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PubMed2003

Co-duplication of olfactory receptor and MHC class I genes in the mouse major histocompatibility complex.

We report the 897 kb sequence of a cluster of olfactory receptor (OR) genes located at the distal end of the major histocompatibility complex (MHC) class I region on mouse chromosome 17 of strain 129/SvJ (H2bc). With additional information from the mouse genome draft sequence, we identified 59 OR loci (approximately 20% pseudogenes) in contrast to only 25 OR loci (approximately 50% pseudogenes) in the corresponding centromeric OR cluster that is part of the 'extended MHC class I region' on human chromosome 6. Comparative analysis leads to three major observations: (i) most of the OR subfamilies have evolved independently in the two species, expanding more in the mouse, and resulting in co-orthologs--subfamilies of highly similar paralogs that keep orthologous relationships with their human counterparts; (ii) three of the mouse OR subfamilies have no orthologs in humans; and (iii) MHC class I loci are interspersed in the OR cluster in mouse but not in human, and were subjected to co-duplication with OR genes. Screening of our sequence against the available sequences of other strains/haplotypes revealed that most of the OR loci are polymorphic and that the number of OR loci may vary among strains/haplotypes. Our findings that MHC-linked OR loci share duplication with MHC class I loci, have duplicated extensively and are polymorphic revives questions about potential reciprocal influences acting on the dynamics and evolution of the H2 region and the H2-linked OR loci.

Alleles↗
PubMed1998

Exit of major histocompatibility complex class II-invariant chain p35 complexes from the endoplasmic reticulum is modulated by phosphorylation.

The Iip35 isoform of the major histocompatibility complex (MHC) class II-associated invariant chain (Ii) contains an endoplasmic reticulum (ER) targeting motif, but in B cell lines the ER retention is ineffective and a fraction of Iip35 is transported through the Golgi complex associated with class II molecules. We found Iip35 (but not Iip33, the major form of Ii) to be phosphorylated in B cell lines, as well as in transfected HeLa cells. The phosphorylation of Iip35 was found to be necessary for the exit of Iip35-class II complexes out of the ER. This requirement suggests that phosphorylation may change the interaction with factors responsible for ER retention/retrieval, and we did find that phosphorylated Iip35 associates with 14-3-3 proteins, a family of adaptor proteins that are involved in coordinating signal transduction pathways. This finding raises the intriguing possibility that the exit of Ii-class II complexes from the ER is regulated by intracellular signaling events.

14-3-3 Proteins↗
PubMedDate not supplied

Activation of major histocompatibility complex class I mRNA containing an Alu-like repeat in polyoma virus-transformed rat cells.

Class I genes of the major histocompatibility complex (MHC) appear to be activated in mouse cells transformed by the DNA tumour virus simian virus 40 (SV40). Conversely, suppression of MHC class I genes has been reported in adenovirus-12-transformed baby kidney rat cells. We have now investigated the expression of genes encoded by the rat MHC locus in rat fibroblast cells transformed by polyoma virus (Py). Using a mouse genomic H-2 clone as a probe in Northern transfer hybridization analysis, we have observed a high level of expression of rat MHC class I messenger RNA in all the transformed rat cell lines analysed. The class I 1.6-kilobase (kb) mRNA activated in Py-transformed rat cells appears to contain an Alu-like type II repeat element, as the same 1.6-kb mRNA is detected using either the H-2 class I sequence or a repetitive Alu-like type II element as a probe. High levels of heterogeneous poly(A)+ transcripts of 0.5-0.8 kb are also observed in Py-transformed rat cells using probes containing an Alu-like type II repetitive element.

Animals↗
PubMed1975

The allogeneic effect: M-locus differences substitute for differences in the H-2 major histocompatibility complex.

The primary immune response against sheep red blood cells in T cell-deficient spleen cell cultures from nude mice was tested in the absence and presence of allogeneic spleen cells. The allogeneic spleen cells differed either in regard to the major histocompatibility complex (H-2) or only with respect to the M-locus. Surprisingly the M-locus different spleen cells were almost as efficient in enhancing the anti-sheep red blood cell response in nude cultures as were the cells differing on the complete H-2 complex. Evidence is presented that AKR anti-theta serum sensitive T cells are responsible for the M-locus-dependent effect edscribed. This effect is shown to be mediated by a factor released from actived T cells stimulated in M-locus different mixed lymphocyte cultures. Since almost identical parameters have been observed in both the M-locus-dependent situation as in the "classical" allogeneic situation we concluded that an allogeneic effect can be induced by T cells responding to a complete set of the major histocompatibility complex (H-2) as well as to lymphocyte-activating determinants (M-locus) alone.

