Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MRL-lpr/lpr mice have a Fas receptor mutation that leads to abnormalities of apoptosis, lymphoproliferation, and a lupus-like autoimmune disease associated with the production of autoantibodies. Other than Fas pathway defects, little is known about molecular abnormalities that predispose to autoimmunity. Protein kinase CK2 (also termed casein kinase II), a serine-threonine protein kinase whose targets include many critical regulators of cellular growth, is highly expressed in a lymphoproliferative disease of cattle and in many human cancers. Overexpression of the CK2alpha catalytic subunit in lymphocytes of transgenic mice leads to T cell lymphoma. We hypothesized that CK2 dysregulation and Fas mutation might cooperatively augment lymphocyte proliferation and transformation. We find that in MRL-lpr/lpr mice bearing the CK2alpha transgene, the lymphoproliferative process is dramatically exacerbated, as these mice develop massive splenomegaly and lymphadenopathy by 12 wk of age in association with increased autoantibody production and accelerated renal disease. The lymphoid organs are filled with the unusual B220+CD4-CD8- T cells typically seen in MRL-lpr/lpr mice, not the B220-CD4+CD8+ or B220-CD4-CD8+ T cells typically seen in CK2a transgenic lymphomas. The T cells do not fulfill the criteria for transformation, as they are polyclonal and not transplantable or immortal in cell culture. Thus, although the lpr lymphoproliferative and autoimmune syndrome is potentiated by the presence of the CK2a transgene, this combination of apoptotic and proliferative abnormalities appears to be insufficient to transform lymphoid cells.
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PMID:Acceleration of lpr lymphoproliferative and autoimmune disease by transgenic protein kinase CK2 alpha. 982 Apr 86

Previous reports have shown abnormal responses mediated via the TCR/CD3 pathway in T lymphocytes from systemic lupus erythematosus (SLE) patients. Recently, we and others have reported augmented TCR/CD3-mediated responses in lupus T cells. It is possible that the pattern of downstream biochemical signals triggered by TCR/CD3 ligation may be altered in T lymphocytes from patients with SLE, thus leading to abnormal distal cell responses. In this paper we have examined the phosphorylation of proteins on tyrosine residues in peripheral blood T lymphocytes from a group of SLE patients and controls. We found a lower frequency of constitutively tyrosine-phosphorylated 119- and 113-kDa substrates and an enhanced frequency of tyrosine-phosphorylated 66- and 25-kDa proteins in unstimulated cultures of SLE T lymphocytes, suggesting an altered pattern of tyrosine phosphorylation in T cells from patients in vivo. Additionally, the protein tyrosine phosphatase (PTP) activity of CD45 immunoprecipitates was lower in unstimulated lupus T cells and was enhanced after stimulation via the CD3 pathway in lupus but not control T lymphocytes. The present results seem to suggest abnormal regulation of in-vivo tyrosine phosphorylation in T cells from patients with SLE.
Lupus 1998
PMID:Abnormal pattern of tyrosine phosphorylation in unstimulated peripheral blood T lymphocytes from patients with systemic lupus erythematosus. 986 92

Abs reactive to DNA and DNA/histone complexes are distinguished by the presence of positively charged amino acids, such as arginine, in the heavy chain complementarity-determining region 3. The presence of these amino acids partly results from atypical V(H)-D-J(H) rearrangements such as D-D fusions and D inversions. Previous results in our laboratory demonstrated that newborn autoimmune MRL/MpJ-+/+ mice undergo these unusual recombinations more frequently when compared with normal C3H/HeJ controls. In addition, the heavy chain junctions in newborn MRL mice demonstrated a preferred usage of V(H)-proximal D genes and distal J(H) genes suggestive of secondary gene rearrangements. In this study we explore the possibility that adult MRL B220(+)IgM(-) pre B cells, which have not yet undergone Ag selection, exhibit similar rearrangement patterns. Indeed, MRL pre-B cells possessed more atypical rearrangements (D-D fusions) than those of C3H/HeJ mice. However, the biased use of upstream D genes and downstream J(H) genes observed in the newborn MRL mice was not present in the pre-B cell library. These results suggest that the heavy chain rearrangement process persists later during B cell life in lupus-prone mice and lead us to propose a model of heavy chain receptor revision in the periphery of autoimmune mice.
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PMID:Heavy chain revision in MRL mice: a potential mechanism for the development of autoreactive B cell precursors. 1103 88

