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PubMed1999

Proteolysis and class I major histocompatibility complex antigen presentation.

The class I major histocompatibility complex (MHC class I) presents 8-10 residue peptides to cytotoxic T lymphocytes. Most of these antigenic peptides are generated during protein degradation in the cytoplasm and are then transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP). Several lines of evidence have indicated that the proteasome is the major proteolytic activity responsible for generation of antigenic peptides--probably most conclusive has been the finding that specific inhibitors of the proteasome block antigen presentation. However, other proteases (e.g. the signal peptidase) may also generate some epitopes, particularly those on certain MHC class I alleles. The proteasome is responsible for generating the precise C termini of many presented peptides, and appears to be the only activity in cells that can make this cleavage. In contrast, aminopeptidases in the cytoplasm and endoplasmic reticulum can trim the N terminus of extended peptides to their proper size. Interestingly, the cellular content of proteases involved in the production and destruction of antigenic peptides is modified by interferon-gamma (IFN-gamma) treatment of cells. IFN-gamma induces the expression of three new proteasome beta subunits that are preferentially incorporated into new proteasomes and alter their pattern of peptidase activities. These changes are likely to enhance the yield of peptides with C termini appropriate for MHC binding and have been shown to enhance the presentation of at least some antigens. IFN-gamma also upregulates leucine aminopeptidase, which should promote the removal of N-terminal flanking residues of antigenic peptides. Also, this cytokine downregulates the expression of a metallo-proteinase, thimet oligopeptidase, that actively destroys many antigenic peptides. Thus, IFN-gamma appears to increase the supply of peptides by stimulating their generation and decreasing their destruction. The specificity and content of these various proteases should determine the amount of peptides available for antigen presentation. Also, the efficiency with which a peptide is presented is determined by the protein's half life (e.g. its ubiquitination rate) and the sequences flanking antigenic peptides, which influence the rates of proteolytic cleavage and destruction.

Animals↗
PubMed1984

Blocking of the response by human T-lymphocytes to extracts of autologous cancer by monoclonal antibody to Class-I major histocompatibility complex gene products in the leukocyte adherence inhibition assay.

In the leukocyte adherence inhibition (LAI) assay, about 34% of adherent T-cells from patients with breast cancer exhibit nonadherence to glass when incubated with extracts of autologous cancer but not with HLA-A, -B, and -C mismatched extracts of breast cancer. To determine whether the recognition by T-cells of tumor antigen was major histocompatibility complex restricted, major histocompatibility complex antigens in the cancer extracts or on the T-cells were coated with monoclonal antibody (MAb) to nonpolymorphic determinants. Nonadherence of T-cells was antagonized by coating the target cancer extracts with MAb to a common framework determinant of Class I HLA-A, -B, and -C antigens or to the nonpolymorphic beta 2-microglobulin, which is noncovalently associated with Class I antigens. By contrast, a MAb to a monomorphic determinant on HLA-DR antigens did not change the positive T-cell response. Moreover, coating the T-cells with MAb to HLA-A, -B, and -C did not inhibit the positive T-cell response. The positive LAI response of buffy coat peripheral blood leukocytes from patients with breast cancer to extracts of allogeneic breast cancer was not affected by coating the cancer extracts with the same MAb, indicating that MAb inhibited T-cell LAI specifically and that the antibody-dependent LAI response of buffy coat peripheral blood leukocytes was not major histocompatibility complex restricted. The results indicate that HLA-A, -B, and -C antigens in extracts of autologous breast cancer restrict the LAI response to tumor antigens of T-cells from patients with breast cancer.

Antibodies, Monoclonal↗
PubMed1997

Excessive degradation of intracellular protein in macrophages prevents presentation in the context of major histocompatibility complex class II molecules.

