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PubMed2002

Pregnancy and interferon tau regulate major histocompatibility complex class I and beta2-microglobulin expression in the ovine uterus.

Major histocompatibility complex (MHC) class I molecules, consisting of an alpha chain and beta2-microglobulin (beta2MG), play an important role in immune rejection responses by discriminating self and nonself and are increased by type I interferons during antiviral responses. Interferon tau (IFNtau), the pregnancy-recognition signal in ruminants, is a type I interferon produced by the ovine conceptus between Days 11 and 21 of gestation. In study 1, expression of MHC class I alpha chain and beta2MG mRNA and protein was detected primarily in endometrial luminal epithelium (LE) and glandular epithelium (GE) on Days 10 and 12 of the estrous cycle and pregnancy. On Days 14-20 of pregnancy, MHC class I and beta2MG expression increased only in endometrial stroma and GE and, concurrently, was absent in LE and superficial ductal GE (sGE). Although neither MHC class I nor beta2MG proteins were detected in Day 20 trophectoderm, beta2MG mRNA was detected in conceptus trophectoderm. In study 2, cyclic ewes were ovariectomized on Day 5, treated daily with progesterone to Day 16, received intrauterine infusions between Days 11 and 16 of either control serum proteins or recombinant ovine IFNtau, and were hysterectomized on Day 17. The IFNtau increased MHC class I and beta2MG expression only in endometrial stroma and GE. During pregnancy, MHC class I and beta2MG gene expression is inhibited in endometrial LE and sGE but, paradoxically, is stimulated by IFNtau in the stroma and GE. The silencing of MHC class I alpha chain and beta2MG genes in the endometrial LE and sGE during pregnancy recognition and establishment may be a critical mechanism preventing immune rejection of the conceptus allograft.

Animals↗
PubMed1991

Class II major histocompatibility complex genes of the sheep.

The class II genes of the sheep major histocompatibility complex (MHC) have been cloned from two unrelated heterozygous sheep into cosmid vectors. By restriction mapping and hybridization with a number of class II probes of human and mouse origin, the cloned genetic material has been assigned to seven distinct alpha genes, 10 distinct beta genes and 14 beta-related sequences. It was difficult to identify homologues of specific HLA class II genes because of a tendency for the ovine genes to cross-hybridize between HLA probes representing different loci. Such cross-hybridization was especially marked among the beta genes. While DQ and DR homologues have been tentatively identified by several criteria, no genes corresponding to DP have been identified. Cosmids containing class II alpha and beta genes have been transfected into mouse LTK- cells, and surface expression of a sheep class II molecule has been obtained.

Animals↗
PubMed1993

Isolation, characterization and evolution of ovine major histocompatibility complex class II DRA and DQA genes.

Four full-length ovine major histocompatibility complex (MHC) class II A cDNA clones coding for new alleles of DRA, DQA1 and DQA2 genes were isolated from two ovine lambda gt10 cDNA libraries. The derived amino acid sequences of these clones resemble class II A molecules from other species in both size and structure. Restriction fragment length polymorphism analysis, using an Ovar-DRA probe on DNA from Merino and Romney sheep revealed only limited polymorphism in contrast to the high levels of polymorphism revealed by Ovar-DQA probes. Comparison of the predicted amino acid sequences for the three ovine A genes with class II A genes from five other species revealed that the most variable region of the molecule is the signal peptide. Although virtually every amino acid site shows variation, within or between species, there are some blocks of highly conserved residues. Within gene comparisons of nucleotide differences reveal that the greatest number of changes is found between the alleles of Ovar-DQA1 and -DQA2 genes and the least between Ovar-DRA1 alleles. Phylogenetic analysis of class II A sequences from several species place DRA and DQA genes on two distinct branches, with Ovar-DRA1 and BOLA-DRA, and Ovar-DQA1 and BOLA-DQA being most similar on their respective branches.

Alleles↗
PubMed1990

Antigens of the major histocompatibility complex in patients with chronic discoid lupus erythematosus.

