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PubMed1999

A mutational analysis of the Abetaz/Aalphad major histocompatibility complex class II molecule that restricts autoreactive T cells in (NZBxNZW)F1 mice. The critical influence of alanine at position 69 in the Aalphad chain.

Autoimmune symptoms of (NZBxNZW)F1 (H-2d/z) mice are reported to be critically related to the heterozygosity at the H-2 complex of the murine major histocompatibility complex (MHC). We previously showed that several Abetaz/Aalphad MHC class II molecule-restricted autoreactive T-cell clones from B/WF1 mice were pathogenic upon transfer to preautoimmune B/WF1 mice. In this study, to identify the crucial amino acid residues in Abetaz/Aalphad molecules for T-cell activation, we generated a panel of transfectant cell lines. These transfectant cell lines express the Abetaz/Aalphad MHC molecules with a mutation at each residue alpha11, alpha28, alpha57, alpha69, alpha70, alpha76 of Aalphad chain and beta86 of Abetaz chain. Replacing alpha69 alanine with threonine, valine or serine completely eliminated the ability to stimulate autoreactive T-cell clones without affecting the ability to present foreign antigen keyhole limpet haemocyanin (KLH) or L-plastin peptide to specific T-cell clones. Replacing beta86 valine with aspartic acid resulted in a decrease in the stimulation for antigen-reactive as well as autoreactive T-cell clones. Substitutions at other residues had minimal or no effect on the stimulation of either auto- or antigen-reactive T-cell clones. These results suggest that alanine at residue 69 of the Aalphad chain is critical for the activation of autoreactive Abetaz/Aalphad-restricted T-cell clones. Possible explanations for this are discussed.

Alanine↗
PubMed1987

Linkage map of the human major histocompatibility complex including the tumor necrosis factor genes.

The tumor necrosis factor (TNF) alpha and beta gene pair has been linked in the human major histocompatibility complex to HLA-B, HLA-C, and, tentatively, HLA-E and HLA-A on one side and to the class III complement/steroid 21-hydroxylase gene cluster on the other by pulsed-field gel electrophoresis. The TNF genes are located 200 kilobases (kb) centromeric of HLA-B and about 350 kb telomeric of the class III cluster. Together with previous data on the linkage and structures of the class II and class III regions, a restriction map of the entire human major histocompatibility complex of about 3500 kb has been prepared.

Chromosome Mapping↗
PubMed1991

Transcription of a subset of human class II major histocompatibility complex genes is regulated by a nucleoprotein complex that contains c-fos or an antigenically related protein.

Transcriptional regulation of the human major histocompatibility complex class II genes requires at least two upstream elements, the X and Y boxes, located in the -50- to -150-base-pair region of all class II promoters. The DRA and DPB promoters contain phorbol ester-responsive elements overlapping the 3' side of their X boxes. Mutation of this sequence down-regulates the efficiency of the DRA promoter, suggesting that a positive regulator(s) binds to this site. In this report, anti-sense c-fos RNA and an anti-c-fos antibody were used to show that the product of the protooncogene c-fos or an antigenically related protein is a component of a complex that binds to the X box and is required for maximal transcription from the DRA and DPB promoters. As c-fos (or its related proteins) cannot bind alone to DNA, these results suggest that it may dimerize with other members of the JUN/AP-1 family, such as hXBP1, to participate in the activation of a subset of class II major histocompatibility complex genes.

Amino Acid Sequence↗
PubMed1999

Recognition of major histocompatibility complex class II antigens by two anti-HLA-DR monoclonal antibodies on canine marrow cells correlates with effects on in vitro and in vivo hematopoiesis.