The endogenous major histocompatibility complex (MHC) class II presentation pathway allows biosynthesized, intracellular antigens access for presentation to MHC class II-restricted T cells. This pathway has been well documented in B cells and fibroblasts, but may not be universally available in all antigen-presenting cell types. This study compares the ability of different antigen-presenting cells, expressing endogenous C5 protein (fifth component of mouse complement) as a result of transfection, to present their biosynthesized C5 to MHC class II-restricted T cells. B cells and fibroblasts expressing C5 were able to present several epitopes of this protein with MHC class II molecules, whereas macrophages were unable to do so, but readily presented C5 from an extracellular source. However, macrophage presentation of endogenous C5 could be achieved when they were treated with low doses of the lysosomotropic agent ammonium chloride. In the presence of an inhibitor of autophagy, presentation of endogenous C5 was abrogated, indicating that biosynthesized C5 is shuttled into lysosomal compartments for degradation before making contact with MHC class II molecules. Taken together, this suggests that proteolytic activity in lysosomes of macrophages may be excessive, compared with fibroblasts and B cells, and destroys epitopes of the C5 protein before they can gain access to MHC class II molecules. Thus, there are inherent differences in presentation pathways between antigen-presenting cell types; this could reflect their specialized functions within the immune system with macrophages focussing preferentially on internalization, degradation, and presentation of extracellular material.

Adenine↗
PubMed1997

Two complementary methods for predicting peptides binding major histocompatibility complex molecules.

Peptides that bind to major histocompatibility complex products (MHC) are known to exhibit certain sequence motifs which, though common, are neither necessary nor sufficient for binding: MHCs bind certain peptides that do not have the characteristic motifs and only about 30% of the peptides having the required motif, bind. In order to develop and test more accurate methods we measured the binding affinity of 463 nonamer peptides to HLA-A2.1. We describe two methods for predicting whether a given peptide will bind to an MHC and apply them to these peptides. One method is based on simulating a neural network and another, called the polynomial method, is based on statistical parameter estimation assuming independent binding of the side-chains of residues. We compare these methods with each other and with standard motif-based methods. The two methods are complementary, and both are superior to sequence motifs. The neural net is superior to simple motif searches in eliminating false positives. Its behavior can be coarsely tuned to the strength of binding desired and it is extendable in a straightforward fashion to other alleles. The polynomial method, on the other hand, has high sensitivity and is a superior method for eliminating false negatives. We discuss the validity of the independent binding assumption in such predictions.

Artificial Intelligence↗
PubMedDate not supplied

Immune responses to self peptides naturally presented by murine class II major histocompatibility complex molecules.

Peptides eluted from murine Major Histocompatibility Complex (MHC) class II molecules are predominantly fragments of self proteins, which include apolipoprotein E, cystatin-c, transferrin receptor, MHC class II and Ii chains. These naturally processed self peptides are expected to be presented during ontogeny. Therefore, immune responses to these peptides in syngeneic hosts may be under physiological control so as to modulate auto-reactivity. As would be expected from our current understanding, T cells reactive to such antigens should be deleted or clonally anergized. To explore this possibility, we investigated the immunogenicity of a number of these self peptides in mice that express MHC class II, from which these peptides were eluted. T cell and antibody responses were measured following immunization of mice with the appropriate peptide. Surprisingly, many of these peptides were highly immunogenic in normal mice. T cells reactive to these self peptides are restricted by syngeneic MHC class II and were blocked by alpha CD4 antibodies. T cells primed with the native protein in vivo could be challenged with the appropriate self peptide in vitro. Some of the self epitopes induce Th1 cells as indicated by IFN-gamma but not IL-4 production and others induce Th2 cells. Antipeptide antibodies were detected only at higher doses of antigen. Our results suggest that T cells specific for many of the naturally processed self peptides are not deleted but tolerance to these peptides is still maintained in vivo. Presumably the high-affinity self-reactive T cells are deleted in the thymus and the low-affinity self peptide reactive T cells remain unresponsive to antigen challenge in vitro. Upon antigen priming in vivo, many of these self-reactive T cells become activated and readily respond to antigen challenge in vitro. These results point to the physiological control of the maintenance of tolerance to naturally processed self peptides.

Amino Acid Sequence↗
PubMed1993

Peptide selection by class I molecules of the major histocompatibility complex.

Class I molecules of the major histocompatibility complex (MHC) bind peptides derived from cytoplasmic proteins. Comparison of over 100 such peptides reveals the importance of the carboxy-terminal residue in selective binding. Recent evidence implicates the proteases and transporters of the processing pathway in providing peptides with the correct residues at the carboxyl terminus.

Journal Article↗
PubMed1996

Neural cells from dogs with spontaneous distemper encephalitis express class II major histocompatibility complex molecules.