The frequencies of the major histocompatibility complex class I, class II and class III antigens were determined in 130 patients (88 women and 42 men) with chronic discoid lupus erythematosus, and compared with those of 764 healthy controls. A significant increase in HLA-B7 (38.0% in the patients vs. 25.8% in the control group), HLA-B8 (29.5% vs. 17.4%), HLA-Cw7 (58.9% vs. 26.1%), HLA-DR2 (46.9% vs. 29.7%), HLA-DR3 (32.0% vs. 19.4%), HLA-DQw1 (76.6% vs. 60.5%), and a decrease in HLA-A2 (41.9% vs. 55.7%) was found. The calculated relative risk values for the respective antigens markedly increased when two or more antigens were present in one patient, with a maximum relative risk value of 7.4 for the combinations of HLA-Cw7, DR3, DQw1 and HLA-B7, Cw7 and DR3, which were found in 17.2% of the patients and in only 2.3% of the controls.

Chronic Disease↗
PubMed1989

Selection for polymorphism in the antigen recognition site of major histocompatibility complex class II molecules.

The genetic basis for the extensive polymorphism of major histocompatibility complex (MHC) class II molecules was investigated by statistical analysis. Nucleotide sequences of human DQA1, DQB1, DRB1, and DRB3 genes and murine A alpha, A beta, and E beta genes were used. The results show that polymorphism is selected for in the antigen recognition site of class II molecules since replacement substitutions in this region were found to occur at a significantly higher frequency than expected in the absence of selection. In contrast, replacement substitutions are selected against in the remaining part of the first domain exon and in the second domain exon. Furthermore, comparing the sequence variability pattern among different class II alpha and beta sequences, using a variability index for each residue, showed that, with few exceptions, highly polymorphic residues occur in the antigen recognition site. There was a strong and highly significant correlation in the variability pattern in the homologous DRB/E beta sequences but not for DQB/A beta or DQA/A alpha sequences. This difference may be related to the fact that both alpha and beta chains of DQ/A molecules are polymorphic, while only beta chains of DR/E molecules vary.

Amino Acid Sequence↗
PubMed1999

The role of H2-O and HLA-DO in major histocompatibility complex class II-restricted antigen processing and presentation.

The function of major histocompatibility complex (MHC) class II molecules is to sample exogenous antigens for presentation to CD4+ T helper cells. After synthesis in the endoplasmic reticulum, class II molecules are directed into the endosomal system by association with the invariant chain (Ii), which is sequentially cleaved, generating class II dimers loaded with Ii-derived peptides (CLIP). These class II-peptide complexes are physiological substrates for H2-M/HLA-DM, a resident of the endosomal/lysosomal system which facilitates the removal of CLIP from newly synthesised class II alpha beta dimers. Exchange of CLIP for antigenic class II-binding peptides is also promoted by the action of H2-M/HLA-DM, resulting in stable peptide-class II complexes that are transported to the cell surface for presentation to CD4+ T cells. Recent evidence suggests that this H2-M/HLA-DM-mediated 'peptide editing' is influenced by another MHC class II-encoded molecule, H2-O/HLA-DO. This non-polymorphic alpha beta heterodimer is associated with H2-M/HLA-DM during intracellular transport and within the endosomal system of B cells. H2-O/HLA-DO alters the peptide exchange function of H2-M/HLA-DM in a pH-dependent manner, so that H2-M/HLA-DM activity is limited to more acidic conditions, corresponding to lysosomal compartments. Indeed, H2-O/HLA-DO may serve to limit the presentation of antigens after fluid phase uptake by B cells, while augmenting presentation of antigens internalised via membrane Ig receptors. Such a mechanism may maintain the fidelity of the B-cell-CD4+ T-cell interaction, counteracting self reactivity arising from less stringent lymphocyte activation. Here, data evaluating the role of H2-O/HLA-DO shall be reviewed and its putative function discussed.

Animals↗
PubMed1999

Major histocompatibility complex class I genes in primates: co-evolution with pathogens.

The major histocompatibility complex (MHC) is the most polymorphic genetic system known, playing a central role in the cellular immune response to pathogens. The relationship between the MHC of humans and non-human primates has increased our understanding of MHC evolution and how polymorphism of this gene family may have been generated. We will review MHC class I evolution in great apes and Old World and New World primates and discuss new data from the simian immunodeficiency virus/rhesus monkey animal model that demonstrate the role of MHC class I alleles in selecting for new populations of viruses. This suggests that certain pathogens co-evolve with the MHC class I molecules they encounter in a population.

Amino Acid Sequence↗
PubMed1995

Binding motifs predict major histocompatibility complex class II-restricted epitopes in the Sendai virus M protein.

