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PubMed1990

Refolding and reassembly of separate alpha and beta chains of class II molecules of the major histocompatibility complex leads to increased peptide-binding capacity.

Class II molecules of the major histocompatibility complex present antigenic peptides to helper T cells. These are heterodimeric glycoproteins consisting of one alpha and one beta chain. Two different alpha/beta heterodimeric conformations as well as the separate alpha and beta chains bind specific peptides. The alpha chain is thought to have one and the beta chain two intramolecular disulfide bonds. In the present study we have reduced these disulfide bonds in the murine major histocompatibility complex molecule I-Ad, which led to the release of bound peptides from all conformations and to unfolding of the separate chains. The separate alpha and beta chains could be refolded to their native structure by reoxidation of the cysteines. Refolding was accompanied by reassembly of the separated chains to the alpha/beta heterodimer. Both the separated alpha and beta chains and the alpha/beta heterodimer bound significantly higher amounts of antigenic peptide after reduction and reoxidation, as compared to the untreated protein.

Animals↗
PubMed1992

T cell epitope selection: dominance may be determined by both affinity for major histocompatibility complex and stoichiometry of epitope.

The majority of T cell hybridomas produced in the BALB/c mouse in response to immunization with lambda repressor cI recognize a peptide fragment comprising of residues 12 to 26 (P12-26). Some other parts of the cI (P1-14, P33-48 and P73-88) are defective in generating T cell responses in the BALB/c mouse. P73-88 may be converted into a T cell determinant if a few more amino acid residues are included (P67-88). Together with P46-67 and P80-102, most peptides derived from cI were capable of eliciting T cell responses by themselves in BALB/c mouse. The mechanisms underlying the selection of P12-26 over the other epitopes when lambda repressor was used as immunogen were examined. The dominant response to P12-26 was attenuated by tolerizing with intravenous administration of P12-26. Under such treatment the T cell response to P12-26 was reduced by 80% but there was no enhancement on the responses toward other epitopes. The selection of P12-26 is, thus, unlikely to be due to a competition at the T cell level. It was also found that the dominance of P12-26 was not simply due to a higher affinity of P12-26 for major histocompatibility complex molecules. For example P12-26 binds better to I-Ad molecule than P80-102, but co-injection with equimole of P12-26 only slightly inhibited P80-102-induced T cell response. Instead, it required a few molar excess of P12-26 to effectively block the association of P80-102 with I-Ad molecules and to inhibit the T cell immunity to P80-102. Since epitopes such as P46-67, P67-88 and P80-102 were generated from lambda repressor cI at a lower molar basis than that of P12-26, it is suggested that the dominance of P12-26 was probably generated by such stoichiometry difference, in addition to the higher affinity of P12-26 for I-Ad molecules.

Amino Acid Sequence↗
PubMed1991

In vitro peptide binding to the heavy chain of the class I molecule of the major histocompatibility complex molecule HLA-A2.

The heavy chain of class I molecules of the major histocompatibility complex forms the binding site for antigenic peptides. We describe the binding of a synthetic peptide to the purified heavy chain of the human major histocompatibility complex molecule HLA-A2. The peptide binding capacity is found to be markedly increased if the protein is first partly denatured by reduction of its disulfide bonds in detergent and subsequently renatured by reoxidation. In the presence of certain detergents, the heavy chain binds peptides even when the protein is partly unfolded.

Amino Acid Sequence↗
PubMed1992

The role of cytokines in polymyositis: interferon-gamma induces class II and enhances class I major histocompatibility complex antigen expression on cultured human muscle cells.

Aberrant expression of class II major histocompatibility complex molecules has been found on target cells of various autoimmune diseases, including muscle fibers in patients with polymyositis-dermatomyositis. In this study the effects of a number of recombinant human cytokines, individually and in combination, on class I and class II molecule expression by cultured human muscle cells were examined with monoclonal antibodies and an immunoperoxidase technique. The following cytokines were tested: interferon-gamma, tumor necrosis factor-alpha, tumor necrosis factor-beta, interleukin-2, interleukin-1 alpha and interleukin-1 beta. Only IFN-gamma induced expression of class II molecules in muscle cells. It also enhanced the preexisting class I molecule expression by muscle cells. These findings suggest that IFN-gamma is involved in the aberrant expression of major histocompatibility complex molecules in the affected muscles of patients with polymyositis-dermatomyositis.

Antibodies, Monoclonal↗
PubMed1994

Processing of viable group A streptococci leads to major histocompatibility complex class II presentation of T cell epitopes from the major protective antigen.