BACKGROUND: The role of major histocompatibility complex class II antigens in hematopoiesis is not well defined. We have shown that in vitro depletion of HLA-DR+ cells from canine marrow (e.g., by anti-HLA-DR monoclonal antibody [mAb] H81.9 and complement) prevents hematopoietic recovery. In vivo administration of the same mAb H81.9 after transplantation of unmanipulated autologous marrow results in graft failure. In vitro mAb H81.9 inhibited colony formation from short-term and long-term marrow cultures. METHODS AND RESULTS: We investigated the effect of another mAb, Ca1.41, which also recognizes nonpolymorphic determinants on human (HLA-DR) and canine major histocompatibility complex class II antigens but is reactive with a narrower spectrum of cells in both canine peripheral blood and marrow than mAb H81.9 (and other anti-HLA-DR mAbs). In contrast to all other anti-HLA-DR mAbs tested, Ca1.41 did not interfere with colony formation in short-term or long-term marrow cultures and spared a population of small mononuclear cells with low forward light scatter that was eliminated via apoptosis by exposure to mAb H81.9. These target cells included lymphocytes and CD34+ hemopoietic precursors that expressed MHC class II molecules as determined by mAb H81.9 but not by mAb Ca1.41. In addition, transmembrane signaling and up-regulation of interleukin-1beta mRNA occurred with mAb H81.9 but not with Ca1.41. Transplantation of autologous marrow treated in vitro cytolytically with mAb Ca1.41 allowed for complete hematopoietic reconstitution. Further, in vivo administration of Ca1.41 posttransplant did not lead to autologous graft failure as had been observed with mAb H81.9. CONCLUSIONS: These results support the notion that major histocompatibility complex class II is expressed on early hematopoietic precursor cells but recognition is dependent upon the mAb used. Preliminary studies show that mAb H81.9 triggered transmembrane signaling, resulting in up-regulation of interleukin-1beta and apoptosis, although mAb Ca1.41 did not. The fact that Ca1.41 binding was modified in the presence of exogenous invariant chain-derived peptide suggests that both binding and signaling are peptide dependent.

Animals↗
PubMed1999

The lifespan of major histocompatibility complex class I/peptide complexes determines the efficiency of cytotoxic T-lymphocyte responses.

Major histocompatibility complex (MHC)/peptide association and stability are determined by specific amino acid interactions between peptide antigens and the MHC groove, and are regarded as a critical feature in ensuring efficient monitoring by T cells. In this investigation we examined the relationship between MHC/peptide stability and the immunostimulatory capacity of MHC/peptide complexes. For this purpose we compared synthetic peptide analogues derived from the immunodominant HLA-A11-presented IVTDFSVIK (IVT) epitope, for their capacity to reactivate IVT-specific memory cytotoxic T-lymphocyte (CTL) responses. The analogues differentiated from the wild-type epitope by single amino acid substitution at position 2. All peptides showed similar affinity for HLA-A11 molecules and were recognized by IVT-specific CTL clones, but induced HLA-A11 complexes at the cell surface with different lifespan. This model offered the possibility of comparing the capacity of an immunogenic epitope to stimulate a unique population of T-cell precursors depending on the lifespan of its presentation at the cell surface. We demonstrated that stable HLA-A11/peptide complexes efficiently stimulate IVT-specific CTL responses, while HLA-A11/peptide complexes with short lifespan do not. The precise identification of the role of amino acid residues in the formation of stable MHC/peptide complexes may be relevant for the design of wild-type-derived epitopes with high immunogenicity. These analogues may have important applications in the immunotherapy of infectious diseases and immunogenic tumours.

Cell Culture Techniques↗
PubMed2004

The major histocompatibility complex origin.

The present review focuses on the history of genes involved in the major histocompatibility complex (MHC), with a special emphasis on class I function in peptide presentation. The MHC class II story is covered in less detail, as it does not have a major impact on the general understanding of the MHC evolution. We first redefine the MHC as the definition evolved over time. We then use phylogenetic analysis to investigate the history of genes involved in the MHC class I process. As not all the genes involved in this process have been phylogenetically analyzed and because new sequences have been recently released in biological databases, we have re-investigated this matter. In the light of the phylogenetic analysis, the functions of the orthologs of the genes involved in MHC processes are examined in species not having an MHC system. We then demonstrate that the emergence of this new function is due to various levels of co-option.

Animals↗
PubMed1989

Cloning of the major histocompatibility complex class II promoter binding protein affected in a hereditary defect in class II gene regulation.

