Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004364 (autoimmune disease)
24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The T lymphocytes that expand with age in the peripheral lymphoid organs of autoimmune disease-prone mice homozygous for the lpr mutation display deficient activation and proliferation in response to mitogenic lectins or antigen. In the present study, an attempt was made to correlate the deficient agonist-induced proliferation of these lpr T cells with early transmembrane signaling events mediated by receptor-coupled phosphoinositide hydrolysis. lpr T cells were capable of binding the agonistic lectin, phytohemagglutinin, in a normal manner. In addition, they expressed on their surface the antigen-specific T cell receptor-CD3 complex, which is required for T cell activation, albeit at a lower density than that found on congenic +/+ T cells. Furthermore, lpr T cells contained normal levels of the Ca2+- and phospholipid-dependent enzyme, protein kinase C, and the enzyme was translocated from the cytosol to the particulate fraction upon phorbol ester treatment. On the other hand, the lpr T cells displayed a markedly deficient agonist-induced phosphoinositide hydrolysis in comparison with their congenic +/+ counterparts, as indicated by the minimal accumulation of the phosphoinositide-derived second messengers, inositol phosphates and diacylglycerol. The defective step(s) in transmembrane signaling was bypassed by a combination of phorbol ester plus Ca2+ ionophore, which reconstituted proliferative responses of lpr T cells to normal levels, suggesting that: (a) the phosphoinositide signaling pathway plays an obligatory role in T cell activation; and (b) signaling events subsequent to phosphoinositide hydrolysis are, for the most part, intact in lpr T cells. The deficient step(s) in lpr T cell activation precedes, therefore, the generation of phosphoinositide-derived second messengers and could be due to defective function of the T cell receptor-CD3 complex, GTP-binding proteins, and/or phosphoinositide-specific phosphodiesterase. It remains to be determined whether the deficient signaling event(s) in lpr T cells is a direct pathologic consequence of the lpr gene, or rather, reflects the immature status of a normally minor thymic subset that is aberrantly exported and expanded in lpr mice.
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PMID:Lpr T cell hyporesponsiveness to mitogens linked to deficient receptor-stimulated phosphoinositide hydrolysis. 283 Nov 96

Recent immunogenetic studies of JRA patients have both helped to clarify subdivision into distinctive subtypes and identified those subtypes which may be related to adult rheumatic disease. Despite the variability of HLA associations from different geographic sources, a consensus appears to be emerging as to the most important associations. In addition to the HLA-DR locus, distinct associations with the HLA-DP and HLA-DQ loci have been described. Family studies have suggested an increased risk with certain haplotypes, particularly in the EOPA JRA population. Although inheritance patterns remain to be defined, recent studies with monoclonal antibodies, alloreactive T cell clones, and DNA have identified the existence of specific epitopes encoded by a variety of Ia molecules which may be more directly related to disease susceptibility. The concept of an epitope dose effect is put forward to account for the variable HLA association with disease, particularly with regard to EOPA JRA. Further developments in the definition of micropolymorphisms of Ia molecules at the genomic level as well as the possible involvement of other genetic loci, in particular T cell receptor variable gene products, should help clarify our understanding of the role of genetic factors in the aetiology of JRA. The studies of the last two decades indicate that inferences made by Carter (1969) on the 'polygenic, weakly penetrant genetic effect' in autoimmune disease are indeed applicable to JRA.
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PMID:Population genetics and molecular biology of the childhood chronic arthropathies. 290 73

In an attempt to determine whether genes involved in T cell antigen recognition are structurally abnormal and thereby promote murine systemic lupus, we analyzed the structural integrity of the D, J, and C region elements of the T cell receptor alpha and beta chain genes in all major lupus strains and several normal strains. Within the limits of restriction fragment length polymorphism analysis, all strains had an identical genomic organization, except the NZW mice, in which a deletion of the C beta 1-D beta 2-J beta 2 elements was found. Sequence analysis of NZW genomic elements containing this deletion placed its probable origin within the first exon of C beta 1, and extending to a complementary region within the first exon of C beta 2. The significance of this abnormality in the pathogenesis of systemic autoimmune disease remains to be determined.
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PMID:Delineation of a defect in T cell receptor beta genes of NZW mice predisposed to autoimmunity. 300 67