Major histocompatibility complex (MHC) class I ligand motifs have been defined for a number of class I molecules and have been successfully used to identify class I-restricted cytotoxic T-cell epitopes. In contrast, the relative degeneracy of sequence motifs in naturally processed MHC class II ligands has suggested that they may be of more limited use. Here, we use a predicted I-Ab ligand motif to identify antigenic peptides in the Sendai virus Enders strain matrix (M) protein. The entire coding sequence of the M protein was derived, and seven peptide sequences that contained the predicted I-Ab motif were identified. Analysis of I-Ab-restricted M-specific T-cell hybridomas for reactivity to these synthetic peptides identified two distinct epitopes. These data demonstrate that MHC class II motifs can be valuable in predicting T-cell epitopes.

Amino Acid Sequence↗
PubMed2001

Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis.

HFE is a nonclassical class I major histocompatibility complex (MHC) molecule that is mutated in the autosomal recessive iron overload disease hereditary hemochromatosis. There is evidence linking HFE with reduced iron uptake by the transferrin receptor (TfR). Using a panel of HFE and TfR monoclonal antibodies to examine human HFE (hHFE)-expressing cell lines, we demonstrate the expression of stable and fully glycosylated TfR-free and TfR-associated hHFE/beta2m complexes. We show that both the stability and assembly of hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MHC molecules. HCMV US2, but not US11, targets HFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined. The reduced expression of classical class I MHC and HFE complexes provides the virus with an efficient tool for altering cellular metabolism and escaping certain immune responses.

Amino Acid Sequence↗
PubMed1991

Identification of cis sequences controlling efficient position-independent tissue-specific expression of human major histocompatibility complex class I genes in transgenic mice.

We previously reported that genomic major histocompatibility complex class I human leukocyte antigen (HLA)-B7 gene constructs with as little as 0.66 kb of 5'- and 2.0 kb of 3'-flanking DNA were expressed efficiently and appropriately in transgenic mice. To identify and characterize the relevant cis-acting regulatory elements in more detail, we have generated and analyzed a series of transgenic mice carrying native HLA-B7 genes with further 5' truncations or intronic deletions and hybrid constructs linking the 5'-flanking region of B7 to a reporter gene. We were unable to detect a specific requirement for sequence information within introns 2 to 7 for either appropriate constitutive or inducible class I expression in adult animals. The results revealed the presence of cis-acting regulatory sequences between -0.075 kb and -0.66 kb involved in driving efficient copy number-dependent constitutive and gamma interferon-enhanced tissue-specific expression. The region from -0.11 to -0.66 kb is also sufficient to prevent integration site-specific "position effects," because in its absence HLA-B7 expression is frequently detected at significant levels at inappropriate sites. Conserved sequence elements homologous to the H-2 class I regulatory element, or enhancer A, and the interferon response sequence are located between about -151 and -228 bp of the B7 gene. Our results also indicate the existence of sequences downstream of -0.11 kb which can influence the pattern of tissue-specific expression of the HLA-B7 gene and the ability of this gene to respond to gamma interferon.

Animals↗
PubMed1989

Immune induction of major histocompatibility complex antigens on a human thyroid cell line (SGHTL-34).

Expression of major histocompatibility complex antigens by epithelial cells may play a role in the aetiology of autoimmune disorders. We have studied the effect of gamma-interferon on SGHTL-34, a human thyroid cell line which constitutively expresses class I but not class II antigens. gamma-Interferon induced the expression of class II and increased the expression of class I molecules (assessed by flow cytofluorimetry) in a dose-dependent manner. Thyrotrophin or phytohaemagglutinin had no effect on either class I or class II expression. However, a supernatant from phytohaemagglutinin-stimulated peripheral blood mononuclear cells, containing 6400 U gamma-interferon/ml, was an effective inducer of both class I and class II antigens. These data clarify earlier studies using primary thyroid cultures, which are contaminated with cells of the immune system.

Cell Line↗
PubMed1991

Regulation of the expression of major histocompatibility complex class I genes in human colorectal cancer.

Products encoded by the major histocompatibility complex class I genes are down-regulated in many tumors. The under-representation of HLA antigens in human tumors is usually associated with a poor prognosis. In this report, the expression of HLA genes in human colorectal carcinomas was studied using HLA-A and HLA-B locus-specific probes. Over 50% of the colorectal carcinomas studied showed a reduction in the amount of steady-state HLA mRNA. For some carcinomas, non-coordinated regulation of the HLA-A and HLA-B genes was observed. The HLA expression in some, but not all cases, could be enhanced by gamma-interferon. Over 60% of the colorectal carcinomas also expressed high level of the c-myc oncogene mRNA. However, no correlation could be made between the increase of c-myc expression and the down-regulation of the HLA genes.