Animals↗
PubMed1998

Identification of a novel highly conserved gene in the centromeric part of the major histocompatibility complex.

A novel highly conserved gene designated Sacm2l alias Are1) has been identified and fine mapped in the centromeric part of the major histocompatibility complex in rat, human, and mouse. Sacm2l is closely linked to the ribosomal protein S18 gene Rps18 with a distance of about 450 bp between the respective translational start points. Numerous Sacm2l-homologous EST sequences can be identified in the database. Northern blot experiments of rat Sacm2l revealed a transcript of 3 kb in each organ tested, and by RT-PCR differentially spliced products could be detected in testis RNA. The deduced amino acid sequence of the rat Sacm2l gene shows a putative coiled-coil region and significant homology to a putative Caenorhabditis elegans protein and the yeast SAC2 protein.

Amino Acid Sequence↗
PubMed1986

Extensive deletions in the Q region of the mouse major histocompatibility complex.

By use of Southern blot analyses and low copy number probes, the fine structure of the Q region of the mouse major histocompatibility complex was studied in more detail. With a probe recognizing the even-numbered genes Q4, Q6, and Q8, it was evident that Q4 and/or the regions flanking Q4 are polymorphic, whereas Q6 and Q8, and their flanking regions are nonpolymorphic. Perhaps the most noteworthy finding is that at least two strain haplotypes, H-2k and H-2f, possessed extensive deletions in the Q region. The most striking deletion was found in the H-2f haplotype, where the Q1 through Q9 genes appear to be missing. Because of these extensive deletions the functional importance of the Q region is questioned.

Animals↗
PubMed1984

Acidification of internalized class I major histocompatibility complex antigen by T lymphoblasts.

It has previously been shown that activated murine T lymphocytes express intracellular vesicles containing the class I major histocompatibility complex (MHC) antigen H-2K. Evidence has also been provided that such vesicles may be part of a cellular pathway of spontaneous H-2K antigen internalization and recycling, which is specific to T-lymphoid cells. Dual fluorescence flow cytometry has now been used to establish that H-2K antigen is acidified upon internalization in concanavalin A-stimulated but not lipopolysaccharide-stimulated murine splenocytes, thus providing further support that in T lymphoblasts this class I MHC antigen may travel intracellular routes similar to those reported for other cell surface receptors.

Animals↗
PubMed1993

Major histocompatibility complex susceptibility genes for dermatitis herpetiformis compared with those for gluten-sensitive enteropathy.

Dermatitis herpetiformis (DH) shares some clinical features and major histocompatibility complex (MHC) markers with gluten-sensitive enteropathy (GSE). We compared MHC haplotypes in 27 patients with DH, 35 patients with GSE, and normal controls. As in GSE, the frequencies of two extended haplotypes, [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7], were increased in patients with DH. Distributions of fragments of extended haplotypes, consisting of some but not all of the elements of complete extended haplotypes, were analyzed to attempt to localize a susceptibility gene. Besides complete extended susceptibility haplotypes, (DR3, DQ2) and (DR7, DQ2) fragments were most common in GSE. In contrast, DH showed only a few such fragments but many instances of the fragment (SC01). The differences in distribution of these fragments in the two diseases were highly significant (P < 0.002). HLA-DQ2 and DR3 had the highest odds ratios for GSE, but the highest odds ratio for DH was for the complotype SC01. These findings suggest that the MHC susceptibility gene for DH is between class II and complotype regions, closest to the complotype, whereas that for GSE is in the class II region.

Celiac Disease↗
PubMed1988

T cells can distinguish between allogeneic major histocompatibility complex products on different cell types.