The objectives were to provide estimates of the prevalence of autoantibody (Ab) directed to CD45 in lupus patients, identify the target autoantigen(s), and determine the ability of such reactivity to mediate neutralization of T lymphocytes. Sera from 64 patients were studied using 2 assays: Western blot and an ELISA with CD45 eluted from 3 cell lines as antigen (U937, Jurkat and Daudi). The role of carbohydrate specificity was investigated using enzyme digestion of blotted glycans, competition with sugars, and inhibition with lectins. Apoptosis was studied through annexin V binding, and cell cycle analysis using the propidium iodide method. AutoAb to CD45 were detected in 16/64 sera (25%) by Western blot, and 21/32 sera (66%) found positive in the ELISA. CD45 purified from Daudi cells was identified in the ELISA, but not in the blot. AutoAb were of the IgM and the IgG isotypes, but not specific for a particular cell type or CD45 isoform: 2 dominant specificities were recognized, one against p180, and another against high MW isoforms. Neuraminidase-induced enhancement of reactivity, together with the inhibitory effect of N-acetyl galactosamine and Dolichos diflorus lectin suggest that the epitopes are carbohydrates. AutoAb which were specific for activated CD4+T cells triggered the annexin V binding, and, in 2 of 4 cases, lymphocytes underwent apoptosis. In conclusion, carbohydrate conformational epitopes may be important as target antigens, and some CD45 autoAb have the capacity to neutralize activated T cells through anergy or apoptosis.
Lupus 2000
PMID:CD45 autoantibodies mediate neutralization of activated T cells from lupus patients through anergy or apoptosis. 1103 38

Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan, HMG), a traditional Japanese herbal medicine, has been used for disorders accompanying aging. Oral administration of HMG from 8 to 16 weeks of age to MRL/lpr mice as a lupus-like autoimmune model ameliorated significantly some nephritis parameters, proteinuria and immune complex deposition in the kidney. Further, HMG reduced significantly the degree of lymphadenopathy and the serum level of immunoglobulin (Ig) G2a anti-dsDNA specific auto-antibody, even at 12 weeks of age. Simultaneously, interferon (IFN)-gamma production from anti-CD3 stimulated B220- T cells was suppressed by HMG, whereas interleukin (IL)-4 production was promoted. Examination of cytokine mRNA expressions in CD4 positive cells showed clearly that T cell differentiation was shifted from T helper (Th)1 to Th2 predominance by HMG. Furthermore, we demonstrated that HMG suppressed IL-12 mRNA expression in spleen cells which is a marker of Th1 predominance in MRL/lpr mice. These results suggested that HMG modulated an imbalance toward Th1 predominance in MRL/lpr mice through inhibition of IL-12 production and ameliorated autoimmune disorders.
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PMID:Immunomodulating effect of a traditional Japanese medicine, hachimi-jio-gan (ba-wei-di-huang-wan), on Th1 predominance in autoimmune MRL/MP-lpr/lpr mice. 1136 38

The neonatal Ab and TCR repertoires are much less diverse, and also very different from, the adult repertoires due to the delayed onset of terminal deoxynucleotidyl transferase (TdT) expression in ontogeny. TdT adds nontemplated N nucleotides to the junctions of Igs and TCRs, and thus its absence removes one of the major components of junctional diversity in complementarity-determining region 3 (CDR3). We have generated TdT-deficient MRL/lpr, Fas-deficient (MRL-Fas(lpr)) mice, and show that they have an increased lifespan, decreased incidence of skin lesions, and much lower serum levels of anti-dsDNA, anti-chromatin, and IgM rheumatoid factors. The generalized hypergammaglobulinemia characteristic of MRL-Fas(lpr) mice is also greatly reduced, as is the percentage of CD4(-)CD8(-)B220(+) (double-negative) T cells. IgG deposits in the kidney are significantly reduced, although evidence of renal disease is present in many mice at 6 mo. CDR3 regions of both IgH and TCR from peripheral lymphocytes of MRL-Fas(lpr) mice are shorter in the absence of TdT, and there is a paucity of arginines in the IgH CDR3 regions of the MRL-Fas(lpr) TdT(-/-) mice. Because the amelioration of symptoms is so widespread, it is likely that the absence of N regions has more of an affect than merely decreasing the precursor frequency of anti-dsDNA B cells. Hence, either the T or B cell repertoires, or more likely both, require N region diversity to produce the full spectrum of autoimmune lupus disease.
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PMID:Terminal deoxynucleotidyl transferase deficiency decreases autoimmune disease in MRL-Fas(lpr) mice. 1154 42