Expression of class II major histocompatibility complex (MHC) molecules by non-immune cells (e.g., parenchymal cells) leads to the presentation of self-antigens, and may have a role in the pathogenesis of many diseases mediated by autoimmunity. Such diseases, characterized by demyelination of the central nervous system and expression of class II MHC molecules on neural cells, include multiple sclerosis, experimental allergic encephalitis and Theiler's murine encephalomyelitis virus infection. Canine distemper encephalitis probably does not have an autoimmune character, but it shares many similarities with the aforementioned diseases. For this reason, the expression of class II MHC molecules in the brains of dogs with canine distemper encephalitis was investigated immunohistochemically. The results presented here demonstrate that canine microglia and astrocytes "upregulate" class II MHC expression in cases of encephalitis associated with chronic canine distemper.

Animals↗
PubMed2001

Kinetics and thermodynamics of beta 2-microglobulin binding to the alpha 3 domain of major histocompatibility complex class I heavy chain.

The major histocompatibility complex (MHC) class I molecule plays a crucial role in cytotoxic lymphocyte function. Functional class I MHC exists as a heterotrimer consisting of the MHC class I heavy chain, an antigenic peptide fragment, and beta2-microglobulin (beta2m). beta2m has been previously shown to play an important role in the folding of the MHC heavy chain without continued beta2m association with the MHC complex. Therefore, beta2m is both a structural component of the MHC complex and a chaperone-like molecule for MHC folding. In this study we provide data supporting a model in which the chaperone-like role of beta2m is dependent on initial binding to only one of the two beta2m interfaces with class 1 heavy chain. beta2-Microglobulin binding to an isolated alpha3 domain of the class I MHC heavy chain accurately models the biochemistry and thermodynamics of beta2m-driven refolding. Our results explain a 1000-fold discrepancy between beta2m binding and refolding of MHC1. The biochemical study of the individual domains of complex molecules is an important strategy for understanding their dynamic structure and multiple functions.

Animals↗
PubMed1992

Invariant chain can function as a chaperone protein for class II major histocompatibility complex molecules.

During biosynthesis, class II major histocompatibility complex molecules are intimately associated with invariant chain (Ii). The Ii-class II association has been shown to block peptide-class II binding and to affect the ultimate conformation of class II expressed on the cell surface. To assess the biochemical basis for the effects of Ii on class II, we have analyzed the biosynthesis of class II in EL4 cells transfected with I-Ad with and without Ii. In these studies, we found that Ii had a profound effect on the biosynthesis of I-Ad. In the absence of Ii, class II could form dimers efficiently, but these dimers appeared to be misfolded and this altered conformation resulted in the loss of some monoclonal antibody epitopes and inefficient transport from the endoplasmic reticulum to the Golgi. In addition, class II that was transported through the Golgi accumulated an abnormally increased molecular mass associated with N-linked glycosylation. Subsequent transfection of Ii into these cells resulted in recovery of normal class II conformation, causing a restoration of monoclonal antibody epitopes, efficient intracellular transport, and normal glycosylation. Together, these data indicate that Ii can have a profound effect on the folding, transport, and modification of class II molecules and suggest that one function of Ii may be to act as a class II-specific chaperone.

Animals↗
PubMed2002

A dominant negative mutant beta 2-microglobulin blocks the extracellular folding of a major histocompatibility complex class I heavy chain.

The major histocompatibility complex class I (MHC1) molecule plays a crucial role in cytotoxic lymphocyte function. beta 2-Microglobulin (beta 2m) has been demonstrated to be both a structural component of the MHC1 complex and a chaperone-like molecule for MHC1 folding. beta 2m binding to an isolated alpha 3 domain of MHC1 heavy chain at micromolar concentrations has been shown to accurately model the biochemistry and thermodynamics of beta 2m-driven MHC1 folding. These results suggested a model in which the chaperone-like role of beta 2m is dependent on initial binding to the alpha 3 domain interface of MHC1 with beta 2m. Such a model predicts that a mutant beta 2m molecule with an intact MHC1 alpha 3 domain interaction but a defective MHC1 alpha 1 alpha 2 domain interaction would block beta2m-driven folding of MHC1. In this study we generated such a beta 2m mutant and demonstrated that it blocks MHC1 folding by normal beta 2m at the expected micromolar concentrations. Our data support an initial interaction of beta 2m with the MHC1 alpha 3 domain in MHC1 folding. In addition, the dominant negative mutant beta 2m can block T-cell functional responses to antigenic peptide and MHC1.

