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At least 73 records · Page 4Linked to original sources
PubMed2006

Interferon-gamma induces major histocompatibility class II transactivator (CIITA), which mediates collagen repression and major histocompatibility class II activation by human aortic smooth muscle cells.

Chronic inflammation in atherosclerosis is responsible for plaque instability through alterations in extracellular matrix. Previously, we demonstrated that major histocompatibility class II (MHC II) transactivator (CIITA) in a complex with regulatory factor for X box 5 (RFX5) is a crucial protein mediating interferon (IFN)-gamma-induced repression of collagen type I gene transcription in fibroblasts. This article demonstrates that, in smooth muscle cells (SMCs), IFN-gamma dramatically increases the expression of CIITA isoforms III and IV, with no increase in expression of CIITA isoform I. Expression of CIITA III and IV correlates with decreased collagen type I and increased MHC II gene expression. Exogenous expression of CIITA I, III, and IV, in transiently transfected SMCs, represses collagen type I promoters (COL1A1 and COL1A2) and activates MHC II promoter. Levels of CIITA and RFX5 increase in the nucleus of cells treated with IFN-gamma. Moreover, simvastatin lowers the IFN-gamma-induced expression of RFX5 and MHC II in addition to repressing collagen expression. However, simvastatin does not block the IFN-gamma-induced expression of CIITA III and IV, suggesting a CIITA-independent mechanism. This first demonstration that RFX5 and CIITA isoforms are expressed in SMCs after IFN-gamma stimulation suggest that CIITA could be a key factor in plaque stability in atherosclerosis.

Aorta↗
PubMed1999

Detailed in vivo analysis of interferon-gamma induced major histocompatibility complex expression in the the central nervous system: astrocytes fail to express major histocompatibility complex class I and II molecules.

To recognize and respond immunologically to foreign antigens, T lymphocytes require the presentation of foreign peptides by MHC molecules. To determine which cells of the central nervous system (CNS) are capable of expressing MHC molecules, we used confocal microscopy and dual immunofluorescence with cell-specific and MHC-specific antibodies to study brain sections of adult mice. We took advantage of transgenic mice that initiate CNS-specific expression of IFN-gamma at 8 weeks of age. This inflammatory cytokine is a strong inducer of MHC expression both in culture and in vivo. From this analysis, we clearly found MHC class I and II expression on endothelial, microglial, and oligodendrocyte cell types, but did not find astrocytes or neurons capable of expressing either MHC class I or II molecules under these conditions. This finding suggests that, although microglia and oligodendrocytes may participate in the antigen presentation process in the organism, we found no in vivo evidence to support the concept that astrocytes act as antigen-presenting cells.

Animals↗
PubMed1994

A human minor histocompatibility antigen which appears to segregate with the major histocompatibility complex.

We obtained a cell line (So1) from a patient who rejected a T-depleted allogeneic BMT. Cytotoxic activity by cell-mediated lympholysis was found using So1 as effector and EBV-transformed donor B cells as targets, but no lysis of the patient's pretransplantation cells and of an unrelated HLA-nonidentical subject was observed, suggesting it was related to recognition of a minor transplantation antigen which could have contributed to rejection of the graft. To define the HLA-restricting element(s), cell-mediated lympholysis experiments were performed with several B cell lines as targets. So1 lysed only targets sharing an HLA-B44 antigen with the patient, thus demonstrating that the minor transplantation antigen recognized was restricted by HLA-B44. The absence of lysis against the patient's pretransplantation cells may be related to the absence of the minor antigen, suggesting that the patient's cytotoxic lymphocytes able to recognize a minor transplantation antigen on the donor cells contributed to the rejection of the HLA-identical graft. Mendelian segregation of this minor antigen was found in familial studies. Lysis was observed with cells from members of 2 families who had an association of HLA-B44 antigen in the haplotype and the minor antigen, whereas in 2 other HLA-B44-positive families, no lysis was found, probably because this minor antigen was absent. Furthermore, these family studies: (1) demonstrated that this minor antigen segregates with the MHC, suggesting its localization on chromosome 6; and (2) showed a close relationship between the minor antigen and HLA-B44, strongly suggesting a linkage disequilibrium between the minor antigen and its restriction antigen B44.

