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PubMed1984

Murine leukemia virus sequences are encoded in the murine major histocompatibility complex.

The studies reported here localize murine leukemia viral sequences to the TL region of the major histocompatibility complex, H-2. We examined a battery of 38 cosmids, isolated from two large genomic libraries constructed from C57BL/10 spleen DNA, that define 25 class I gene sequences. The viral probes used hybridized with only four cosmids, containing overlapping mouse sequences, that define four class I gene-related sequences in a region of 90 kilobases of DNA. The data show that two distinct viral envelope sequences are contained in the cluster. One of these sequences is situated with its 3' end next to the 3' end of a class I sequence. The other sequence, which does not contain the entire viral envelope, is proximal to the 3' end of a different class I sequence. Hybridization of the viral probes with the H-2 cosmid clones does not appear to be due to homology between viral and H-2 sequences. Rather, the viral sequences detected appear to be linked to or inserted amid class I genes. These findings may be significant in understanding molecular mechanisms involved in the generation of H-2 class I gene diversity.

Animals↗
PubMed1993

Characterization of cytotoxic T lymphocyte epitopes of a self-protein, p53, and a non-self-protein, influenza matrix: relationship between major histocompatibility complex peptide binding affinity and immune responsiveness to peptides.

We previously described a motif prediction of major histocompatibility complex allele-specific peptides and an in vitro assay for actual measurement of peptide binding to human leukocyte antigen HLA-A2.1 molecules. Using this method we have identified candidate cytotoxic T lymphocyte (CTL) epitopes derived from a non-self-protein (influenza matrix) and self-protein (p53). We now show that results of binding assays performed over a range of peptide concentrations indicate that distinct differences in HLA-A2.1 peptide binding affinities exist between the influenza matrix and p53 protein. The results for the influenza matrix protein indicate that the peptide that shows the highest binding affinity to HLA-A2.1 is identical to the known immunodominant peptide recognized by influenza virus-specific CTLs. The results for p53 indicate that one of the peptides with a low binding affinity is capable of inducing specific CTL responses, but CTLs recognizing the highest affinity binding peptides were not obtained. These findings are discussed in terms of the distinct implications for induction of cellular immune responses directed against peptides with different binding affinities for HLA-A2.1 of proteins that constitute attractive targets for tumor immunotherapy.

Amino Acid Sequence↗
PubMed1990

Major histocompatibility complex antigens in human liver transplants.

Liver transplantation is performed successfully across major HLA differences between donor and recipient. This may be influenced by the organ specific expression of major histocompatibility complex (MHC) molecules which determine the local immune reactivity and rejection response. The tissue expression of MHC molecules on parenchymal and infiltrating cells has been studied in transplanted human liver using monoclonal antibodies and immunohistological methods. A strong induction of class I (HLA-A,B,C; beta 2-microglobulin) and class II (HLA-DR,DQ,DP) MHC antigens was demonstrated on hepatocytes, bile duct epithelium and endothelial cells during rejection episodes and viral and bacterial infections. The massive induction of donor antigens on hepatocytes, bile ducts and endothelia forms part of, and may also augment, the rejection response. During quiescent states without infection or rejection after transplantation, however, a rather restricted expression of class I and class II donor MHC antigens is present. In addition, the donor Kupffer cells and interstitial dendritic cells are gradually replaced by recipient accessory cells expressing self-MHC molecules. The changes in antigen density and distribution of donor MHC alloantigens as the replacement of accessory cells capable of presenting antigens to T-lymphocytes may influence the course of immune reactivity and the rejection response in the liver. This may partly explain the favourable clinical course long after transplantation. Preliminary clinical investigations of the effect of HLA matching have shown a dualistic effect of the matching of class I or class II HLA antigens. The role of HLA matching in liver transplants in large clinical studies, with specific immunological testing however, remains to be investigated. This may lead to prospective HLA matching with wider organ availability and improved preservation time in the future.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA Antigens↗
PubMed1988

Restriction fragment length polymorphism of DQ and DR class II genes of the bovine major histocompatibility complex.

