Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rheumatoid arthritis (RA) is a common, chronic, autoimmune, inflammatory disease that is influenced by genetic factors including gender. Many studies suggest that the genetic risk for RA is determined by the MHC, in particular class II alleles with a 'shared epitope' (SE), and multiple non-MHC loci. Other studies indicate that RA and other autoimmune diseases, in particular insulin-dependent diabetes mellitus (IDDM) and autoimmune thyroid disease (ATD), share genetic risk factors. Rat collagen-induced arthritis (CIA) is an experimental model with many features that resemble RA. The spontaneous diabetes-resistant bio-breeding rat, BB(DR), is of interest because it is susceptible to experimentally induced CIA, IDDM and ATD, and it has an SE in its MHC class II allele. To explore the genetics of CIA, including potential gender influences and the genetic relationships between CIA and other autoimmune diseases, we conducted a genome-wide scan for CIA regulatory loci in the F(2) progeny of BB(DR) and CIA-resistant BN rats. We identified 10 quantitative trait loci (QTLs), including 5 new ones (Cia15, Cia16*, Cia17, Cia18* and Cia19 on chromosomes 9, 10, 18 and two on the X chromosome, respectively), that regulated CIA severity. We also identified four QTLs, including two new ones (Ciaa4* and Ciaa5* on chromosomes 4 and 5, respectively), that regulated autoantibody titer to rat type II collagen. Many of these loci appeared to be gender influenced, and most co-localized with several other autoimmune trait loci. Our data support the view that multiple autoimmune diseases may share genetic risk factors, and suggest that many of these loci are gender influenced.
Hum Mol Genet 2000 Sep 22
PMID:Genetic dissection of a rat model for rheumatoid arthritis: significant gender influences on autosomal modifier loci. 1100 27

The major histocompatibility complex (MHC) class II transactivator CIITA plays a pivotal role in the control of the cellular immune response through the quantitative regulation of MHC class II expression. We have analyzed a region of CIITA with similarity to leucine-rich repeats (LRRs). CIITA LRR alanine mutations abolish both the transactivation capacity of full-length CIITA and the dominant-negative phenotype of CIITA mutants with N-terminal deletions. We demonstrate direct interaction of CIITA with the MHC class II promoter binding protein RFX5 and could also detect novel interactions with RFXANK, NF-YB, and -YC. However, none of these interactions is influenced by CIITA LRR mutagenesis. On the other hand, chromatin immunoprecipitation shows that in vivo binding of CIITA to the MHC class II promoter is dependent on LRR integrity. LRR mutations lead to an impaired nuclear localization of CIITA, indicating that a major function of the CIITA LRRs is in nucleocytoplasmic translocation. There is, however, evidence that the CIITA LRRs are also involved more directly in MHC class II gene transactivation. CIITA interacts with a novel protein of 33 kDa in a manner sensitive to LRR mutagenesis. CIITA is therefore imported into the nucleus by an LRR-dependent mechanism, where it activates transcription through multiple protein-protein interactions with the MHC class II promoter binding complex.
Mol Cell Biol 2000 Oct
PMID:CIITA leucine-rich repeats control nuclear localization, in vivo recruitment to the major histocompatibility complex (MHC) class II enhanceosome, and MHC class II gene transactivation. 1100 67

Contact sensitivity is a T-cell-mediated immune disease that can occur when low-molecular-weight chemicals penetrate the skin. In vivo topical application of chemical sensitizers results in morphological modification of Langerhans cells (LC). Moreover, within 18 h, LC increase their major histocompatibility complex (MHC) class II antigens expression and migrate to lymph nodes where they present the sensitizer to T lymphocytes. We wanted to determine if such an effect could also be observed in vitro. However, because of the high genetic diversity encountered in humans, assays were performed with dendritic cells (DC) obtained from a Balb/c mouse strain. The capacity of a strong sensitizer, DNBS (2,4-dinitrobenzene sulfonic acid), to modulate the phenotype of bone marrow-derived DC in vitro, was investigated. A specific and marked increase of MHC class II molecules expression was observed within 18 h. To eliminate the use of animals in sensitization studies, the XS52 DC line was tested at an immature stage. A 30-min contact with the strong sensitizers DNBS and oxazolone, or the moderate mercaptobenzothiazole, resulted in upregulation of MHC class II molecules expression, analyzed after 18-h incubation. This effect was not observed with irritants (dimethyl sulfoxide and sodium lauryl sulfate) nor with a neutral molecule (sodium chloride). These data suggested the possibility of developing an in vitro model for the identification of the sensitizing potential of chemicals, using a constant and non animal-consuming material.
In Vitr Mol Toxicol 2000
PMID:Contact sensitizers specifically increase MHC class II expression on murine immature dendritic cells. 1103 22