Adult↗
PubMed1980

Major histocompatibility complex-restricted self recognition. A monoclonal anti-I-Ak reagent blocks helper T cell recognition of self major histocompatibility complex determinants.

The functional role of cell surface Ia antigens has been studied for in vitro antibody responses, using as a probe the ability of anti-Ia reagents to inhibit these responses. A hybridoma monoclonal anti-Ia reagent specific for a product of I-Ak (Ia.17) profoundly inhibited in vitro antibody responses to TNP-KLH by spleen cells of the I-Ak but not I-Ab haplotype. This inhibition by anti-I-Ak product, but not by interaction with T or B cell product, in spite of the fact that functional B cells as well as accessory cells could be shown to express the determinant detected by this hybridoma reagent. These results suggest that the Ia expressed by accessory cells in of unique functional importance in these responses. To further characterize the function of Ia antigens in this response system, the mechanism of anti-I-Ak inhibition was determined. The inhibition resulting from interaction of anti-I-Ak with accessory cell Ia was not mediated by nonspecific suppressor cells, nor was there nonspecific interference with accessory cell function as a result of the binding of anti-Ia antibody. The relationship between anti-Ia inhibition and T helper cell recognition of self determinations on accessory cells was analyzed using T cells from radiation bone marrow chimeras. It was demonstrated that (B10 X B10.A)F1 leads to B10 (F1 leads to B10) chimera T cells were able to cooperate with B10 (H-2b and I-Ab) but not B10.A (H-2a and I-Ak) accessory cells for responses to TNP-KLH; F1 leads to B10.A T cells were able to cooperate with B10.A but not B10 accessory cells; and both chimera populations were able to cooperate with (B10 X B10.A)F1 (F1) accessory cells. Monoclonal anti-I-Ak inhibited the cooperation of F1 leads to B10.A T cells with the same F1 accessory cells. Thus, inhibition by anti-I-Ak is dependent upon active helper T cell recognition of I-Ak-encoded determinants expressed on accessory cells. These findings demonstrate that T cells recognize self Ia determinants expressed on accessory cells, and that such recognition is required for the generation of T cell-dependent antibody responses.

Animals↗
PubMed1989

Analysis of peptide binding patterns in different major histocompatibility complex/T cell receptor complexes using pigeon cytochrome c-specific T cell hybridomas. Evidence that a single peptide binds major histocompatibility complex in different conformations.

The interaction of TCR, antigen, and MHC complex has been analyzed using synthetic peptide antigens and a series of single amino acid-substituted analogues. Two similar antigens, mouse cytochrome c (mcyt c) and pigeon cytochrome c (pcyt c), elicit T cell responses in strains of mice bearing MHC class II Ek beta Ek alpha (B10.A), Eb beta Ek alpha [B10.A(5R)], and Es beta Ek alpha [B10.S(9R)]. The immunogenic regions of these antigens are located in the peptide sequence p88-104 for pcyt c and m88-103 for mcyt c. The limited T cell repertoire for these antigens is comprised of four groups of T cell phenotypes that have very few differences in their TCR gene make up. In this paper, we examine the diversity in their fine specificity for each of the antigens, m88-103 and p88-104, complexed with each of the I-Ek haplotypes. Epitopes, i.e., residues that interact with the TCR, and agretopes, i.e., residues in the MHC-binding site, were assigned for the two peptide antigens in the presence of APC bearing E beta kEk alpha, Eb beta Ek alpha, or Eb beta Ek alpha using T cell hybridomas of the phenotypes I, IIIa, and IV. From our results, we conclude that first, the substitution of any residue between 95 and 104 of the cytochrome c peptide changed the antigenic potency of the peptide for at least one of the hybridomas. Second, each T cell type has a different recognition pattern of epitopes and agretopes for a particular antigen-MHC complex, thus, ruling out a static model of T cell recognition, which assigns certain, invariant agretopic residues to the peptide by which it interacts with the MHC molecule independently of the TCR. Third, the same T cell hybridoma responded to the antigens differently when presented on various MHC molecules, implying that overall changes in the MHC groove, as displayed by the three haplotypes, may affect the efficiency in binding the peptide. Fourth, since most of the residues are used as epitopes by at least one of the T cell specificities, the peptide appears to be recognized in a different conformation by each T cell hybridoma phenotype; and, finally, the epitopic and agretopic residues do not segregate, for any one of the T cell specificities, in such a way that suggests they are recognized in a helical conformation. In summary, our results suggest that a single peptide may generate diversity in the T cell response by virtue of its conformational flexibility within the TCR-MHC-antigen complex.