Carcinoma↗
PubMed1987

Monoclonal antibodies to human major histocompatibility complex class II antigens.

The production and characterization of monoclonal antibodies to major histocompatibility complex (MHC) class II molecules have contributed significantly to delineating the number and structure of gene products of the D region of HLA. The "first generation" of class II monoclonal antibodies detected monomorphic determinants, often reacting with multiple class II loci gene products. Later generations of anti-class II monoclonal detected serologic specificities like those previously detected by human alloantisera. In addition, numerous antibodies have been generated against polymorphic HLA class II determinants which have not been previously described using human allosera. Biochemical analysis utilizing techniques such as radiolabeling and immunoprecipitation, one- and two-dimensional gel electrophoresis, Western blotting, limited N-terminal amino acid sequencing, and peptide mapping have localized the epitopes detected by polymorphic anti-class II monoclonals to various class II locus gene products. Such analyses with monoclonal antibodies have also identified class II gene products previously identified only with cellular reagents. The fact that several monoclonal antibodies with similar serologic specificity detect different class II locus gene products underscores the complexity of the HLA-D region and suggests some possible mechanisms for the generation of polymorphisms in this region.

Antibodies, Monoclonal↗
PubMed1984

Recognition and response to alloantigens in vivo. I. Negative and positive selection of MLR reactivity in murine peripheral blood lymphocytes to major histocompatibility complex and Mls antigens.

Specific mixed lymphocyte reaction (MLR) responsiveness to allogeneic major histocompatibility complex (MHC), or minor lymphocyte-stimulating (Mls) determinants, was depleted in the peripheral blood lymphocytes (PBL) obtained from mice 24 to 48 hr after i.v. injection of 5 to 7.5 X 10(7) MHC or Mlsa-incompatible spleen cells, respectively. Results of cell mixture experiments suggest that the generation of suppressor cells was not the explanation for this specific reduction in MLR proliferation occurring with these PBL responder cells. To gain additional insight into parameters involved in the recognition of allodeterminants in vivo, experimental manipulations of the host environment and donor cell inoculum utilized in the negative selection procedure were employed. For example, removal of the spleen in the recipient animal, an anatomic site in which injected allogeneic cells and corresponding host antigen-reactive cells (ARC) are trapped, still permitted the specific depletion in murine PBL of host ARC for donor foreign MHC antigens. This finding may implicate other sites such as the liver where unprimed host alloreactive clones are trapped. In addition, irradiation of allogeneic donor cells significantly reduced their capacity to trap alloreactive T cell clones in vivo, whereas heat treatment of the donor cells completely eliminated this ability, even though the Ia determinants were still expressed, measured by flow cytometry. After the negative selection period, kinetic analysis of proliferation showed that 3, 4, or 5 days after injection of MHC-incompatible allogeneic spleen cells, the PBL of the recipient showed specific hyperresponsiveness to the MHC-haplotype of the donor cells. Interestingly, these primed PBL responder cells had the volume distribution of small resting cells; thoracic duct lymphocytes (TDL), positively selected by adoptive transfer of T cells to irradiated semiallogeneic recipients, are reported to be mainly blast cells. In contrast to the MLR hyperresponsiveness that results from priming with MHC-incompatible splenocytes, PBL, obtained at these later time points from mice primed with Mlsa-incompatible, H-2-compatible splenocytes, showed complete unresponsiveness in MLR to these Mlsa-bearing stimulator cells, as well as some nonspecific reduction in proliferation to MHC-incompatible stimulator cells regardless of their Mls genotype.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients.

Major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) is a rare inborn error of the immune system characterized by impaired antigen presentation and combined immunodeficiency. It causes severe and unremitting infections leading to progressive liver and lung dysfunctions and death during childhood. As in other combined immunodeficiency disorders, bone marrow transplantation (BMT) is considered the treatment of choice for MHC class II deficiency. We analyzed the files of 19 patients who have undergone BMT in our center. Of the 7 patients who underwent HLA-identical BMT, 3 died in the immediate posttransplant period of severe viral infections, whereas the remaining 4 were cured, with recovery of normal immune functions. Of the 12 patients who underwent HLA-haplo-identical BMT, 3 were cured, 1 was improved by partial engraftment, 7 died of infectious complications due to graft failure or rejection, and 1 is still immunodeficient because of engraftment failure. A favorable outcome in the HLA-non-identical BMT group was associated with an age of less than 2 years at the time of transplantation. All the patients with stable long-term engraftment had persistently low CD4 counts after transplantation (105 to 650/microL at last follow up), but no clear susceptibility to opportunistic infections despite persisting MHC class II deficiency on thymic epithelium and other nonhematopoietic cells. We conclude that HLA-identical and -haploidentical BMT can cure MHC class II deficiency, although the success rate of haploidentical BMT is lower than that in other combined immunodeficiency syndromes. HLA-haploidentical BMT should preferably be performed in the first 2 years of life, before the acquisition of chronic virus carriage and sequelae of infections.