DQ alpha, DQ beta, DR alpha and DR beta class II genes of the bovine major histocompatibility complex (MHC) were investigated by Southern blot hybridizations using human probes. Hybridizations of these probes to genomic DNA, digested with PvuII or TaqI, revealed extensive restriction fragment length polymorphisms (RFLPs). The polymorphisms were interpreted genetically by analysing a family material, comprising five sires, 48 dams and 50 offspring, and a population sample comprising 197 breeding bulls. The analysis resolved 20 DQ alpha, 17 DQ beta, 5 DR alpha and 25 DR beta RFLP types. The segregation data were consistent with simple Mendelian inheritance of the RFLPs. The analysis of the bull sample showed that it is possible to apply the RFLP method for routine typing of class II polymorphism in population samples. The linkage disequilibrium in the DQ-DR region was found to be extremely strong as only about 20 DQ and about 30 DQ-DR haplotypes were observed despite the large number of possible haplotypes. Close linkage to the blood group locus M was also found; the M' allele occurred in strong linkage disequilibrium with the class II haplotype DQ1BDR alpha 4DR beta 1B. A population genetic analysis of the DQ data in the sample of breeding bulls revealed that the frequency of homozygotes was significantly lower than Hardy-Weinberg expectation and that the allele frequency distribution deviated significantly from the one expected for selectively neutral alleles.

Alleles↗
PubMed1992

Association of the major histocompatibility complex with avian leukosis virus infection in chickens.

1. Association of the B blood group, the major histocompatibility complex (MHC) in chickens, with avian leukosis virus (ALV) infection shown by shedding of group-specific (gs) antigen was studied in an Australorp line selected for short oviposition interval to improve egg production. Three haplotypes (B8a, B9a and B21) were segregating in this line at frequencies of 66.7, 15.6 and 17.8%, respectively, averaged over three generations. 2. The relative risk (odds ratio) of a hen becoming a gs-antigen shedder was calculated for progenies of the dams shedding gs-antigen and those of non-shedding dams separately and pooled over three generations. In the progenies of shedding dams, the relative risk was not significantly different from 1.0 for the three haplotypes. In contrast, in the progenies of non-shedding dams, the relative risk was 0.67, 0.48 and 2.53 for B8a, B9a and B21, respectively, with the last two ratios being significantly different from 1.0. 3. The average effect of haplotype substitution on probability of shedding was estimated from a linear logistic model. The estimates (relative to zero for B8a) for B9a and B21, respectively, were -0.26 and 0.03 among the progenies of shedding dams, and -0.16 and 0.87 among the progenies of non-shedding dams. The last estimate only was highly significant. 4. These results suggest that the three haplotypes were similar in susceptibility to congenital infection through hatching eggs, but differed in susceptibility to post-hatching infection from other infected birds.

Animals↗
PubMedDate not supplied

A critical review of the role of the major histocompatibility complex in fertilization, preimplantation development and feto-maternal interactions.

From conception to old age, the major histocompatibility complex (MHC) is at the centre of immune responses that aid survival, fitness and adaptation of mammalian species to the environment. Its main function is that of controlling adaptive immunity, particularly T-cell-mediated immunity towards pathogens. In several species, including humans, the MHC is also able to elicit T-cell-mediated immune responses to allogeneic MHC antigens (non-self MHC antigens expressed by another individual from the same species). Although this phenomenon was originally identified in mice by the somewhat unnatural means of tissue transplantation, it was soon realized that it may also play an important role in the natural state, since the mammalian fetus in the maternal uterus is semi-allogeneic, due to the presence of MHC genes inherited from the father. Thus, during normal pregnancy the maternal immune system undergoes changes that lead to tolerance of the fetus. The MHC can play a dual role in the reproduction process: firstly influencing mating choice in some species, affecting the mother-father MHC matching; and secondly influencing the development of the fertilized ovum during the preimplantation period. In this review we examine the role of the MHC at three distinct levels: (i) MHC expression in gametes and its role in fertilization; (ii) MHC expression in placental tissue; and (iii) MHC expression in embryonic tissue. We suggest that the MHC plays a pleiotropic role, both in fitness (survival and reproductive success) and in development, thereby ensuring the survival of the species in future generations.

Animals↗
PubMed1995

Major histocompatibility complex control of the class of the immune response to the hapten trinitrophenyl.

This paper investigates major histocompatibility complex (MHC) regulation of the class of the immune response given in vitro and in vivo following immunization of the congenic BALB/k (H-2k) and BALB/c (H-2d) mice with the hapten trinitrophenyl (TNP). TNP-immune lymph node cells from BALB/k mice produced high levels of interferon-gamma (IFN-gamma), interleukin-5 (IL-5) and IL-2 when stimulated with TNP-antigen-presenting cells (APC) in vitro, while TNP-immune lymph node cells from BALB/c mice produced very low levels of these cytokines. No significant difference was found in antigen-specific production of IL-3, IL-4 and tumour necrosis factor-alpha (TNF-alpha). There was a strong correlation between the pattern of cytokine production in vitro and the secondary antibody production in vivo. Sera from BALB/k mice had anti-TNP IgG2a, IgG2b and IgG3 levels threefold greater, and anti-TNP IgA levels eightfold greater, than BALB/c mice. The level of specific IgG1 and IgE was only marginally raised in BALB/k mice. In contrast to these strain differences in cytokine and antibody production, there was no difference in two measures of cellular immunity: contact sensitivity in vivo and antigen-specific lymphocyte response in vitro. Our results suggest that there is a good correlation between the production of cytokines in vitro and antibody response in vivo, but not with measures of cellular immunity. Moreover, this MHC control of the class of the immune response to TNP does not fit into the T-helper type-1 (Th1)-Th2 paradigm.