Amino Acid Sequence↗
PubMedDate not supplied

Rabbit major histocompatibility complex. IV. Expression of major histocompatibility complex class II genes.

The rabbit MHC class II DP, DQ, and DR alpha and beta chain genes were transfected into murine B lymphoma cells. The transfected cells expressed R-DQ and R-DR molecules on the cell surface but they did not express the R-DP genes either on the cell surface or at the level of mRNA. Northern blot analyses showed that the R-DP genes were expressed, albeit at low levels, in rabbit spleen. Similar analyses showed that the R-DQ and R-DR genes were expressed at high levels in rabbit spleen. A new monoclonal anti-rabbit class II antibody, RDR34, has been developed and shown to react with the R-DR transfected cells and not with the R-DQ transfected cells. The previously described monoclonal anti-rabbit class II antibody, 2C4, reacted with the R-DQ transfected cells and not with the R-DR transfected cells. Thus, 2C4 and RDR34 MAb's are specific for the R-DQ and R-DR molecules, respectively. Each of the antibodies reacted with approximately 50% of rabbit spleen cells as shown by immunofluorescent antibody studies.

Animals↗
PubMed1985

Low expression of human histocompatibility leukocyte antigen-DR is associated with hypermethylation of human histocompatibility leukocyte antigen-DR alpha gene regions in B cells from patients with systemic lupus erythematosus.

The relationship between the expression of HLA-DR antigens and the HLA-DR alpha gene methylation was examined in systemic lupus erythematosus (SLE). Using permanent B cell lines, we found reduced DR expression in SLE. The low DR expression was correlated with high anti-DNA antibody titers in patients' sera. The amounts of DR alpha message were lower in SLE cells than in normal controls, suggesting that the low expression of DR antigens is associated with gene functions. The extent of DNA methylation was examined at five CCGG sites in the HLA-DR alpha locus. DNA from both SLE and normal cells showed variable methylation patterns. Since the DR alpha gene is a single-copy gene, such a variability is the result of assaying a mixture of transformed clones containing methylated DR alpha gene, with other clones containing unmethylated DR alpha gene. A distinctive feature of normal cells was a consistent methylation pattern: 12 normal cell lines showed exactly the same pattern. In contrast, 28 SLE cell lines showed a cell-line-specific methylation, and hypermethylation at the DR alpha locus. The hypermethylation is often associated with transcriptionally inactive genes. Thus, our results suggest that (a) B cells with hypermethylated DR genes might express no or few DR antigens; (b) the ratio of cells with differently methylated DR genes is consistent in normal individuals, while, in SLE patients, cells with hypermethylated DR genes predominate, resulting in apparently reduced DR antigen expression; and (c) the aberrant DR expression could be associated directly with immunoregulatory dysfunctions in SLE disease.

Antibodies, Antinuclear↗
PubMed1992

Major histocompatibility complex class I restriction fragment length polymorphism analysis in highly inbred chicken lines and lines selected for major histocompatibility complex and immunoglobulin production.

Selected chicken populations were analyzed by restriction fragment length polymorphism (RFLP) with a chicken MHC Class I (B-F) cDNA probe. The 13 highly inbred chicken lines differed in genetic origin and in MHC (B) haplotype, as distinguished by using hemagglutination with antisera against B-G and B-F antigens. The S1 sublines differed for B haplotype and antibody response to a synthetic polypeptide, GAT. In the highly inbred lines, band-sharing between lines from different origins was less than that between lines from same origin, showing the influence of the genetic background on chicken MHC Class I gene RFLP. In the S1 line, use of three restriction endonucleases (BglII, PvuII, and TaqI) produced MHC Class I RFLP patterns that were associated with B haplotype, but not with immune response to GAT (IrGAT). A previous study in the authors' laboratory also demonstrated an association of MHC Class II beta RFLP patterns with B haplotype, but not IrGAT, in the same line, suggesting that IrGAT is not controlled by MHC Class I or Class II beta genes.

Animals↗