The regulation of major histocompatibility complex class II gene expression is directly involved in the control of normal and abnormal immune responses. In humans, HLA-DR, -DQ, and -DP class II heterodimers are encoded by a family of alpha- and beta-chain genes clustered in the major histocompatibility complex. Their expression is developmentally controlled and normally restricted to certain cell types. This control is mediated by cis-acting sequences in class II promoters and by trans-acting regulatory factors. Several nuclear proteins bind to class II promoter sequences. In a form of hereditary immunodeficiency characterized by a defect in a trans-acting regulatory factor controlling class II gene transcription, we have observed that one of these nuclear factors (RF-X) does not bind to its target sequence (the class II X box). A cDNA encoding RF-X was isolated by screening a phage expression library with an X-box binding-site probe. The recombinant protein has the binding specificity of RF-X, including a characteristic gradient of affinity for the X boxes of HLA-DR, -DP, and -DQ promoters. RF-X mRNA is present in the regulatory mutants, indicating a defect in the synthesis of a functional form of the RF-X protein.

Base Sequence↗
PubMed1985

Major histocompatibility complex regulation of the immune response.

The ability of an organism to distinguish self from nonself is determined by a cluster of genes located in the major histocompatibility complex. Recent advances in molecular genetics and cellular immunology have begun to elucidate the mechanisms responsible for immune response regulation. In this review article, the genetic organization of the murine and human major histocompatibility complexes and the manner by which their gene products modulate immune responsiveness are discussed.

Animals↗
PubMed1991

Self peptide requirement for class II major histocompatibility complex allorecognition.

Using a dinitrophenylated and biotinylated peptide antigen, we have developed an affinity chromatography procedure to purify complexes of a given peptide species and a given class II major histocompatibility complex antigen away from class II molecules occupied by other peptides. We show that hen egg lysozyme peptide-I-Ed complexes purified according to this procedure have a greatly enhanced capacity to activate hen egg lysozyme-specific T cells but have lost the capacity to activate three different alloreactive T-cell hybridomas. These data demonstrate that the class II molecule in and of itself is not sufficient to activate alloreactive T cells. Rather, the data suggest that recognition of specific complexes formed between allo-class II and particular autologous peptides may be required. Alternatively, alloreactive T cells may be recognizing "empty" major histocompatibility complex molecules.

Amino Acid Sequence↗
PubMed1997

Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction.

BACKGROUND: It has been suggested that T cells primed by processed donor major histocompatibility complex antigen (the "indirect" pathway of allorecognition) may be responsible for mediating chronic allograft rejection. The purpose of this study was to develop a clinically useful assay to study the occurrence of indirect allorecognition during chronic rejection in humans. METHODS: A panel of 20 mer peptides corresponding to the hypervariable regions of HLA-DRB1*0101, DRB1*1501, and DRB1*0301 were synthesized. Lymphocytes obtained from renal allograft recipients were cocultured with these peptides. Proliferation was assayed by DNA incorporation of [3H]thymidine, and positive proliferation was defined by a statistically significant increase in counts per minute over background with a minimum stimulation index of 2. The precursor frequency of allopeptide reactive T cells was determined by limiting dilution analysis. RESULTS: Lymphocytes from 82% of patients who were mismatched for at least one of the three DR molecules and had chronic allograft dysfunction specifically proliferated to the mismatched allopeptides (n=11). Proliferation was seen in only 6% of control subjects (2/33, P<0.0001). The proliferative response was low grade and was best detected on day 7-8 of culture in vitro. The precursor frequency of peptide-specific T cells was more than 10-fold higher compared with controls (P<0.001). CONCLUSIONS: These data demonstrate for the first time that T cells of patients with chronic graft dysfunction are primed to recognize and respond to specific donor-derived major histocompatibility complex allopeptides. Our results support the hypothesis that T cells primed via the indirect pathway of allorecognition may be important mediators of chronic rejection and provide the rationale to develop specific therapeutic strategies to prevent or interrupt this process.

Adult↗
PubMed2003

Targeting foreign major histocompatibility complex molecules to tumors by tumor cell specific single chain antibody (scFv).

Down-regulation of the major histocompatibility complex (MHC) is one of the major mechanisms that tumor cells adopted to escape immunosurveillance. Therefore, specifically coating tumor cells with foreign MHC may make tumor cells a better target for immune recognition and surveillance. In this study, we designed and generated a fusion protein, H2Kd/scPSMA, consisting of a single chain antibody against human prostate specific membrane antigen (PSMA) and the extracellular domain of mouse H-2Kd. The expression of this fusion protein in B16F0 mouse melanoma cells was confirmed by RT-PCR and fluorescent activated cell sorting (FACS). Our animal study showed that the expression of H2Kd/scPSMA in B16F0/PSMA5, a B16F0 cell line expressing human PSMA, significantly inhibited tumor growth as demonstrated in the pulmonary metastasis assay and tumor growth study and improved overall survival.

