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PubMed1996

Major histocompatibility complex regulation of cytokine production.

This review describes the phenomenon of the major histocompatibility complex (MHC) control of cytokine production both in experimental animals and in humans. H-2 (mouse MHC) regulates which type of cytokine is selectively produced in response to the hapten trinitrophenyl (TNP). T cells from TNP-immune H-2k mice produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-3, IL-5, tumor necrosis factor-alpha (TNF-alpha), IL-10, and very low levels of IL-4 on reexposure to the specific antigen in vitro. By contrast, T cells from H-2d mice produce IL-3, TNF-alpha, IL-10, and IL-4 but very low levels of IL-2, IL-5 and IFN-gamma. As MHC-congenic matched strains (BALB/k and BALB/c) are used, this makes it unlikely that non-MHC genes influence the class of response observed. A similar pattern of haplotype regulation of cytokine production is observed in humans. In fact, peripheral blood mononuclear cells from HLA-B8,DR3-positive and negative individuals differ in their ability to produce IL-2, IL-5, and IFN-gamma on stimulation with the mitogen phytohemagglutinin while producing similar amounts of IL-4, IL-6, and IL-10. The following main considerations emerge from these observations. The MHC/peptide complex generated after antigen immunization, indicates which class of cytokine production is preferentially induced and, therefore, the outcome of the immune response. Furthermore, MHC genotype may affect cytokine production (and then immune responses) by completely different mechanism(s), that is, by an antigen-nonspecific control that does not depend on the ability of MHC molecules to bind in different ways the different peptides. Accurate control of the functional repertoire of an immune response is a critical parameter in response to infections as well as in immunopathology. MHC control of the class of the immune response at the level of cytokine production is a sophisticated way in which this occurs. This control might be involved in adaptive immune responses to infections as well as in immunopathology.

Animals↗
PubMed2001

The multiple roles of major histocompatibility complex class-I-like molecules in mucosal immune function.

The human major histocompatibility complex (MHC) on chromosome 6 encodes three classical class-I genes: human leukocyte antigens (HLA) A, B, and C. These polymorphic genes encode a 43- to 45-kDa cell surface glycoprotein that, in association with the 12-kDa beta2-microglobulin molecule, functions in the presentation of nine amino acid peptides to the T-cell receptor of CD8-bearing T lymphocytes and killer inhibitory receptors on natural killer cells. In addition to these ubiquitously expressed, polymorphic proteins, the human genome also encodes several nonclassical MHC class-I-like, or class Ib, genes that, in general, encode nonpolymorphic molecules involved in various specific immunological functions. Many of these genes, including CD1, the neonatal Fc receptor for IgG, HLA-G, HLA-E, the MHC class-I chain-related gene A, and Hfe, are prominently displayed on epithelial cells, suggesting an important role in epithelial cell biology.

CD8 Antigens↗
PubMed1988

Chromosomal localization of the major histocompatibility complex of the horse (ELA) by in situ hybridization.

The first gene assignment to a horse chromosome is reported for equine leucocyte antigen (ELA), the major histocompatibility complex of the horse. A cloned DNA sequence derived from a class I gene of the porcine major histocompatibility complex was used as a probe for an in situ hybridization experiment. We present the regional localization of ELA, using this sequence, to equine chromosome 20q14-q22.

Animals↗
PubMed2006

Marek's disease virus up-regulates major histocompatibility complex class II cell surface expression in infected cells.

Many herpesviruses modulate major histocompatibility complex (MHC) expression on the cell surface as an immune evasion mechanism. We report here that Marek's disease virus (MDV), a lymphotrophic avian alphaherpesvirus, up-regulates MHC class II cell surface expression in infected cells, contrary to all other herpesviruses examined to date. This MDV-induced class II up-regulation was detected both in vitro and in vivo. This effect was not solely an indirect effect of interferon, which is a highly potent natural inducer of MHC class II expression, since MHC class II up-regulation in cultured primary fibroblast cells was confined to the infected cells only. MHC class II up-regulation was also observed in infected cells of the bursa of Fabricius during the lytic phase of MDV infection in birds and upon reactivation of MDV from latency in an MDV-transformed cell line. As MDV is a strictly cell-associated virus and requires activated T cells for its life cycle, this up-regulation of MHC class II in infected cells may contribute to virus spread within the infected host by increasing the chance of contact between productively infected cells and susceptible activated T cells.