Susceptibility to multiple sclerosis (MS) is associated with certain MHC class II haplotypes, in particular HLA-DR2. Two DR beta chains, DRB1*1501 and DRB5*0101, are co-expressed in the HLA-DR2 haplotype, resulting in the formation of two functional cell surface heterodimers, HLA-DR2a (DRA*0101, DRB5*0101) and HLA-DR2b (DRA*0101, DRB1*1501). Both isotypes can present an immunodominant peptide of myelin basic protein (MBP 84-102) to MBP-specific T cells from MS patients. We have determined the crystal structure of HLA-DR2a complexed with MBP 86-105 to 1.9 A resolution. A comparison of this structure with that of HLA-DR2b complexed with MBP 85-99, reported previously, reveals that the peptide register is shifted by three residues, such that the MBP peptide is bound in strikingly different conformations by the two MHC molecules. This shift in binding register is attributable to a large P1 pocket in DR2a, which accommodates Phe92, in conjunction with a relatively shallow P4 pocket, which is occupied by Ile95. In DR2b, by contrast, the small P1 pocket accommodates Val89, while the deep P4 pocket is filled by Phe92. In both complexes, however, the C-terminal half of the peptide is positioned higher in the binding groove than in other MHC class II/peptide structures. As a result of the register shift, different side-chains of the MBP peptide are displayed for interaction with T cell receptors in the DR2a and DR2b complexes. These results demonstrate that MHC molecules can impose different alignments and conformations on the same bound peptide as a consequence of topological differences in their peptide-binding sites, thereby creating distinct T cell epitopes.
J Mol Biol 2000 Nov 24
PMID:Structural basis for the binding of an immunodominant peptide from myelin basic protein in different registers by two HLA-DR2 proteins. 1108 Apr 54

The CIITA coactivator is essential for transcriptional activation of MHC class II genes and mediates enhanced MHC class I transcription. We now report that CIITA contains an intrinsic acetyltransferase (AT) activity that maps to a region within the N-terminal segment of CIITA, between amino acids 94 and 132. The AT activity is regulated by the C-terminal GTP-binding domain and is stimulated by GTP. CIITA-mediated transactivation depends on the AT activity. Further, we report that, although constitutive MHC class I transcription depends on TAF(II)250, CIITA activates the promoter in the absence of functional TAF(II)250.
Mol Cell 2001 Jan
PMID:Transcriptional coactivator, CIITA, is an acetyltransferase that bypasses a promoter requirement for TAF(II)250. 1117 16

The expression of MHC class II molecules is actively regulated upon various cellular stimuli. Since apoptosis is an inducible cellular process, it was asked whether cells undergoing apoptosis would also modulate their expression of class II molecules. Using an EBV-transformed B-cell line, the cell surface expression of HLA-DR molecules was analyzed by fluorescence-activated flow cytometry on normal and oxidant-treated apoptotic cells. A rapid and continuous decrease in HLA-DR expression was observed in apoptotic cells. RNA analysis and semiquantitative RT-PCR of cytoplasmic beta-actin mRNA showed that apoptotic cells contain partially degraded RNA and much lower amounts of beta-actin mRNA. Nevertheless, when compared after normalization of intact mRNA amounts, the HLA-DRB mRNA signals were of similar strength in normal and apoptotic cells as determined by semiquantitative RT-PCR. Thus, the decrease in the number of class II molecules during apoptosis underlies no specific program for downregulation of HLA-DRB mRNA transcription but is due to a nonspecific degradation of RNA molecules accompanied by cell death.
Mol Cells 2000 Dec 31
PMID:Downregulation of MHC class II expression by oxidant-induced apoptosis in EBV-transformed B-cells. 1121 70

Specific and major histocompatibility complex (MHC)-restricted T-cell recognition of antigenic peptides is based on interactions of the T-cell receptor (TCR) with the MHC alpha helices and solvent exposed peptide residues termed TCR contacts. In the case of MHC class II-presented peptides, the latter are located in the positions p2/3, p5 and p7/8 between MHC anchor residues. For numerous epitopes, peptide substitution studies have identified the central residue p5 as primary TCR contact characterized by very low permissiveness for peptide substitution, while the more peripheral positions generally represent auxiliary TCR contacts. In structural studies of TCR/peptide/MHC complexes, this has been shown to be due to intimate contact between the TCR complementarity determining region (CDR) three loops and the central peptide residue. We asked whether this model also applied to two HLA-DR presented epitopes derived from an antigen targeted in type 1 diabetes. Large panels of epitope variants with mainly conservative single substitutions were tested for human leukocyte antigen (HLA) class II binding affinity and T cell stimulation. Both epitopes bind with high affinity to the presenting HLA-DR molecules. However, in striking contrast to the standard distribution of TCR contacts, recognition of the central p5 residue displayed high permissiveness even for non-conservative substitutions, while the more peripheral p2 and p8 TCR contacts showed very low permissiveness for substitution. This suggests that intimate TCR interaction with the central peptide residue is not always required for specific antigen recognition and can be compensated by interactions with positions normally acting as auxiliary contacts.
Mol Immunol 2000 Oct
PMID:Structural analysis of two HLA-DR-presented autoantigenic epitopes: crucial role of peripheral but not central peptide residues for T-cell receptor recognition. 1125 3