In the response of T cells to foreign antigens, the ligand for the T cell alpha/beta receptor is presented on a cell surface as a fragment of antigen complexed to one of the membrane molecules encoded in the major histocompatibility complex (MHC). The receptor apparently interacts via its variable elements (V beta, D beta, J beta, V alpha and J alpha) with residues within both the antigen and MHC portion of the ligand. The frequency of T cells responding to a conventional antigen plus self MHC is usually quite low, presumably reflecting the relative rarity of receptors with the particular combination of variable elements to match the antigen/MHC ligand. T cells also respond to allogeneic forms of MHC molecules in the absence of added antigen. In this case the frequency of responding T cells is very high. One hypothesis to explain this observation is that, in the absence of foreign antigen, MHC molecules are complexed to a large array of peptides derived from self-proteins. In this case the combination of the polymorphic MHC amino acid residues and many different self peptides presents so many possible ligands that the likelihood of recognition by a given T cell receptor is quite high. The recent crystallography experiments which revealed a dramatic binding cleft on the face of a human MHC molecule have given impetus to this view, but as yet there is no direct supporting evidence. We have recently described a close association between murine T cell receptors utilizing the V beta 17a element and reactivity to various allogeneic forms of the murine MHC molecule, I-E (ref. 8). In this paper, we show that this I-E ligand is detected on B cells, but not on I-E+ macrophages or fibroblasts expressing a transfected I-E gene. These results strongly suggest a B cell specific product combines with I-E to form the allogeneic ligand for V beta 17a+ receptors and thus support the concept of alloreactivity described above.

Animals↗
PubMed1985

Association of spontaneous thyroiditis with the major histocompatibility complex of the rat.

Overt insulin-dependent diabetes mellitus in the rat is associated with the u haplotype of the rat major histocompatibility complex (MHC), RT1. Thyroiditis of sufficient severity to result in elevation of TSH levels is seen in Buffalo rats (RT1b). In order to examine the association of autoimmune thyroid disease with MHC gene products, we have crossed inbred Buffalo rats with diabetic BB rats and examined the RT1 genotype, the histology of thyroid and pancreatic tissue, and two indices of thyroid function. The data indicate that animals having pancreatic lymphocytic infiltration and insulinopenic overt diabetes mellitus had at least one RT1u haplotype. All but one animal having severe histological thyroid lymphocytic infiltration had at least one RT1b haplotype. Rats with severe thyroiditis had higher mean TSH levels than rats with normal histology or rats with mild thyroiditis. We conclude that gene products of the rat MHC affect the severity of spontaneous organ-specific autoimmune disease in terms of clinically apparent as well as tissue inflammatory disease.

Animals↗
PubMed1989

The role of class I major histocompatibility complex antigens in prolonging the survival of hepatic allografts in the rat.

In an attempt to study the role of class I major histocompatibility complex antigens in inducing immunological unresponsiveness, the survival rates of hepatic allografts were compared in rats pretreated with blood taken from various rat strains. A single intravenous injection of 1 ml fresh heparinized whole blood seven days before transplantation significantly prolonged the survival of subsequent donor-specific hepatic allografts in the fully allogeneic ACI(RT1a)-to-LEW(RT1l) rat combination. However, pretreatment with blood taken from the third-party strain BN(RT1n) did not produce suppression of rejection, attesting to the specificity of the pretransplant transfusion effect. Interestingly, pretransplant transfusion of PVG.r1 blood, sharing only the RT1.A MHC region with ACI, significantly prolonged the survival of ACI-to-LEW hepatic allografts. In addition, no lymphocytotoxic antibodies could be detected at 30 or 100 days after transplantation in animals with long-surviving hepatic allografts pretreated with either PVG.r1 or ACI whole blood. On the other hand, pretreatment with PVG(RT1c) blood increased the survival of ACI-to-LEW hepatic allografts only moderately compared with controls. This finding may be consistent with a partial effect of some third-party blood transfusion. The experimental data suggest that the class I MHC antigens can be immunosuppressive in rat hepatic allografts. Adoptive transfer of 5 x 10(7) splenocytes taken from long-term-surviving hepatic allografts pretreated with donor ACI whole blood or PVG.r1 blood into irradiated (750 rads) LEW rats prolonged the survival of donor-type skin grafts, whereas third-party strain (BN) grafts were rejected. This finding suggests the presence of donor-specific suppressor cells.

Animals↗
PubMed1988

Family relationships of murine major histocompatibility complex class I genes. Sequence of the T2Aa pseudogene, a member of gene family 3.