Amino Acid Substitution↗
PubMed2001

Dynamic tuning of T cell reactivity by self-peptide-major histocompatibility complex ligands.

Intrathymic self-peptide-major histocompatibility complex class II (MHC) molecules shape the T cell repertoire through positive and negative selection of immature CD4(+)CD8(+) thymocytes. By analyzing the development of MHC class II-restricted T cell receptor (TCR) transgenic T cells under conditions in which the endogenous peptide repertoire is altered, we show that self-peptide-MHC complexes are also involved in setting T cell activation thresholds. This occurs through changes in the expression level of molecules on thymocytes that influence the sensitivity of TCR signaling. Our results suggest that the endogenous peptide repertoire modulates T cell responsiveness in the thymus in order to enforce tolerance to self-antigens.

Animals↗
PubMed1991

Production and characterization of alloantisera specific for bovine class II major histocompatibility complex antigens.

Ten alloantisera defining five major histocompatibility complex (MHC) class II specificities of the bovine lymphocyte antigen (BoLA) complex were produced and characterized. Eight antisera defining four of the specificities were generated by immunizing cattle with class I compatible-class II incompatible lymphocytes. The alloantiserum defining the fifth class II specificity was produced by skin implant immunization. A pregnancy serum specific for one of the class II specificities was also identified. The class II antigens recognized by these antisera were designated 'Dx' antigens to indicate that they are BoLA-D region antigens encoded by one or more undetermined class II loci. The molecules identified by the alloantisera are heterodimers composed of a 34-kd alpha and a 26- to 28-kd beta chain, and are expressed on B-lymphocytes but not on resting T-lymphocytes. In family studies the BoLA-Dx antigens segregated in linkage with the BoLA-A locus alleles. Most of the BoLA-A alleles present in the Cornell Holstein herd at a high frequency were found to exist in gametic association with two or more serologically defined class II haplotypes. On the basis of a population study it was determined that three pairs of class I and class II alleles (w10-Dx4, w31-Dx5, and c3-Dx2) were present in the Cornell herd at significantly increased frequencies.

Alleles↗
PubMed1993

Isolation and characterization of cDNA clones for chicken major histocompatibility complex class II molecules.

The chicken major histocompatibility complex (MHC), the B complex, is being intensively analysed at the DNA level. To further probe the molecular structure of chicken MHC class II genes, cDNA clones coding for chicken MHC class II (B-L) beta chain molecules were isolated from an inbred G-B2 Leghorn chicken spleen and liver. Twenty-nine cDNA clones were isolated from the spleen and eight cDNA clones were isolated from the liver. Based on restriction maps, most clones could be clustered into one family of genes. Four cDNA clones were sequenced (S7, S10 and S19 from the spleen and L1, which was identical to S19, from the liver). Complete amino acid sequences of B-L beta chain molecules were predicted from the nucleotide sequences of the cDNA clones. Although both the nature and the location of the conserved residues were similar in chicken and mammalian sequences, some species-specific differences were found, suggesting that the structures of the B-L molecules of this haplotype are similar, but not identical, to their mammalian counterparts.

Amino Acid Sequence↗
PubMed1976

Genetics of transplantation: the major histocompatibility complex.

A genetic region called the major histocompatibility complex of MHC (which plays an important role in the control of graft survival) has been defined in a large number of different species. Several different loci of the MHC have been described, including loci coding for transplantation antigens. These antigens can be divided into two categories: first, the SD antigens that were originally defined serologically and that appear to function as targets for the killer lymphocytes involved in the rejection of a graft and second, the LD antigens that were originally defined by lymphocyte response in the mixed leukocyte culture test and that stimulate helper T lymphocytes. In addition, there are genes for other antigens (referred to as immune response-associated or Ia antigens) and genes that control the ability of an animal to respond immunologically to antigenic stimuli, the immune response or Ir genes. There is evidence for epistatic interaction between these genes in that immune recognition of LD and SD antigens lead to a more pronounced development of cytotoxic (killer) cells than does stimulation by either antigen alone. In addition, the genetic control of immune responsiveness appears, at least in some systems, to reside in two very closely linked genes that may function better in the cis than in the transposition. This latter finding suggests a possible explanation for the strong linkage disequilibrium found between genes of the MHC. A number of new tests have been described to define the antigens of the MHC. Results of these tests have been used for studies of transplantation immunology but in addition to study the very strong associations that exist between some of the MHC antigens in man and various diseases.