Following their migration into the thymus, hemopoeitic stem cell precursors enter a complex developmental pathway involving proliferation, differentiation and alphabetaT-cell receptor (alphabetaTCR)-mediated selection procedures, in order to generate mature T-cell populations ready for export to the periphery. Thus, a critical stage during intrathymic T-cell development involves the generation of functionally mature CD4+8- and CD4-8+ cells from immature CD4+8- precursor thymocytes, a poorly understood process referred to as positive selection. While interactions between the alphabetaTCR and MHC-peptide complexes are known to be essential for the initiation of positive selection, additional unknown signals are also required. Using an in vitro reaggregate thymic organ culture system which allows comparison of the abilities of various cell types to induce maturation of CD4+8+ precursors, we provide evidence that both MHC-peptide complexes and specialised accessory molecules must be provided by thymic epithelium for efficient mediation of positive selection. Moreover, analysis of positive selection in the presence of thymic and non-thymic stromal cells expressing MHC class II molecules with the same limited peptide array suggests that this unique ability of thymic epithelium to mediate positive selection of CD4+8- cells is not solely due to presentation of a specialised peptide repertoire, but is dependent upon provision of specialised accessory interactions.
Cell Mol Biol (Noisy-le-grand) 2001 Feb
PMID:Specialisation of thymic epithelial cells for positive selection of CD4+8+ thymocytes. 1129 46

During thymic development, immature thymocytes are selected through the interaction with self peptides loaded on self MHC molecules. Although there is a great deal of debates on how specifically thymocytes recognize self peptides during thymic selection, recent data suggest an important role of peptide diversity in selecting an adequate T-cell repertoire in the thymus. The findings that human T-cells, unlike mouse T-cells, express MHC class II molecules on their surfaces and can play as antigen presenting cells suggesting possible peripheral T-T interaction network has not been intensively studied so far. However, the facts that human thymocytes have surface expression of MHC class II molecules and thymocytes can be selected by thymocytes in in vitro re-aggregation culture system led us to propose a novel hypothesis - "T-T interaction during thymic selection". Our proposition is that peripheral T-T interaction through TCR-derived peptides might reflect the selection process in the thymus and that T-T interaction also plays an important role in thymic selection. This review deals with our thymic T-T interaction hypothesis and its implications on human T-cell development.
Cell Mol Biol (Noisy-le-grand) 2001 Feb
PMID:T-T interaction during thymic selection. 1129 48

To establish new tools for studying human thymic stromal cells, we transfected adherent cells from a human postnatal thymus using a plasmid encoding SV40 large T antigen. Among the cell lines obtained, we characterized four epithelial cell lines (LT-TEC1 to LT-TEC4) and one thymic myoid cell line (MITC). Several morphological, functional and phenotypic differences were observed between these 2 cell types. Epithelial cells were heterogeneous and larger than myoid cells. Untreated LT-TEC lines expressed MHC class I, ICAM-1 and LFA-3 antigens and not MHC class II antigens, similarly to primary thymic epithelial cells (PTEC), while MITC line expressed only class I and LFA-3 antigens. After IFN-gamma treatment, MHC class II and ICAM-1 antigens were markedly upregulated in LT-TEC lines but not in MITC, indicating the absence or a dysfunction of regulatory factors in MITC line. Myoid cells expressed mRNA for all the subunits of the acetylcholine receptor (AChR) while epithelial cells expressed only the alpha, beta and epsilon subunits. Strikingly, LT-TEC produced much more C-C chemokines and IL-6 than MITC cells, while these latter produced higher levels of IL-8 and TNF-alpha. Altogether, these results reveal phenotypic and functional differences between these two stromal cell types, suggesting a potential involvement of myoid cells in the thymic function.
Cell Mol Biol (Noisy-le-grand) 2001 Feb
PMID:Phenotypic and functional characterization of human thymic stromal cell lines. 1129 52


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