The major histocompatibility complex of the mouse contains numerous class I genes, most of which are encoded in the Qa and Tla regions. By hybridizations, the murine class I genes have been classified into three major families (Rogers, J. H. (1985a) Immunogenetics 21, 343-353). As yet, complete sequences are available only for members of family 1 (several H-2 and Qa genes) or family 2 (the pseudoallelic Tla genes T3b and T13c). We here present the complete nucleotide sequence of a gene from the Tla region that belongs to family 3. This gene, T2Aa, is a pseudogene by several criteria. The general structure of the gene is nonetheless well preserved. A comparison of the T2Aa sequence to those of other murine class I genes confirms the classification into three gene families. Members of gene families 2 and 3, located in the Tla region, are no more similar to each other than to family 1 (the H-2 and Qa2,3 genes). This suggests that families 2 and 3 were both created by ancient duplications of the functionally important family 1 genes. The fact that families 2 and 3 have diverged extensively both from family 1 and from each other may suggest that they are devoid of function.

Amino Acid Sequence↗
PubMed1992

Evolution of the major histocompatibility complex: isolation of class II A cDNA clones from the cartilaginous fish.

Along with the T-cell receptor and immunoglobulin, the major histocompatibility complex (MHC) plays a key role in mounting immune responses to foreign antigen. To gain insights into the evolution of the MHC, class II A cDNA clones were isolated from nurse sharks, a member of the class of cartilaginous fish. Two closely related cDNA clones, which might encode allelic products, were identified; of the three amino acid substitutions found in the alpha 1 domain, two were located at positions postulated to interact with processed peptides. The deduced nurse shark MHC class II alpha chains showed conspicuous structural similarity to their mammalian counterparts. Isolation of cDNA clones encoding typical MHC class II alpha chains was unexpected since no direct evidence for T-cell-mediated immune responses has been obtained in the cartilaginous fish. The cartilaginous fish is phylogenetically the most primitive class of vertebrates from which any MHC gene has been isolated.

Amino Acid Sequence↗
PubMed2006

Major histocompatibility complex alleles, sexual responsivity, and unfaithfulness in romantic couples.

Preferences for mates that possess genes dissimilar to one's own at the major histocompatibility complex (MHC), a polymorphic group of loci associated with the immune system, have been found in mice, birds, fish, and humans. These preferences may help individuals choose genetically compatible mates and may adaptively function to prevent inbreeding or to increase heterozygosity and thereby immunocompetence of offspring. MHC-dissimilar mate preferences may influence the psychology of sexual attraction. We investigated whether MHC similarity among romantically involved couples (N= 48) predicted aspects of their sexual relationship. All women in our sample normally ovulated, and alleles at three MHC loci were typed for each person. As the proportion of MHC alleles couples shared increased, women's sexual responsivity to their partners decreased, their number of extrapair sexual partners increased, and their attraction to men other than their primary partners increased, particularly during the fertile phase of their cycles.

Adolescent↗
PubMed1981

Transplantation in miniature swine. VIII. Recombination within the major histocompatibility complex of miniature swine.

Offspring of heterozygous parents derived from three herds of miniature swine, each of which is homozygous at the major histocompatibility complex (MHC), were screened for recombination within the MHC. The swine were typed serologically at weaning and later typed by mixed lymphocyte reaction (MLR). Two intra-MHC recombinants were discovered, both of which involved the exchange of D region specificities without apparent dissociation of ABC region specificities, confirming the localization of the SLA-D region outside of the SLA-ABC regions. The first recombinant was the offspring of an SLAc/d (cd) by dd mating and typed serologically as cd but typed by MLR as dd. The second recombinant was the offspring of a cd by cd mating. It typed serologically as cc but stimulated cc in one-way MLR and retained its reactivity to dd, thus suggesting a possible recombination within the D region. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of 3H-leucine-labeled lymphocyte surface antigens demonstrated that corresponding Ia antigens were also exchanged during these recombinant events supporting the hypothesis that genes coding for Ia antigens are identical or closely linked to D region genes encoding the MLR specificities.

Animals↗
PubMed1997

Major histocompatibility complex (MHC) class III genetics in two Amerindian tribes from southern Brazil: the Kaingang and the Guarani.

