non-self, which is the basis for protective immunity against pathogenic infections and disease while at the same time representing a serious obstacle for tissue transplantation. All known MHC family members, like the majority of secreted, cell surface, and other immune-related molecules, carry asparagine (N)-linked glycans. The immune system has evolved increasing complexity in higher-order organisms along with a more complex pattern of protein glycosylation, a relationship that may contribute to immune function beyond the early protein quality control events in the endoplasmic reticulum that are commonly known. The broad MHC family maintains peptide sequence motifs for glycosylation at sites that are highly conserved across evolution, suggesting importance, yet functional roles for these glycans remain largely elusive. In this review, we will summarize what is known about MHC glycosylation and provide new insight for additional functional roles for this glycoprotein modification in mediating immune responses.     

The major histocompatibility complex and the chemosensory recognition of individuality in rats

The present experiments provide the first evidence that congenic strains of rats, which differ only in the MHC, produce discriminably different urinary chemosignals. Urine from adult male PVG and PVG.R1 rats, which differ only in the A region (class 1) of the MHC, was used in a habituation-dishabituation task, with male PVG-RTlu, Wistar albino, and Lister hooded rats as subjects. Urine from PVG males was easily distinguished from that of PVG.R1 males by all three strains. Individual PVG males were not distinguished by their urine odours, but individual PVG.R1 males appeared to have discriminably different odours. A repetition of this experiment indicated that this discrimination may have been due to impurities in the urine. Odours from serum were not sufficient for discrimination between the two strains, nor was the class 1 molecule purified from the urine. Urine with the class 1 molecule removed (remainder fraction) could, however, be used to distinguish between the strains. The chemicals in the urine which give this distinctive odour may be fragments of the class 1 molecule or small molecules associated with the class 1 molecule. The MHC appears to control the odour cues which are used by mammals for individual recognition and may provide an olfactory basis for kin recognition but the mechanism by which the MHC controls these olfactory signals is unknown.