We have previously mapped major histocompatibility complex (MHC) class II-restricted T cell epitopes of the surface M protein of type 5 group A streptococci (M5) and show here that two out of four epitopes investigated were efficiently processed during incubation of viable streptococci with spleen cells for presentation to M5-specific murine T cell clones. Viable streptococci were processed more efficiently than heat-killed bacteria suggesting that secreted virulence factors of streptococci do not obstruct processing of streptococcal antigens in the dose range used. Epitopes from different regions of M5 could be ranked according to the efficiency with which they were processed, which may contribute to their relative immunodominance. It was further demonstrated that T cell clones specific for M5 308-319, an epitope from the M type conserved carboxy-terminal half of M5, cross-reacted between M5, M6 and M12, but not M49, streptococci. Helper T cell epitopes which are shared between streptococcal M types and are presented by MHC class II molecules on antigen-presenting cells after processing of viable streptococci could be particularly useful in the design of multivalent streptococcal vaccines.

Amino Acid Sequence↗
PubMed1990

Class I and class II major histocompatibility complex antigen expression on hepatocytes: a study in children with liver disease.

Controversy exists regarding major histocompatibility complex antigen expression on hepatocytes. In this study, hepatocyte expression of class I and II major histocompatibility complex antigens was investigated in diseased and normal livers, using indirect immunofluorescent staining of mechanically isolated, viable hepatocytes. Hepatocytes were obtained from 76 children: 10 with autoimmune chronic active hepatitis, nine with primary sclerosing cholangitis, nine with chronic hepatitis B virus infection, five after liver transplantation, 19 with extrahepatic biliary atresia, 11 with alpha 1-antitrypsin deficiency, four with idiopathic neonatal hepatitis and nine with histologically normal liver. Immunohistochemistry was performed in all cases; flow cytofluorimetry was performed for class I antigens in 38 cases and performed for class II antigens in 18 cases. From three children with autoimmune chronic active hepatitis and two with chronic hepatitis B virus infection, isolated hepatocytes were also incubated with gamma-interferon before staining and analysis. By fluorescence microscopy, class I antigens were detected on hepatocytes from all children, the highest percentage (100%) of positive cells and the most intense staining were observed in untreated patients with autoimmune chronic active hepatitis or primary sclerosing cholangitis and in those with acute rejection of a liver transplant. Reduced class I antigen expression occurred in chronic hepatitis B virus infection. Class II antigens were only detected on hepatocytes from eight patients: three with autoimmune chronic active hepatitis and five with primary sclerosing cholangitis, all untreated. Flow cytofluorimetric analysis confirmed the results obtained by fluorescence microscopy, but it also demonstrated a weak class II antigen expression during liver allograft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1998

Retinoic acid up-regulates the expression of major histocompatibility complex molecules and adhesion/costimulation molecules (specifically, intercellular adhesion molecule ICAM-1) in human cervical cancer.

OBJECTIVE: Retinoids are a class of compounds that are structurally related to vitamin A and have been found to be effective in the prevention and treatment of cervical cancer. To investigate whether enhanced immunogenicity might be responsible for such efficacy, we evaluated the effects of retinoic acid on the expression of major histocompatibility complex class I and class II and intercellular adhesion molecule ICAM-1 in human cervical carcinoma cell lines. STUDY DESIGN: The expression of surface antigens (major histocompatibility complex class I and class II and ICAM-1) was evaluated by fluorescence-activated cell sorter analysis in 3 human cervical carcinoma cell lines after exposure to therapeutic doses of retinoic acid. In addition, the effects on human leukocyte antigen class I messenger ribonucleic acid expression were also evaluated by Northern blot analysis after such treatment. RESULTS: CaSki, SiHa, and HT-3 cervical cancer cells expressed variable levels of major histocompatibility complex class I and ICAM-1 antigens, whereas class II surface antigens were not detectable. Exposure to therapeutic doses of retinoic acid were able to significantly increase the expression of major histocompatibility complex class I and ICAM-1 antigens in all the cell lines when compared with untreated tumor cells but were not able to induce the expression of class II surface human leukocyte antigens. Northern blot analysis showed that for major histocompatibility complex class I molecules such up-regulation was the result of an increased expression at the transcriptional level of major histocompatibility complex class I messenger ribonucleic acid. CONCLUSIONS: These data indicate that retinoic acid increases the expression of immunologically important surface antigens, suggesting that the efficacy of retinoic acid in the treatment of cervical cancer may be, at least in part, the result of immunologic modulation. Such findings support additional clinical research investigating the use of retinoids for the treatment of cervical cancer.