Animals↗
PubMed1993

Biochemical and serological identification of major histocompatibility complex antigens in outbred chickens.

Serology and biochemistry were used to identify major histocompatibility complex (MHC) types in chicken lines selected for high and low antibody response to sheep red blood cells. Serological typing was performed by direct haemagglutination, using antisera obtained by erythrocyte alloimmunization within the lines. Four serotypes were identified, called preliminarily B114, B119, B121 and B124. Subsequently, these types were characterized for their B-G and B-F products by biochemical analysis, using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and one-dimensional IEF (isoelectric focusing) respectively. The B114, B119 and B121 serotypes displayed each characteristic banding patterns for both B-G and B-F. No additional types or subtypes were identified by biochemistry within these serotypes. The B124 serotype however could be subtyped into three different haplotypes with specific banding patterns for B-G and B-F. None of the haplotypes in the selection lines were identical for both B-G and B-F with the tested reference B haplotypes. Comparison of B-G alleles revealed similar, but not identical B-G patterns for B114 and B-G14, whereas B124C and B-G23, as well as B119 and B-G19 displayed indistinguishable patterns. For B-F, only B121 and B-F21 banding patterns were indistinguishable by IEF. All other B-F types differed from the reference types.

Alleles↗
PubMed2002

Recruitment of heterogeneous nuclear ribonucleoprotein A1 in vivo to the LMP/TAP region of the major histocompatibility complex.

Sequences containing the matrix recognition signature were identified adjacent to the LMP/TAP gene cluster in the human and mouse major histocompatibility complex class II region. These sequences were shown to function as nuclear matrix attachment regions (MARs). Three of the five human MARs and the single mouse MAR recruit heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) in vivo during transcriptional up-regulation of the major histocompatibility complex class II genes. The timing of this recruitment correlates with a rise in mature TAP1 mRNA. Two of the human MARs bind hnRNP-A1 in vitro directly within a 35-bp sequence that shows over 90% similarity to certain Alu repeat sequences. This study shows that MARs recruit and bind hnRNP-A1 upon transcriptional up-regulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

Differential expression of HLA-DR, HLA-DP, and HLA-DQ antigenic determinants of the major histocompatibility complex in human endometrium.

We reported on the expression of HLA-DR molecules of the major histocompatibility complex in human endometrium. We now report on the expression of two other class II molecules, the HLA-DP and HLA-DQ determinants. These molecules were localized by monoclonal antibodies in 11 proliferative and 12 secretory endometria by avidin-biotin-complex (ABC) procedure. The expression of all three molecules was invariable and consistent throughout the entire menstrual cycle in endothelial and lymphoid cells. HLA-DR molecules were expressed in endometrial epithelium, particularly in the basalis in the mid to late proliferative phases of the cycle. In contrast, through the entire menstrual cycle, the expression of HLA-DP and HLA-DQ antigenic determinants was absent, and only occasionally a focal expression of these molecules was seen in endometrial epithelium. The in vitro induction of expression of the class II molecules in human endometrial epithelial cell cultures (HEE) by IFN-gamma was dose-dependent. After treatment with low doses of IFN-gamma, these cells primarily expressed HLA-DR molecules in vitro. The differential expression of the molecules of the major histocompatibility complex in human endometrial epithelium in vivo may be due to the differential sensitivity of th epithelium in response to cytokine(s).

Antibodies, Monoclonal↗
PubMed1989

Induction of antitumor immunity in mice by allo-major histocompatibility complex class I gene transfectant with strong antigen expression.

An allo-major histocompatibility complex class I gene (H-2Kb) was transfected to murine mastocytoma P1.HTR (P815 subline) cells, after which several transfectant clones were obtained. Two clones, which expressed a low level of H-2Kb antigen, grew well and killed the syngeneic DBA/2 mice when they were inoculated ip. These mice lived longer than the mice given injections of the parental P1.HTR tumor. However, one clone, which expressed a high level of H-2Kb antigen, was rejected completely by the syngeneic DBA/2 mice and induced a generation of H-2Kb-specific cytotoxic T cells. Interestingly, the mice that had rejected the clone with high H-2Kb expression received strong anti-tumor immunity for rejection of the parental P1.HTR tumor challenged at the high dose.