Animals↗
PubMed2005

Single nucleotide polymorphisms in the gene encoding the major histocompatibility complex class II transactivator (CIITA) in systemic lupus erythematosus.

BACKGROUND: The major histocompatibility complex (MHC) class II transactivator (CIITA) is a master switch of antigen presentation and activates expression of the MHC II gene. Insufficient up regulation of MHC class II molecules is reported to be one of the major immunological mechanisms in systemic lupus erythematosus (SLE). OBJECTIVE: To examine the association between single nucleotide polymorphisms (SNPs) in the human CIITA gene (MHC2TA) and SLE. METHODS: Promoters and coding regions of MHC2TA were evaluated for polymorphisms in 100 patients with SLE and 100 healthy donors. Eight oligonucleotide primer sets that covered the coding region and each promoter region were used for genomic analysis of SNPs. RESULTS: Allele frequencies of previously reported SNPs did not differ between healthy donors and patients with SLE. Additionally, a new polymorphism in an intronic region at nt 485 (A-->A/G) was identified, which is close to the polymorphism at nt 474 that has been associated with one of the disease causing CIITA cDNA mutations in bare lymphocyte syndrome. This SNP was found in 11% of patients with SLE and in 3% of healthy donors, suggesting it may have a role in the pathogenesis of SLE. CONCLUSIONS: A newly identified polymorphism in an intronic region at nt 485 (A-->A/G) may have an important role in the pathogenesis of SLE.

Adolescent↗
PubMed1997

A fragment of the major histocompatibility complex class II-associated p41 invariant chain inhibits cruzipain, the major cysteine proteinase from Trypanosoma cruzi.

A peptide fragment derived from the p41 form of the invariant chain (Ii) associated with the major histocompatibility complex (MHC) class II molecule has been shown to inhibit the mammalian lysosomal cysteine proteinase, cathepsin L, and to be a novel cysteine proteinase inhibitor, distinct from cystatins. Here we report that this same fragment also binds to and inhibits cruzipain, the cathepsin L-like enzyme from the protozoan parasite Trypanosoma cruzi. The binding of the Ii fragment to cruzipain is fast (k(ass) = 2.4 x 10(7) M(-1) s(-1) and tight (Ki = 5.8 x 10(-11) M). The inhibition is competitive. These results suggest the possibility of using the invariant chain as a model for the specific inhibition of cruzipain in vivo, i.e. as a potential drug to combat Chagas' disease.

Alternative Splicing↗
PubMed1994

Expression of major histocompatibility complex antigen in Lewis rat cornea.

Fresh rat corneas as well as corneas preserved in several different corneal preservation media were stained with Avidin-Biotin-peroxidase Complex method in order to evaluate major histocompatibility complex (MHC) antigen expression. In fresh corneas, class I antigen was identified in corneal epithelium, stroma and endothelium. Class II antigen was identified only in stroma. In corneas preserved in the media which contained chondroitin and dextran for 7 days, class I antigen was somewhat decreased but class II antigen was increased. In corneas preserved in the medium which contained insulin or epidermal growth factor for 7 days, class II antigens seemed to be increased compaired to the fresh cornea. Expression of MHC antigens of corneas in the medium with fetal bovine serum were similar to those of fresh corneas.

Animals↗
PubMed2006

Ovar-Mhc--ovine major histocompatibility complex: role in genetic resistance to diseases.

Research on the structure of the ovine major histocompatibility complex (MHC), Ovar-Mhc, and its association with resistance to various diseases in sheep has received increasing attention during recent years. The term 'resistance' is used to denote the capacity of an animal to defend itself against disease or to withstand the effects of a harmful environmental agent. The Ovar-Mhc is poorly characterised when compared to MHCs of other domestic animals. However, its basic structure is similar to that of other animals, comprising Class I, II and III regions. Products of the Class I and II genes, the histocompatibility molecules, are of paramount importance as these present antigens to T-lymphocytes, thereby eliciting immune responses. Several studies have been conducted in sheep on the involvement of MHC genes/antigens in genetic resistance to diseases, the majority being concerned with gastrointestinal nematodes. Studies on resistance to footrot, Johne's disease and bovine leukaemia virus (BLV)-induced leukaemogenesis have also been reported. Genes of all three regions were implicated in the disease association studies. In addition to disease resistance, Ovar-Mhc genes have been found to be associated with traits such as marbling and birthweight. The use of genetic markers from within the Ovar-Mhc may be useful, via marker-assisted selection, for increasing resistance to various diseases provided they do not impact negatively on other economically-important traits. This review summarises current knowledge of the role of Ovar-Mhc in genetic resistance to diseases in sheep.