Bone Marrow Transplantation↗
PubMed1994

[Human major histocompatibility complex: the HLA system].

The HLA (human leukocyte antigens) system, or human major histocompatibility complex, is the most polymorphic functional genetic entity known at present. It consists of HLA class I genes and molecules (A, B and C) which control CD8+ cell-mediated antiviral responses, and class II genes and molecules (DR, DQ and DP) which control CD4+ cell responses (anti-bacterial and anti-toxin). HLA molecules function by presenting antigenic peptides to CD8+ cells (class I) and CD4+ cells (class II). Antigen presentation depends on the intracellular location of the antigen. Antigens present in the exocytosis pathway are presented by class I molecules, while class II molecules present antigens associated with the endocytosis pathway. More than 200 alleles have been detected by means of serological testing (microlymphocytotoxicity) and biochemical methods (IEF) in the HLA class I system, and now by means of molecular biology techniques for class II molecules (PCR-SSO and PCR-RFLP). This molecular typing has revealed the amino acids in HLA molecules that confer genetic susceptibility or resistance to numerous HLA-associated diseases. This is the case for example of ankylosing spondylitis (region 45-46 of HLA-B27 molecules), juvenile diabetes (aa 57 of D beta Q) and rheumatoid arthritis (aa 65-71 of DR beta). Thus, the HLA system is a genetic tool for diagnostic and therapeutic decision-making.

Animals↗
PubMedDate not supplied

Major histocompatibility complex class II deficiency needs an early diagnosis: report of a case.

Major histocompatibility complex (MHC) class II deficiency is a rare primary immunodeficiency disorder characterized by defects in human leukocyte antigen class II expression, inconsistent expression of human leukocyte class I molecules, and a lack of cellular and humoral immune responses to foreign antigens. Clinical onset occurs early in life with recurrent infections and chronic diarrhea. The prognosis is poor, and mean age at the time of death is 4 years. The only curative treatment is bone marrow transplantation (BMT), which allows the immune system's reconstitution. BMT should be done early in life, because long-term survival seems to depend on the number of previous viral infections. We report the case of an MHC class II deficiency discovered late in a 4-year-old girl by means of immunohistochemistry of small bowel biopsy revealing the absence of MHC class II expression. The child received a BMT twice but died because of a overwhelming viral infection. This case underlines the necessity to explore children presenting with infections and chronic diarrhea in order to find MHC class II deficiency. Usually, diagnosis is performed on cytospins, but when it has been missed clinically, it can be performed by using immunohistochemistry on small bowel biopsies.

Bone Marrow Transplantation↗
PubMed1997

Analysis of primate major histocompatibility complex (MHC)-DQA1 locus by PCR-single strand conformation polymorphism (SSCP).

Major histocompatibility complex (Mhc) gene products play an important role in the immune responses against pathogens and autoimmunity, disease resistance and transplantation. Non-human primates (NHPs) are increasingly being utilized as models to test the safety and efficacy of candidate vaccines. Mhc typing of NHPs is an important component of the vaccine trial studies and in the investigations of any associations between Mhc alleles and disease. Routine typing of primate Mhc alleles has been hampered by unavailability of well characterised immunological reagents. In this study, we have used PCR amplification and SSCP for screening polymorphisms in the primate DQA1 locus. Using this technique, 9 African primate species (36 individuals) were analyzed. Ten individuals showed three or four electrophoretic band patterns and the rest two-band patterns indicating this technique can be used to discriminate homozygous and heterozygous individuals prior to DNA sequencing. This method may also be used to screen primates for Mhc-DQA1 allelic polymorphism. However, practical application of this technique for routine typing of primate Mhc-DQA1 alleles depends on availability of adequate nucleotide sequence information.

Alleles↗