Animals↗
PubMed1984

DNA polymorphism of the C4 genes. A new marker for analysis of the major histocompatibility complex.

Polymorphisms of the proteins encoded by genes that lie within the major histocompatibility complex (MHC) have served as useful markers for organ transplantation and in genetic analysis of a large number of MHC-linked diseases. To extend the range of MHC polymorphic markers, we used a complementary-DNA probe specific for the fourth component of human complement (C4) to identify a new variant within the MHC. Polymorphic variants at the DNA level were detected among subjects with identical phenotypes of the corresponding protein. C4 genomic polymorphisms are inherited with the segment of the short arm of chromosome 6 that carries the HLA-DR and complement loci. The autosomal codominant mode of inheritance of this genetic marker and its utility for evaluation of 21-hydroxylase-deficiency congenital adrenal hyperplasia, one of the many MHC-linked diseases, were established.

Adrenal Hyperplasia, Congenital↗
PubMed1991

Genetic control of sex-dependent meiotic recombination in the major histocompatibility complex of the mouse.

Meiotic recombination within the proximal region of the major histocompatibility complex (MHC) of the mouse is not random but occurs in clusters at certain restricted sites, so-called recombinational hotspots. The wm7 haplotype of the MHC, derived from the wild mouse, enhances recombination specifically during female meiosis within a fragment of 1.3 kb of DNA located between the A beta 3 and A beta 2 genes in genetic crosses with laboratory haplotypes. Previous studies revealed no significant strain differences in nucleotide sequences around the hotspot, irrespective of the ability of the strain to enhance the recombination. It appeared that a distant genetic element might, therefore, control the rate of recombination. In the present study, original recombinants whose breakpoints were defined by direct sequencing of PCR-amplified DNAs were tested for the rate of secondary recombination in the crosses with laboratory strains in order to determine the location of such a genetic element. The results clearly demonstrated that the chromosomal segment proximal to the hotspot is essential for enhancement of recombination. Moreover, the male recombination is suppressed by a segment distal to the hotspot.

Alleles↗
PubMed1996

[Expression of major histocompatibility complex of advanced non-small cell lung cancer (NSCLC)].

Expression of major histocompatibility complex of lung cancer was examined to study the malignant potential of the tumor using immunochemical staining (anti-HLA class I monoclonal antibody; w6/32). Nuclear DNA contents and the labeling index of proliferating cell nuclear antigen (PCNA) were measured as well. Forty three advanced (p-stage IIIa) lung cancers resected by lobectomy (33 cases), pneumonectomy (9 cases), and segmentectomy (1 case) entered the study. Mediastinal lymph node dissection was performed in every case during the operation. Of the 43 cases, expression of HLA class I was positive in 17 and negative in 26. The patients with positive HLA expression showed significantly better prognosis than those with negative HLA expression in terms of 5 year survival (p < 0.01). The patients with aneuploid pattern and positive HLA class I expression had the best prognosis on the survival curve (p < 0.01). When the PCNA positive rate was high, the prognosis was poor. And the patients with negative PCNA and positive HLA class I expression had significantly better prognosis than the others (p < 0.01). These findings suggest that the expression of HLA class I on the tumor cells is an important prognostic factor in the patients with NSCLC.

Carcinoma, Non-Small-Cell Lung↗
PubMed2003

Genetic variation of microsatellite loci in the major histocompatibility complex (MHC) region in the southeast Asian house mouse (Mus musculus castaneus).

Major histocompatibility complex (MHC) genes are the most polymorphic loci known for vertebrates. Here we employed five microsatellite loci closely linked to the MHC region in an attempt to study the amount of genetic variation in 19 populations of the southeast Asian house mouse (Mus musculus castaneus) in Taiwan. The overall polymorphism at the five loci was high (He = 0.713), and the level of polymorphism varied from locus to locus. Furthermore, in order to investigate if selection is operating on MHC genes in natural mouse populations, we compared the extent and pattern of genetic variation for the MHC-linked microsatellite loci (the MHC loci) with those for the microsatellite loci located outside the MHC region (the non-MHC loci). The number of alleles and the logarithm of variance in repeat number were significantly higher for the MHC loci than for the non-MHC loci, presumably reflecting linkage to a locus under balancing selection. Although three statistical tests used do not provide support for selection, their lack of support may be due to low statistical power of the tests, to weakness of selection, or to a profound effect of genetic drift reducing the signature of balancing selection. Our results also suggested that the populations in the central and the southwestern regions of Taiwan might be one part of a metapopulation structure.