Antibody Formation↗
PubMed2006

Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands.

Genes of the major histocompatibility complex (MHC), which play a critical role in immune recognition, influence mating preference and other social behaviors in fish, mice, and humans via chemical signals. The cellular and molecular mechanisms by which this occurs and the nature of these chemosignals remain unclear. In contrast to the widely held view that olfactory sensory neurons (OSNs) in the main olfactory epithelium (MOE) are stimulated by volatile chemosignals only, we show here that nonvolatile immune system molecules function as olfactory cues in the mammalian MOE. Using mice with targeted deletions in selected signal transduction genes (CNGA2, CNGA4), we used a combination of dye tracing, electrophysiological, Ca2+ imaging, and behavioral approaches to demonstrate that nonvolatile MHC class I peptides activate subsets of OSNs at subnanomolar concentrations in vitro and affect social preference of male mice in vivo. Both effects depend on the cyclic nucleotide-gated (CNG) channel gene CNGA2, the function of which in the nose is unique to the main population of OSNs. Disruption of the modulatory CNGA4 channel subunit reveals a profound defect in adaptation of peptide-evoked potentials in the MOE. Because sensory neurons in the vomeronasal organ (VNO) also respond to MHC peptides but do not express CNGA2, distinct mechanisms are used by the mammalian main and accessory olfactory systems for the detection of MHC peptide ligands. These results suggest a general role for MHC peptides in chemical communication even in those vertebrates that lack a functional VNO.

Animals↗
PubMed2006

'Ovar-Mhc' - ovine major histocompatibility complex: structure and gene polymorphisms.

The major histocompatibility complex (MHC) in sheep, Ovar-Mhc, is poorly characterised, when compared to other domestic animals. However, its basic structure is similar to that of other mammals, comprising class I, II and III regions. Currently, there is evidence for the existence of four class I loci. The class II region is better characterised, with evidence of one DRA, four DRB (one coding and three non-coding), one DQA1, two DQA2, and one each of the DQB1, DQB2, DNA, DOB, DYA, DYB, DMA, and DMB genes in the region. The class III region is the least characterised, with the known presence of complement cascade (C4, C2 and Bf), TNFalpha and CYP21 genes. Products of the class I and II genes, MHC molecules, play a pivotal role in antigen presentation required for eliciting immune responses against invading pathogens. Several studies have focused on polymorphisms of Ovar-Mhc genes and their association with disease resistance. However, more research emphasis is needed on characterising the remaining Ovar-Mhc genes and developing simplified and cost-effective methods to score gene polymorphisms. Haplotype screening, employing multiple markers rather than single genes, would be more meaningful in MHC-disease association studies, as it is well known that most of the MHC loci are tightly linked, exhibiting very little recombination. This review summarises the current knowledge of the structure of Ovar-Mhc and polymorphisms of genes located in the complex.

Animals↗
PubMed1996

Pemphigus vulgaris in distant relatives of two families: association with major histocompatibility complex class II genes.

We describe major histocompatibility complex (MHC) class II gene haplotypes in two extended families, each of which has two members with pemphigus vulgaris (PV). One family is of Ashkenazi Jewish descent and the other family of English-Scottish descent. In one family the patients are distant relatives; in the other, both share the same mother but have different fathers. The affected relatives in the two families have never shared a common environment and live in distant states. All four PV patients, regardless of whether they were of Ashkenazi Jewish or of English-Scottish descent, had the same haplotype, namely HLA-DRB1 0402, DQA1 0301, DQB1 0302. Thus the PV patients, even though distantly related within a family, had the same MHC class II haplotype previously documented in Jewish patients. This observation further supports the concept that PV may result from an enhanced genetic susceptibility or predisposition to the disease.

Adult↗