Animals↗
PubMed1993

Loss of Th1-associated function in peripheral T cells but not thymocytes in tolerance to major histocompatibility complex alloantigen.

Mice of the strains A.TH and A.TL were rendered neonatally tolerant to class II major histocompatibility complex (MHC) by the injection of (A.TH x A.TL)F1 spleen and bone marrow cells within 24 hr of birth. Spleen and thymus cells from adult tolerant mice bearing long-term surviving skin grafts were compared with those from normal mice for their in vitro reactivity towards the tolerogen. In a primary mixed lymphocyte reaction (MLR), spleen cells from normal mice proliferated in response to 'tolerogen', generated cytotoxic cells and produced interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) but no IL-4 or IL-5. In contrast, although spleen cells from tolerant mice proliferated and produced IL-2, they failed to generate cytotoxic cells or produce IFN-gamma but produced large amounts of IL-4 and IL-5. The loss of the ability of tolerant cells to generate cytotoxicity or IFN-gamma was profound in that no activity was detected in a secondary MLR and mRNA for IFN-gamma could not be detected by reverse transcription polymerase chain reaction (RT-PCR). To see whether the alteration in function occurred centrally or peripherally, thymus cells from normal and tolerant mice were tested for function. Normal thymocytes produced IFN-gamma, IL-4 and IL-5 in a primary MLR and generated cytotoxic cells in a secondary MLR. In contrast to spleen cells, thymus cells from tolerant mice retained their ability to generate IFN-gamma or cytotoxic cells in response to tolerogen. Overall the results point to a profound switch in peripheral tolerogen-specific responses from a Th 1-biased response in normal mice to a Th2-biased response in tolerant mice and suggest that the alteration in function is post thymic.

Animals↗
PubMed1997

Characterization of immune response to Eimeria tenella antigens in a natural immunity model with hosts which differ serologically at the B locus of the major histocompatibility complex.

A model to simulate natural immunity to Eimeria tenella was developed in three chicken lines which differ at the B locus of the major histocompatibility complex. Homozygous, 1-day-old chicks of the B19B19, B24B24, or B30B30 genotype were trickle immunized by being orally fed a small infectious dose of E. tenella oocysts for 5 consecutive days. These naturally exposed birds were then challenged at different times between 5 and 24 days after the final dose, and the level of protection was assessed 6 days after challenge, using body weight gain and intestinal lesion scores. The duration of immunity in naturally exposed birds differed among the major histocompatibility complex lines. Trickle immunization of the B19B19 haplotype afforded the longest and strongest level of protection compared to the other two haplotypes tested. In addition, in vitro splenic and peripheral blood lymphocyte proliferative responses in trickle-immunized birds were measured against sporozoite, merozoite, and tissue culture-derived E. tenella parasite antigens isolated from the recently described SB-CEV-1/F7 established cell line. The lymphocytes obtained from B19B19 birds trickle immunized responded in vitro to the E. tenella-infected SB-CEV-1/F7 tissue culture-derived parasite antigen. Furthermore, antigen-specific immune responses appeared earlier in immune, challenged B19B19 birds than in their naive, challenged counterparts. The development of a model simulating natural immunization will serve as a foundation to further characterize both humoral and cell-mediated responses to E. tenella tissue culture-derived parasite antigens and to better understand host protective immune responses to avian coccidiosis.

Animals↗
PubMed1999

Fcgamma receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization.

Dendritic cells (DCs) express several receptors for the Fc portion of immunoglobulin (Ig)G (FcgammaR), which mediate internalization of antigen-IgG complexes (immune complexes, ICs) and promote efficient major histocompatibility complex (MHC) class II-restricted antigen presentation. We now show that FcgammaRs have two additional specific attributes in murine DCs: the induction of DC maturation and the promotion of efficient MHC class I-restricted presentation of peptides from exogenous, IgG-complexed antigens. Both FcgammaR functions require the FcgammaR-associated gamma chain. FcgammaR-mediated MHC class I-restricted antigen presentation is extremely sensitive and specific to immature DCs. It requires proteasomal degradation and is dependent on functional peptide transporter associated with antigen processing, TAP1-TAP2. By promoting DC maturation and presentation on both MHC class I and II molecules, ICs should efficiently sensitize DCs for priming of both CD4(+) helper and CD8(+) cytotoxic T lymphocytes in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

The alloantigenic organization of RT1Aa, a class I major histocompatibility complex molecule of the rat.