In contrast to parental New Zealand Black (NZB) or New Zealand White (NZW) mice, (NZB x NZW)F1 mice exhibit a lupus-like disease characterized by high levels of immunoglobulin G (IgG) antinuclear antibodies in their serum and a fatal immune-complex glomerulonephritis. At least three gene loci have been identified in NZW mice that could potentially contribute to a T cell-dependent autoimmune disease, including the T cell receptor alpha- and beta-chain gene complexes and the major histocompatibility complex (MHC). The NZW T cell receptor beta-chain complex appeared to be particularly unusual in that the C-beta-1, D-beta-2, and J-beta-2 gene segments have been deleted. Approximately one half of (NZB x NZW)F1 x NZB backcross mice developed severe renal disease and elevated levels of IgG antibodies to double-stranded deoxyribonucleic acid and histone, suggesting that only one dominant gene or closely linked group of genes accounts for the NZW genetic contribution to F1 disease. Despite the extremely unusual nature of the NZW T cell receptor beta-chain gene complex, we found no association of disease expression with the presence of this allele in the backcross mice. There was also no correlation of disease incidence with the presence of the NZW T cell receptor alpha-chain allele. In contrast, nearly 90 percent of the backcross mice with the NZW MHC expressed severe autoimmune disease compared with 12 percent of the mice that did not carry this haplotype. Thus, the NZW MHC or gene(s) linked to this locus appears to be the only dominant NZW genetic contribution to F1 disease. Recent preliminary studies mapping genes that are located centromeric and telomeric to the NZW MHC suggest that the disease-associated gene(s) lies within the MHC.
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PMID:Genetic contributions to lupus-like disease in NZB/NZW mice. 326 57

Unlike parental NZB or NZW mice, (NZB X NZW)F1 mice exhibit a lupus-like disease characterized by high serum levels of IgG antinuclear antibodies and a fatal immune-complex glomerulonephritis. At least three unlinked gene loci can be distinguished in NZW mice that conceivably contribute to a T cell-dependent autoimmune disease, including the MHC (H-2z) and the T cell receptor alpha and beta chain gene complexes. We undertook an (NZB X NZW)F1 X NZB backcross to determine the relative contribution of these NZW genes to lupus-like renal disease and autoantibody production in F1 mice. The incidence of severe renal disease and elevated levels of IgG antibodies to dsDNA and histone in the backcross mice was approximately half of that observed in (NZB X NZW)F1 mice. Furthermore, there was a strong correlation between the presence of the NZW H-2z haplotype and lupus-like disease in backcross mice. Approximately 90% of backcross mice with disease carried the NZW H-2z locus compared with 16% of mice without disease; nearly 90% of H-2d/z mice expressed severe autoimmune disease. In contrast, no association was apparent between the presence of the NZW T cell receptor alpha chain gene complex or beta chain gene complex and severe renal disease or autoantibody production. Thus, the NZW MHC or gene(s) linked to this locus appear to be the only dominant NZW genetic contribution to F1 disease.
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PMID:The contribution of NZW genes to lupus-like disease in (NZB x NZW)F1 mice. 349 6

To determine the transacting genetic factors of NZW contributing to the development of autoimmune disease in (NZB X NZW)F1 (B/W F1) mice, we examined the relationship between the T cell receptor beta chain gene deletion and the severity of autoimmune manifestations in 76 B/W F1 X NZB backcross mice. Very high association between the T cell receptor beta chain gene deletion and the development of autoimmune manifestations including the production of IgG anti-DNA antibodies and circulating retroviral gp70 immune complexes was observed, indicating that a defect in the NZW T cell receptor beta chain gene or a locus closely linked to it contributes to the autoantibody formation in B/W F1.
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PMID:Does the deletion within T cell receptor beta-chain gene of NZW mice contribute to autoimmunity in (NZB X NZW)F1 mice? 375 54