Blotting, Northern↗
PubMed1987

Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy.

We have studied major histocompatibility complex markers in randomly ascertained Caucasian patients with gluten-sensitive enteropathy and their families. The frequencies of extended haplotypes, defined as haplotypes of specific HLA-B, DR, BF, C2, C4A, and C4B allelic combinations, occurring more frequently than expected, were compared on patient chromosomes, on normal chromosomes from the study families, and on chromosomes from normal families. Over half of patient chromosomes consisted almost entirely of two extended haplotypes [HLA-B8, DR3, SC01] and [HLA-B44, DR7, FC31] which, with nonextended HLA-DR7, accounted for the previously observed HLA markers of this disease: HLA-B8, DR3, and DR7. There was no increase in HLA-DR3 on nonextended haplotypes or in other extended haplotypes with HLA-DR3 or DR7. The distribution of homozygotes and heterozygotes for HLA-DR3 and DR7 was consistent with recessive inheritance of the major histocompatibility complex-linked susceptibility gene for gluten-sensitive enteropathy. On the other hand, by odds ratio analysis and from the sum of DR3 and DR7 homozygotes compared with DR3/DR7 heterozygotes, there was an increase in heterozygotes and a decrease in homozygotes suggesting the presence of modifying phenomena.

Celiac Disease↗
PubMed1997

An in vitro study of the dynamic features of the major histocompatibility complex class I complex relevant to its role as a versatile peptide-receptive molecule.

The major histocompatibility complex class I complex consists of a heavy chain and a light chain (beta2-microglobulin, beta2m), which assemble with a short endogenously derived peptide in the endoplasmic reticulum. The class I peptide can be directly exchanged, either at the cell surface or, as recently described, in vesicles of the endocytic compartments, thus allowing exogenous peptides to enter the class I presentation pathway. To probe the interactions between the components of the class I molecule, we analyzed the exchange of peptide and beta2m by using purified, recombinant H2-Kb/peptide complexes in a cell-free in vitro system. The exchange of competitor peptide was primarily dependent on the off-rate of the original peptide in the class I binding groove. Peptide exchange was not enhanced by the presence of exogenous beta2m, as exchange occurred to the same extent in its absence. Thus, the exchange of peptide and beta2m are independent events. The exchange rate of beta2m also was not affected by the dissociation rates of the original peptides. Furthermore, peptides could substantially exchange into class I molecules over a pH range of 5.5 to 7.5, conditions prevalent in certain endocytic compartments. We conclude that the dynamic properties of the components of class I molecules explain its function as a highly peptide-receptive molecule. The major histocompatibility complex class I can readily receive peptides independent of the presence of exogenous beta2m, even at a low pH. Such properties are relevant to class I peptide acquisition, which can occur at the cell surface, as well as in specialized endosomes.

Amino Acid Sequence↗
PubMed1993

Murine cytomegalovirus interacts with major histocompatibility complex class I molecules to establish cellular infection.

The expression of stable, correctly folded major histocompatibility complex class I molecules conferred susceptibility to murine cytomegalovirus (MCMV) in cells which were previously resistant to infection, demonstrating that these molecules interact critically with MCMV to initiate infection. All class I molecules could potentiate MCMV infection but H-2Dd and Kb molecules were most efficient. Monoclonal antibodies specific for the alpha 1 and/or alpha 2 domains of Dd and Kb inhibited infection. Infection of L cells transfected with hybrid major histocompatibility complex class I molecules demonstrated that allelic control of susceptibility to MCMV mapped to the alpha 1 domain of Dd when in correct configuration with the alpha 2 and alpha 3 domains. In MCMV-resistant RMA-S cells, an improvement in the conformation of class I molecules introduced susceptibility to infection.

Animals↗
PubMed2004

Cholesterol depletion suppresses the translational diffusion of class II major histocompatibility complex proteins in the plasma membrane.