Over 300 monoclonal IgG alloantibodies have been prepared against RT1Aa , the class I major histocompatibility complex molecule of the DA rat. In this study a combination of techniques is exploited to show that all these antibodies can be allocated to 9 antigenic sites which form a continuous antigenic surface, that is, no site is completely isolated from the rest. The results suggest that techniques for the identification of antigenic sites using competitive inhibition of monoclonal antibody binding are generally valid, in the sense that competition between antibodies appears most commonly to represent competition between combining sites for a structural feature of the antigenic surface. From the distribution of antibodies between sites, it is clear that the RT1Aa molecule has three immunogenic areas against which nearly all the antibodies studied were directed. Of these areas one is both antigenically complex, consisting of four closely spaced sites, and remarkably immunodominant. Antibodies directed at sites between the major areas are extremely rare.

Animals↗
PubMed1993

Major histocompatibility complex genes have an increased brain expression after scrapie infection.

We have examined the expression of the major histocompatibility complex (MHC) antigens and related genes in scrapie-infected hamster brain. Both the class I and the class II MHC genes as well as the class II-associated invariant chain were found to have an increased brain expression after scrapie infection. The increased expression of the class I complex was immunohistochemically localized primarily to neurons, though some astrocytes contained much smaller amounts of the class I complex. While there is no detectable immune response to scrapie infection, the possibility that increased MHC expression affords some defense against the scrapie agent is discussed.

Animals↗
PubMed1993

Major histocompatibility complex and human papillomavirus type 16 E7 expression in high-grade vulvar lesions.

To determine whether expression of the human papillomavirus (HPV) type 16 E7 open reading frame influences expression of major histocompatibility complex (MHC) antigens on the surface of squamous epithelial cells, serial frozen sections from seven HPV type 16-positive, high-grade vulvar intraepithelial neoplasia (VIN 2-3) lesions were tested for viral transcription by RNA-RNA in situ hybridization, for MHC expression by immunohistochemical staining with antibodies to MHC class I and II molecules, and for keratinocyte differentiation by immunohistochemical staining with anti-filaggrin and cytokeratin 10 antibodies. Despite the histologic appearance of high-grade VIN lesions, expression patterns of cytokeratin 10 and filaggrin suggested a certain degree of keratinocyte differentiation in all specimens. These differentiation markers were especially prominent in parakeratotic and hyperkeratotic superficial areas, which did not express MHC antigens or contain E7 mRNA. Expression of MHC class I molecules within dysplastic tissues was greater than within HPV type 16-negative, normal vulvar epithelium from the same patients. In five of the VIN 2-3 specimens anti-MHC class I antibodies reacted more strongly with cells of the basal and suprabasal layers than with cells of the epithelial surface. In one lesion basal cells stained less intensively than surface cells, whereas in another specimen all epithelial layers were equally MHC class I positive. Staining with anti-MHC class II antibodies was generally restricted to isolated foci, representing invading lymphocytes, tissue macrophages, and Langerhans cells. In two lesions, however, there was heterogeneous keratinocyte expression of MHC class II proteins, perhaps due to inflammation. Major histocompatibility complex antigen detection was independent of the presence or distribution pattern of E7-specific transcripts. Hence, a correlation between MHC and E7 expression appears unlikely in warty VIN lesions.

Adult↗
PubMed1992

Solution binding of an antigenic peptide to a major histocompatibility complex class I molecule and the role of beta 2-microglobulin.

The major histocompatibility complex-encoded class I molecule, a noncovalent dimer of a polymorphic 45-kDa heavy chain and a nonpolymorphic 12-kDa beta 2-microglobulin (beta 2m) light chain, binds peptide antigen prior to its interaction with T-cell antigen receptors. We report here that the binding in aqueous solution at 37 degrees C of a soluble purified murine major histocompatibility complex class I protein, H-2Lds (a soluble analogue of H-2Ld consisting of the alpha 1 and alpha 2 domains of H-2Ld, the alpha 3 domain and the C terminus of Q10b), to an antigenic peptide is controlled by the light-chain subunit beta 2m. Analysis of the equilibrium binding data favors a model in which two classes of peptide binding sites exist, the high-affinity class having an equilibrium constant for dissociation, KH, of 3.7 x 10(-7) M and accounting for 12% of the theoretically available sites. Studies of binding in the presence of excess beta 2m indicate that this increases the concentration of available high-affinity sites. These data are consistent with a ternary model in which high-affinity sites are generated by the interaction of beta 2m with the peptide-binding class I heavy chain.