Animals↗
PubMed2000

SNP profile within the human major histocompatibility complex reveals an extreme and interrupted level of nucleotide diversity.

The human major histocompatibility complex (MHC) is characterized by polymorphic multicopy gene families, such as HLA and MIC (PERB11); duplications; insertions and deletions (indels); and uneven rates of recombination. Polymorphisms at the antigen recognition sites of the HLA class I and II genes and at associated neutral sites have been attributed to balancing selection and a hitchhiking effect, respectively. We, and others, have previously shown that nucleotide diversity between MHC haplotypes at non-HLA sites is unusually high (>10%) and up to several times greater than elsewhere in the genome (0.08%-0.2%). We report here the most extensive analysis of nucleotide diversity within a continuous sequence in the genome. We constructed a single nucleotide polymorphism (SNP) profile that reveals a pattern of extreme but interrupted levels of nucleotide diversity by comparing a continuous sequence within haplotypes in three genomic subregions of the MHC. A comparison of several haplotypes within one of the genomic subregions containing the HLA-B and -C loci suggests that positive selection is operating over the whole subgenomic region, including HLA and non-HLA genes. [The sequence data for the multiple haplotype comparisons within the class I region have been submitted to DDBJ/EMBL/GenBank under accession nos. AF029061, AF029062, and AB031005-AB031010. Additional sequence data have been submitted to the DDBJ data library under accession nos. AB031005-AB03101 and AF029061-AF029062.]

Base Composition↗
PubMed2003

Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse.

In mammals, the Major Histocompatibility Complex class I and II gene clusters are separated by an approximately 700-kb stretch of sequence called the MHC class III region, which has been associated with susceptibility to numerous diseases. To facilitate understanding of this medically important and architecturally interesting portion of the genome, we have sequenced and analyzed both the human and mouse class III regions. The cross-species comparison has facilitated the identification of 60 genes in human and 61 in mouse, including a potential RNA gene for which the introns are more conserved across species than the exons. Delineation of global organization, gene structure, alternative splice forms, protein similarities, and potential cis-regulatory elements leads to several conclusions: (1) The human MHC class III region is the most gene-dense region of the human genome: >14% of the sequence is coding, approximately 72% of the region is transcribed, and there is an average of 8.5 genes per 100 kb. (2) Gene sizes, number of exons, and intergenic distances are for the most part similar in both species, implying that interspersed repeats have had little impact in disrupting the tight organization of this densely packed set of genes. (3) The region contains a heterogeneous mixture of genes, only a few of which have a clearly defined and proven function. Although many of the genes are of ancient origin, some appear to exist only in mammals and fish, implying they might be specific to vertebrates. (4) Conserved noncoding sequences are found primarily in or near the 5'-UTR or the first intron of genes, and seldom in the intergenic regions. Many of these conserved blocks are likely to be cis-regulatory elements.

Alternative Splicing↗
PubMed1998

Expression of major histocompatibility complex class II antigen in neoplastic cells of canine cutaneous histiocytoma.

Forty five cases of canine cutaneous histiocytoma (CCH) were examined by immunohistology for expression and distribution of major histocompatibility complex (MHC) class II antigen in neoplastic cells. In addition, expression of lysozyme and calprotectin (leucocyte protein L1) in neoplastic cells was investigated. Furthermore, B and T lymphocytes were demonstrated by antibodies against the CD3 antigen, IgG, and IgM. Neoplastic cells showed two staining patterns for MHC class II antigen: focal juxtanuclear cytoplasmic staining and/or rim-like staining along the cell periphery. In 24 cases, a predominant or exclusive focal juxtanuclear cytoplasmic MHC class II antigen reaction in neoplastic cells, and the presence of few diffusely distributed infiltrating CD3 antigen-positive T lymphocytes were observed. Tumors with numerous neoplastic cells exhibiting staining for MHC class II antigen along the cell periphery (n = 21) showed increased inflammatory alterations, represented by disseminated and nodular infiltrations of mainly CD3 antigen-positive T cells. B cells, plasma cells, exudate macrophages, and neutrophils were rarely seen disseminated between neoplastic cells whereas their number increased within focal inflammatory infiltrates. The focal cytoplasmic reaction for MHC class II antigen in neoplastic cells might represent newly synthesized MHC class II molecules stored in vesicles, whereas staining of the cell periphery might occur due to accumulation of MHC class II molecules along the plasma membrane. The increasing expression of MHC class II molecules on the cell surface might be the decisive factor for onset and progression of tumor regression. However, the exact mechanism of priming and activation of T cells by neoplastic cells and the nature of the presented antigen are not yet known.