Animals↗
PubMed1991

Intracellular transport and localization of major histocompatibility complex class II molecules and associated invariant chain.

The intracellular transport and location of major histocompatibility complex (MHC) class II molecules and associated invariant chain (Ii) were investigated in a human melanoma cell line. In contrast to the class II molecules, which remain stable for greater than 4 h after synthesis, the associated Ii is proteolytically processed within 2 h. During or shortly after synthesis the NH2-terminal cytoplasmic and membrane-spanning segment is in some of the Ii molecules cleaved off; during intracellular transport, class II associated and membrane integrated Ii is processed from its COOH terminus in distinct steps in endocytic compartments. Immunocytochemical studies at the light and electron microscopic level revealed the presence of class II molecules, but not of Ii on the cell surface. Intracellularly both Ii and class II molecules were localized in three morphologically and kinetically distinct compartments, early endosomes, multivesicular bodies, and prelysosomes. This localization in several distinct endosomal compartments contrasts with the localization of class II molecules in mainly one endocytic compartment in B lymphoblastoid cell lines. As in these lymphoblastoid cell lines Ii is known to be rapidly degraded it is conceivable that the rate of proteolysis of the class II associated Ii and its dissociation from class II molecules modulates the retention of the oligomeric complex in endocytic compartments, and as a consequence the steady-state distribution of these molecules within the endosomal system.

Biological Transport↗
PubMed1992

Specific low-affinity recognition of major histocompatibility complex plus peptide by soluble T-cell receptor.

The T-cell receptor is necessary and sufficient for recognition of peptides presented by major histocompatibility complex molecules. Other adhesion molecules, like CD4 or CD8, play an auxiliary role in antigen recognition by T cells. Here we analyse T-cell receptor (TCR) binding using a soluble rather than a cell-bound receptor molecule. A TCR-immunoglobulin chimaera is constructed with the variable and the first constant regions of both the TCR alpha- and beta-chains linked to the immunoglobulin light-chain constant regions. This soluble TCR is expressed, assembled and secreted as an alpha beta heterodimer by a myeloma cell line transfected with the recombinant genes. Furthermore, the soluble TCR is biologically active: it specifically inhibits antigen-dependent activation of the relevant T-cell clones and thus discriminates between proper and irrelevant peptides presented by major histocompatibility complex molecules.

Animals↗
PubMed2000

A functionally essential domain of RFX5 mediates activation of major histocompatibility complex class II promoters by promoting cooperative binding between RFX and NF-Y.

Major histocompatibility complex class II (MHC-II) molecules occupy a pivotal position in the adaptive immune system, and correct regulation of their expression is therefore of critical importance for the control of the immune response. Several regulatory factors essential for the transcription of MHC-II genes have been identified by elucidation of the molecular defects responsible for MHC-II deficiency, a hereditary immunodeficiency disease characterized by regulatory defects abrogating MHC-II expression. Three of these factors, RFX5, RFXAP, and RFXANK, combine to form the RFX complex, a regulatory protein that binds to the X box DNA sequence present in all MHC-II promoters. In this study we have undertaken a dissection of the structure and function of RFX5, the largest subunit of the RFX complex. The results define two distinct domains serving two different essential functions. A highly conserved N-terminal region of RFX5 is required for its association with RFXANK and RFXAP, for assembly of the RFX complex in vivo and in vitro, and for binding of this complex to its X box target site in the MHC-II promoter. This N-terminal region is, however, not sufficient for activation of MHC-II expression. This requires an additional domain within the C-terminal region of RFX5. This C-terminal domain mediates cooperative binding between the RFX complex and NF-Y, a transcription factor binding to the Y box sequence of MHC-II promoters. This provides direct evidence that RFX5-mediated cooperative binding between RFX and NF-Y plays an essential role in the transcriptional activation of MHC-II genes.

Amino Acid Sequence↗