Population genetic studies of the major histocompatibility complex (MHC) class III region, comprising C2, BF and C4 phenotypes, and molecular genetic data are rarely available for populations other than Caucasoids. We have investigated three Amerindian populations from Southern Brazil: 131 Kaingang from Ivaí (KIV), 111 Kaingang (KRC) and 100 Guarani (GRC) from Rio das Cobras. Extended MHC haplotypes were derived after standard C2, BF, C4 phenotyping and restriction fragment length polymorphism (RFLP) analysis with TaqI, together with HLA data published previously by segregation analysis. C2 and BF frequencies corresponded to other Amerindian populations. C4B*Q0 frequency was high in the GRC (0.429) but low in the Kaingang. Unusual C4 alleles were found, viz. C4A*58, A*55 and C4B*22 (presumably non-Amerindian) and aberrant C4A*3 of Amerindian origin occurring with a frequency of 0.223 in the GRC. C4A*3 bands of homo- and heterozygous individuals carrying this variant were Rodgers 1 positive and Chido 1,3 positive, showed a C4A specific lysis type and a C4A like alpha-chain. Polymerase chain reaction studies and sequencing showed that this is based on a C4A*3 duplication with a regular C4A*3 and a partially converted C4A*0304 carrying the C4B specific epitopes Ch 6 and Ch 1,3. Associations of class III haplotypes with particular RFLP patterns were similar to those reported for Caucasoids. The previously described association between combined C4A and CYP21P deletions and the 6.4 kb TaqI fragment was not seen in these Amerindians. This fragment occurred within a regular two locus gene structure in the Kaingang, representing a "short" gene at C4 locus I. C4 and CYP21 duplications were frequently observed. The distribution of extended MHC haplotypes provides evidence for a close relationship between the KIV and KRC and a larger genetic distance between the two Kaingang groups and the GRC.

Brazil↗
PubMed1995

Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies.

LMP2 and LMP7, two subunits of the proteasomes encoded in the major histocompatibility complex, are speculated to play a role in the generation of endogenous peptides for presentation by class I molecules to cytotoxic T cells. Their possible role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) has not been documented. In this study of Caucasian subjects, we have analyzed the polymorphisms of four genes within the HLA class II region (LMP2, LMP7, and HLA-DRB1 and -DQB1) in 198 unrelated IDDM patients and 192 normal controls ascertained from the southeastern United States. A genomic polymorphism of LMP7 was found strongly associated with IDDM, and the Arg/His-60 polymorphism in LMP2 was found associated with IDDM only in subjects containing an HLA DR4-DQB1*0302 haplotype. To determine whether the apparent associations between LMP genes and IDDM resulted from the strong linkage disequilibria observed between LMP and HLA-DR/DQ genes, we compared LMP gene frequencies in extended LMP-HLA haplotypes derived from control and diabetic families. Our results suggest that LMP genes have independent effects on IDDM susceptibility.

Autoimmune Diseases↗
PubMed1992

Major histocompatibility complex conformational epitopes are peptide specific.

Serologically distinct forms of H-2Kb are stabilized by loading cells expressing "empty" class I major histocompatibility complex (MHC) molecules with different H-2Kb binding peptides. The H-2Kb epitope recognized by monoclonal antibody (mAb) 28.8.6 was stabilized by ovalbumin (OVA) (257-264) and murine cytomegalovirus (MCMV) pp89 (168-176) peptides, but not by vesicular stomatic virus nucleoprotein (VSV NP) (52-59) and influenza NP (Y345-360) peptides. The H-2Kb epitope recognized by mAb 34.4.20 was stabilized by VSV NP (52-59) peptide but not by OVA (257-264), MCMV pp89 (168-176), or influenza NP (Y345-360) peptides. Immunoprecipitation of H-2Kb molecules from normal cells showed that 28.8.6 and 34.4.20 epitopes were only present on a subset of all conformationally reactive H-2Kb molecules. Using alanine-substituted derivatives of the VSV peptide, the 28.8.6 epitope was completely stabilized by substitution of the first residue and partially stabilized by substitution of the third or the fifth residues in the peptides. These results indicate that distinct conformational MHC epitopes are dependent on the specific peptide that occupies the antigenic peptide binding groove on individual MHC molecules. The changes in MHC epitopes observed may also be important in understanding the diversity of T cell receptors used in an immune response and the influence of peptides on development of the T cell repertoire.

Amino Acid Sequence↗