Amino Acid Sequence↗
PubMed1995

H-2M3a violates the paradigm for major histocompatibility complex class I peptide binding.

The major histocompatibility (MHC) class I-b molecule H-2M3a binds and presents N-formylated peptides to cytotoxic T lymphocytes. This requirement potentially places severe constraints on the number of peptides that M3a can present to the immune system. Consistent with this idea, the M3a-Ld MHC class I chimera is expressed at very low levels on the cell surface, but can be induced significantly by the addition of specific peptides at 27 degrees C. Using this assay, we show that M3a binds many very short N-formyl peptides, including N-formyl chemotactic peptides and canonical octapeptides. This observation is in sharp contrast to the paradigmatic size range of peptides of 8-10 amino acids binding to most class I-a molecules and the class I-b molecule Qa-2. Stabilization by fMLF-benzyl amide could be detected at peptide concentrations as low as 100 nM. While N-formyl peptides as short as two amino acids in length stabilized expression of M3a-Ld, increasing the length of these peptides added to the stability of peptide-MHC complexes as determined by 27-37 degrees C temperature shift experiments. We propose that relaxation of the length rule may represent a compensatory adaptation to maximize the number of peptides that can be presented by H-2M3a.

Amino Acid Sequence↗
PubMed1976

T cell-specific human alloantisera-detecting antigens segregating outside the major histocompatibility complex.

Two sera demonstrated non-HLA lymphocytotoxicity on the basis of reactivity with the cells of siblings genotypically identical to the serum donors for the major histocompatibility complex. These two sera, Bl and Caf, once contaminating HLA antibodies were removed by absorption with pooled platelets, demonstrated allogeneic lymphocytotoxicity that was restricted to T lymphocytes. Reactivity of the absorbed sera segregated independently of the major histocompatibility complex in 3 of 12 families tested. Unlike both cold lymphotoxins and HLA antibodies, the absorbed sera showed little temperature sensitivity against allogeneic cells, although reactivity of the Bl serum to autologous cells and to cells of the donor's HLA identical sibling did show a decrease with increasing temperature and restriction of activity to the 19S-containing fraction. Granulocytes were unreactive with the absorbed sera. Such sera may provide probes of minor transplantation antigens or markers, or both, of lymphoid subpopulations.

Adult↗
PubMed1990

Susceptibility or resistance to lysis by alloreactive natural killer cells is governed by a gene in the human major histocompatibility complex between BF and HLA-B.

The specificity recognized on normal allogeneic cells by a given alloreactive (1-anti-A) natural killer clone is controlled by a gene locus termed EC1. Because the EC1 locus was previously shown to be located on chromosome 6, families characterized by a recombinant major histocompatibility complex haplotype were analyzed to map this locus more precisely. The breakpoint of recombination was studied by standard HLA typing, complement typing, and restriction fragment length polymorphism analysis of a series of genes located between the complement cluster genes and HLA-B within the major histocompatibility complex region. Three of 10 families analyzed were informative. From the data obtained, the EC1 locus maps between BF and HLA-B and presumably is one of the normal genes recently described in this region.

Antigens, Differentiation↗
PubMed1992

Major histocompatibility complex (MHC)-encoded HAM2 is necessary for antigenic peptide loading onto class I MHC molecules.

The mutant murine lymphoma cell line RMA-S is unable to present endogenous antigens due to its inability to efficiently assemble class I major histocompatibility complex molecules and antigenic peptides. Therefore, it has been suggested that RMA-S cells are defective either in peptide generation or in peptide transport into the endoplasmic reticulum, where class I major histocompatibility complex molecule assembly is believed to occur. As proteasomes and the putative peptide transporters HAM1 and HAM2 have been implicated in class I antigen processing, we have investigated their expression in RMA-S and its wild-type counterpart RMA. Both proteasomes and HAM1 proteins are expressed at similar levels and show identical subcellular distributions in the two cell lines. However, only one copy of the HAM2 gene is present in RMA-S cells, and it contains a point mutation that leads to a premature stop codon. Thus, the HAM2 protein is absent from RMA-S cells. These data demonstrate that HAM2 is essential for peptide loading onto class I molecules.

Amino Acid Sequence↗