Animals↗
PubMed2005

The turnover kinetics of major histocompatibility complex peptides of human cancer cells.

Peptides presented by the major histocompatibility complex (MHC) are derived from the degradation of cellular proteins. Thus, the repertoire of these peptides (the MHC peptidome) should correlate better with the cellular protein degradation scheme (the degradome) than with the cellular proteome. To test the validity of this statement and to determine whether the majority of MHC peptides are derived from short lived proteins, from defective ribosome products, or from regular long lived cellular proteins we analyzed in parallel the turnover kinetics of both MHC peptides and cellular proteins in the same cancer cells. The analysis was performed by pulse-chase experiments based on stable isotope labeling in tissue culture followed by capillary chromatography and tandem mass spectrometry. Indeed only a limited correlation was observed between the proteome and the MHC peptidome observed in the same cells. Moreover a detailed analysis of the turnover kinetics of the MHC peptides helped to assign their origin to normal, to short lived or long lived proteins, or to the defective ribosome products. Furthermore the analysis of the MHC peptides turnover kinetics helped to direct attention to abnormalities in the degradation schemes of their source proteins. These observations can be extended to search for cancer-related abnormalities in protein degradation, including those that lead to loss of tumor suppressors and cell cycle regulatory proteins.

Amino Acid Sequence↗
PubMed1990

Gene imprinting and major histocompatibility complex class I antigen expression in the rat placenta.

Ultrastructural immunocytochemical studies of the expression of major histocompatibility complex class I antigens in the placentas of inbred rats were performed using placentas derived from natural matings and from embryo transfers into females made pseudopregnant by mechanical stimulation. The studies utilized the WF (u) and DA (a) strains and monoclonal antibodies to all of the class I antigens involved. All four mating combinations of the two strains showed that only paternal antigens were expressed in the placenta and that they were limited to the basal trophoblast. This conclusion was confirmed using embryo transfer experiments. In allogeneic natural matings, the allele-specific class I transplantation antigens were not expressed on the membrane of the basal trophoblast but they were expressed in embryo transfers involving embryos of the same genotype. In both types of pregnancies, the pregnancy-associated (Pa) antigen was present on the membrane of the basal trophoblast. The antibody response to DA X DA and to WF X DA embryos transferred into pseudopregnant WF females was against the allele-specific RT1.Aa antigen and the Pa antigen, whereas the antibody response to the heterozygous embryo in the natural WF (female) X DA (male) mating was against the Pa antigen only. These results are consistent with the hypothesis that the suppression of the expression of the allele-specific major histocompatibility complex class I antigens occurs shortly after fertilization and that it requires the uterine environment of a natural mating.

Animals↗
PubMed1998

Cathepsins B and D are dispensable for major histocompatibility complex class II-mediated antigen presentation.

Antigen presentation by major histocompatibility complex (MHC) class II molecules requires the participation of different proteases in the endocytic route to degrade endocytosed antigens as well as the MHC class II-associated invariant chain (Ii). Thus far, only the cysteine protease cathepsin (Cat) S appears essential for complete destruction of Ii. The enzymes involved in degradation of the antigens themselves remain to be identified. Degradation of antigens in vitro and experiments using protease inhibitors have suggested that Cat B and Cat D, two major aspartyl and cysteine proteases, respectively, are involved in antigen degradation. We have analyzed the antigen-presenting properties of cells derived from mice deficient in either Cat B or Cat D. Although the absence of these proteases provoked a modest shift in the efficiency of presentation of some antigenic determinants, the overall capacity of Cat B-/- or Cat D-/- antigen-presenting cells was unaffected. Degradation of Ii proceeded normally in Cat B-/- splenocytes, as it did in Cat D-/- cells. We conclude that neither Cat B nor Cat D are essential for MHC class II-mediated antigen presentation.

Animals↗