Glycosylphosphatidylinositol (GPI)-linked and native major histocompatibility complex class II I-E(k) were used as probes to determine the effect of varying cholesterol concentration on the mobility of proteins in the plasma membrane. These proteins were imaged in Chinese hamster ovary cells using single-molecule fluorescence microscopy. Observed diffusion coefficients of both native and GPI-linked I-E(k) proteins were found to depend on cholesterol concentration. As the cholesterol concentration decreases the diffusion coefficients decrease by up to a factor of 7 for native and 5 for GPI-linked I-E(k). At low cholesterol concentrations, after sphingomyelinase treatment, the diffusion coefficients are reduced by up to a factor of 60 for native and 190 for GPI-linked I-E(k). The effect is reversible on cholesterol reintroduction. Diffusion at all studied cholesterol concentrations, for both proteins, appears to be predominantly Brownian for time lags up to 2.5 s when imaged at 10 Hz. A decrease in diffusion coefficients is observed for other membrane proteins and lipid probes, DiIC12 and DiIC18. Fluorescence recovery after photobleaching measurements shows that the fraction of immobile lipid probe increases from 8 to approximately 40% after cholesterol extraction. These results are consistent with the previous work on cholesterol-phospholipid interactions. That is, cholesterol extraction destroys liquid cholesterol-phospholipid complexes, leaving solid-like high melting phospholipid domains that inhibit the lateral diffusion of membrane components.

Actins↗
PubMed1980

The major histocompatibility complex in the turkey: do erythrocytes bear serologically detectable H antigens?

An attempt was made to identify erythrocyte cell surface antigens associated with the major histocompatibility complex in the turkey. Two turkey lines, A and B, from the University of Minnesota, putatively homozygous for different major histocompatibility complex alleles, were used for this study. A total of 79 birds were immunized either by skin grafting or by injection of homogenized skin preparation in Freund's incomplete adjuvant. Antisera produced with skin grafts and homogenized skin inoculated intramuscularly both contained red cell agglutinins of low titer. Because agglutination reactions were weak, no sera were suitable for use as line-specific typing fluids. Thus, we were unable to demonstrate that turkey erythrocytes contain serologically detectable major histocompatibility antigens corresponding to the B major histocompatibility system in the chicken or the H-2 system in mice. Rather, the turkey major histocompatibility complex is more like that in rabbits, dogs, monkeys and humans.

Animals↗
PubMed1987

Ethanol: an enhancer of major histocompatibility complex antigen expression.

Ethanol enhances expression of cell surface class I major histocompatibility complex (MHC) antigens in a variety of cell lines; up to an eightfold increase is observed in an embryonic cell line. In ethanol-treated L cells, increased cell surface expression of MHC antigens occurs with a concomitant increase in steady-state RNA levels. This effect is promoter dependent and restricted, because not all gene products are elevated. The effective ethanol concentration (1%) is physiologically attainable, leading to speculations about the role of elevated MHC antigens in alcohol-related diseases.

Animals↗
PubMed2002

Baboon placentas express soluble and membrane-bound Paan-AG proteins encoded by alternatively spliced transcripts of the class Ib major histocompatibility complex gene, Paan-AG.

The human class Ib major histocompatibility complex (MHC) molecule, HLA-G, is unique in its limited polymorphism, high expression in the placenta and generation of multiple transcripts by alternative splicing. The proteins encoded by these transcripts are believed to modulate maternal-fetal immunological relationships during pregnancy. The baboon placenta contains messages encoded by a novel MHC gene, Paan-AG, which is evolutionarily related to the HLA-A locus, but shares unique characteristics with HLA-G. In this study, we show that the Paan-AG message is alternatively spliced to generate at least seven transcripts. One of these transcripts retains intron 4 and encodes a soluble glycoprotein with three external domains and a unique 21-amino-acid sequence at the carboxyl terminus, similar to soluble HLA-G1. This glycoprotein was detected in first trimester placental villous cytotrophoblast and syncytiotrophoblast, and in extravillous cytotrophoblast cells in the basal plate in term placenta. Four of the transcripts ( Paan-AG1, Paan-AG2, Paan-AG3, Paan-AG4) encode membrane-bound class Ib MHC glycoprotein isoforms. Paan-AG1 protein expression was similar to that of sPaan-AG, while Paan-AG2 protein was not detected in these tissues. The other two transcripts ( Paan-AGx and Paan-AGxi) contain a truncated exon 3 and multiple stop codons. Paan-AG1 and Paan-AGx transcripts were detected in a number of non-placental tissues, but these transcripts contained multiple stop codons. Because of the structural similarities and common features of organ-specific expression and splicing of the message, studies on Paan-AG may be of value in dissecting the functions of the class Ib proteins in human pregnancy.

Alternative Splicing↗
PubMed1994

Effects of bile acids and cholestasis on major histocompatibility complex class I in human and rat hepatocytes.