DNA profiles (immunoprints) were generated for 120 patients suffering from early onset pauciarticular chronic arthritis (EOPA-JCA) and > 500 healthy controls utilizing highly polymorphic microsatellites in the vicinity of immunorelevant genes. Six T cell receptor (TCR) markers for the CD3D, TCRDVAJ, TEA, TCRBV6S1, BV6S3, BV6S7 and BV13S2 genes were analysed. Furthermore markers for the cell surface molecule CD40L, for cytokine genes (IL-1A, IL-2, IFN-alpha, FGF-alpha, TNF-alpha), the chromosomal region of the IRF2 and the cytokine receptor gene IL5RA were studied as well as two polymorphisms within the promotor region of the TNF-alpha gene. Coding region polymorphisms were evidenced indirectly by repeat length variation or they were predicted from the microsatellite distribution profiles and then confirmed by direct sequence analysis. Statistical evaluations were performed with respect to known predispositions, predominance of females (> 80%) and HLA-DR and -DQ haplotypes. Cell surface molecules (TCR, CD40L, IL5RA) as well as almost all cytokines (IL-1A, IFN alpha, FGFA, IRF2 region) were excluded as predisposing in our JCA panel. The TNF-alpha microsatellite alleles (GT)10-12 contribute considerably to manifestation of the disease, in HLA-DRB1*11(12) individuals (RR = 12.8). The TNF-alpha allele is not found in linkage disequilibrium with HLA-DRB1*11(12) and may be present on either chromosome 6. Thus, a novel susceptibility factor probably within the TNFA/TNFB gene region has been identified via linkage with the TNF-alpha microsatellite allele. Apparently complex compositions of the genetic background rather than single genes provide the precondition for manifestation of the autoimmune disease EOPA-JCA. Immunoprinting unravels the variability of the immunological genome via the semi-directed microsatellite approach efficiently.
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PMID:Immunoprinting excludes many potential susceptibility genes as predisposing to early onset pauciarticular juvenile chronic arthritis except HLA class II and TNF. 749 83

The molecular diversity of gamma delta T cells has not previously been investigated in experimental allergic encephalomyelitis (EAE). This study characterised the gamma delta T cell receptor (TCR) variable (V) region repertoires of T cells infiltrating the brains of EAE mice during development of the disease. TCR gamma- and delta-specific cDNAs were synthesised from total RNA prepared from brain samples and transcription of rearranged V genes was assessed by polymerase chain reaction amplification of TCR V-C transcripts and Southern blot analysis. In the early stages of EAE, the TCR gamma-chain repertoire consisted of V gamma 1-3 and V gamma 6 transcripts and, similarly, a few V delta transcripts that used primarily V delta 1, V delta 4 and V delta 5 gene segments were detected. During the progression of EAE, however, most V gamma and V delta TCR transcripts were observed in the brain. These results indicate that in the course of murine EAE there is an initial infiltration into the brain of a restricted population of gamma delta T cells followed by a heterogeneous gamma delta TCR repertoire as the disease develops. Moreover, the data suggest that gamma delta T cells may play a role in the pathogenesis of demyelinating autoimmune disease.
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PMID:Gamma delta T cell receptor variable region usage during the development of experimental allergic encephalomyelitis. 749 85

The feasibility of using T cell receptor (TcR) antagonist peptides to inhibit autoimmune disease has been examined. First, the fine antigenic structure of the I-As-restricted encephalitogenic determinant proteolipid protein (PLP) 139-151 has been analyzed. It was found that residues 145 and 148 were I-As anchor residues, and residue 144 appeared to be especially critical in T cell activation. Residues 142, 143, 146, and 147 were found to be crucial for activation of some, but not all, of the T cells studied. Next, good I-As-binding nonantigenic analogs were tested for TcR antagonism. Accordingly, several single substitution analogs were identified which could act as TcR antagonists. Moreover, when two such analogs were combined, the resulting TcR antagonist pool inhibited most of the PLP 139-151-specific T cell clones in vitro. When the efficacy of this TcR antagonist pool in inhibiting EAE induction in vivo was examined, it was found that the analog pool was a remarkably potent inhibitor of disease induction. The TcR antagonist pool was approximately 10-fold more potent than our best major histocompatibility complex blocker and was still capable of significant inhibition when injected in equimolar amounts with the encephalitogenic PLP 139-151 determinant.
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PMID:T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis. 751 36

Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease that serves as an animal model for multiple sclerosis. Oral administration of myelin basic protein (MBP) suppresses EAE by inducing peripheral tolerance. T cell clones were isolated from the mesenteric lymph nodes of SJL mice that had been orally tolerized to MBP. These clones were CD4+ and were structurally identical to T helper cell type 1 (TH1) encephalitogenic CD4+ clones in T cell receptor usage, major histocompatibility complex restriction, and epitope recognition. However, they produced transforming growth factor-beta with various amounts of interleukin-4 and interleukin-10 and suppressed EAE induced with either MBP or proteolipid protein. Thus, mucosally derived TH2-like clones induced by oral antigen can actively regulate immune responses in vivo and may represent a different subset of T cells.
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PMID:Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. 752 Jun 5


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