BACKGROUND/AIMS: Major histocompatibility complex (MHC) class I molecules, which are normally poorly expressed on the surface of hepatocytes, are overexpressed during cholestasis. The mechanisms responsible for this overexpression were examined. METHODS: The expression of class I molecules, assessed by flow cytofluorimetry, and the class I messenger RNA (mRNA) transcripts, assessed by Northern blot analysis, were measured on normal human hepatocytes in primary culture. RESULTS: Chenodeoxycholic acid induced an overexpression of MHC class I molecules, whereas ursodeoxycholic acid did not. The level of class I mRNA closely reflected that of the membrane protein. Moreover, cholestasis, induced in the rat by ligation-section of the common bile duct, increased the MHC class I mRNA level. Actinomycin D inhibited bile acid-induced class I transcription of rat hepatocytes in primary culture, whereas cycloheximide did not. Finally, class I mRNA expression was induced in hepatocytes by phorbol myristate acetate and by forskolin. This hyperexpression, as well as that observed with chenodeoxycholic acid, was suppressed by an inhibitor of protein kinase C and protein kinase A. CONCLUSIONS: Taken together, these results suggest that chenodeoxycholic acid, as interferon, activates protein kinase C and protein kinase A, resulting in the induction of MHC class I expression.

Adult↗
PubMed2006

Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes.

Major histocompatibility complex (MHC) class II molecules present products of lysosomal proteolysis to CD4(+) T cells. Although extracellular antigen uptake is considered to be the main source of MHC class II ligands, a few intracellular antigens have been described to gain access to MHC class II loading after macroautophagy. However, the general relevance and efficacy of this pathway is unknown. Here we demonstrated constitutive autophagosome formation in MHC class II-positive cells, including dendritic, B, and epithelial cells. The autophagosomes continuously fuse with multivesicular MHC class II-loading compartments. This pathway was of functional relevance, because targeting of the influenza matrix protein 1 to autophagosomes via fusion to the autophagosome-associated protein Atg8/LC3 led to strongly enhanced MHC class II presentation to CD4(+) T cell clones. We suggest that macroautophagy constitutively and efficiently delivers cytosolic proteins for MHC class II presentation and can be harnessed for improved helper T cell stimulation.

Antigen Presentation↗
PubMed2003

Generation of major histocompatibility complex class I antigens.

Presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules on the surface of antigen-presenting cells is an effective extracellular representation of the intracellular antigen content. The intracellular proteasome-dependent proteolytic machinery is required for generating MHC class I-presented peptides. These peptides appear to be derived mainly from newly synthesized defective ribosomal products, ensuring a rapid cytotoxic T lymphocyte-mediated immune response against infectious pathogens. Here we discuss the generation of MHC class I antigens on the basis of the currently understood molecular, biochemical and cellular mechanisms.

Antigen Presentation↗
PubMed1990

An interferon gamma-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes.

Interferons (IFNs) induce transcription of major histocompatibility complex (MHC) class I genes through the conserved IFN consensus sequence (ICS) that contains an IFN response motif shared by many IFN-regulated genes. By screening mouse lambda ZAP expression libraries with the ICS as a probe, we isolated a cDNA clone encoding a protein that binds the ICS, designated ICSBP. Protein blot analysis with labeled oligonucleotide probes showed that ICSBP binds not only the MHC class I ICS but also IFN response motifs of many IFN-regulated genes, as well as a virus-inducible element of the IFN-beta gene. The ICSBP cDNA encodes 424 amino acids and a long 3' untranslated sequence. The N-terminal 115 amino acids correspond to a putative DNA-binding domain and show significant sequence similarity with other cloned IFN response factors (IRF-1 and IRF-2). Because of the structural similarity and shared binding specificity, we conclude that ICSBP is a third member of the IRF gene family, presumably playing a role in IFN- and virus-mediated regulation of many genes. Although IRF-1 and IRF-2 share some similarity in their C-terminal regions, ICSBP shows no similarity to IRF-1 or IRF-2 in this region, suggesting that it is more distantly related. We show that ICSBP mRNA is expressed predominantly in lymphoid tissues and is inducible preferentially by IFN-gamma. The induction by IFN-gamma appears to be predominant in lymphocytes and macrophages, implying that ICSBP plays a regulatory role in cells of the immune system. The presence of multiple factors that bind common IFN response motifs may partly account for the complexity and diversity of IFN action as well as IFN-regulated gene expression.

Amino Acid Sequence↗