The mechanisms of autoantibody production are not well understood. Germinal centers (GC) may be important sites of immune disregulation in autoimmune diseases. In this study, we document the presence of spontaneous GC formation in the spleens of several autoimmune mouse strains that spontaneously develop autoimmune Type I diabetes and a lupus-like disease. In contrast, mouse strains that do not develop lupus did not exhibit spontaneous formation of GC. In all of the autoimmune strains studied, GC were present at 1-2 months of age, a time that closely parallels the appearance of autoantibodies. Like the GC that develop after purposeful immunization, GC in autoimmune mice contained B220(+), PNA(+), and GL-7(+) B cells, and FDC-M1(+) follicular dendritic cells. In addition, spontaneously formed GC in autoimmunity and those caused by immunization were abrogated in a similar way by a short-term treatment with anti-CD40 ligand antibody. These data indicate that spontaneously forming GC in autoimmunity are similar to those appearing after purposeful immunization.
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PMID:Spontaneous formation of germinal centers in autoimmune mice. 1159 Jan 94

B cell receptor (BcR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated co-receptors. Mounting evidence indicates that abnormal BcR signaling, such as occurs in SHP-1 and Lyn-deficient mice, results in production of pathogenic autoantibodies and lupus-like glomerulonephritis, suggesting that altered signaling thresholds could underlie the development of systemic autoimmunity. To test this hypothesis, we investigated expression of BcR-associated signaling molecules in lymphocytes from patients with systemic lupus erythematosus (SLE) during inactive phases of the disease. We found that the transmembrane regulatory protein tyrosine phosphatase CD45 is expressed at abnormal levels. Strikingly, this reduction persisted during four months of follow-up. By contrast, despite its potent role as a regulator of thymus-independent immune responses and of B cell life span, the CD22 co-receptor is expressed at normal levels in B lymphocytes isolated ex vivo from SLE patients. We also noted unusual levels of the cytosolic protein tyrosine kinase Lyn and the protein tyrosine phosphatase SHP-1 in the lymphocytes of the patients. Since in normal B cells Lyn and SHP-1 act in concert within a common negative pathway in which CD45 counteracts SHP-I regulatory role, we propose that this feedback regulatory pathway is crippled to different degrees in human SLE B cells. Break of the balance between positive and negative signaling molecules likely modifies the BcR signaling thresholds. Such alterations, together with other factors, may contribute to the disruption of self-tolerance in this disease.
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PMID:Expression of B cell receptor-associated signaling molecules in human lupus. 1168 80

A set of 87 multicase families with systemic lupus erythemathosus (SLE) from European (Iceland, Sweden, England, Norway, Italy, and Greece) and recently admixed (Mexico, Colombia, and the United States) populations were genotyped and analyzed for 62 microsatellite markers on chromosome 1. By parametric two-point linkage analysis, six regions (1p36, 1p21, 1q23, 1q25, 1q31, and 1q43) were identified that have LOD scores of Z>or=1.50, with different contributions, depending on the population of origin of the families (European or admixed American). All of the regions have been described previously and have therefore been confirmed in this analysis. The locus at 1q31 showed a significant three-point LOD score of Z=3.79 and was contributed by families from all populations, with several markers and under the same parametric model. Analysis of a known mutation in the CD45 gene did not support the role that this mutation plays in disease. We conclude that the locus at 1q31 contains a major susceptibility gene, important to SLE in general populations.
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PMID:A major susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31. 1237 47

Mutations in a number of signaling components in mice can lead to strong autoimmune phenotypes. In some cases, these mutations likely compromise important feedback inhibitory pathways that downregulate antigen receptor signaling. For example, a deficiency of Lyn leads to a severe lupus-like autoimmunity. This autoimmunity may result from loss of a feedback inhibitory pathway in which Lyn phosphorylates CD22, triggering recruitment of the tyrosine phosphatase SHP-1 to the plasma membrane, which then dampens BCR signaling. Loss of Lyn also compromises an inhibitory pathway involving Fc gamma RIIb and SHIP, an inositol phosphatase. Mutation of Fyn exacerbates the autoimmunity caused by loss of Lyn. This may be due in part to a nonimmunological compromise in the integrity of the podocytes in the kidney, which may make the kidneys more susceptible to immune complex-induced damage. Fyn-deficient mice exhibit a number of immunological abnormalities and also exhibit some autoimmunity, although this is less severe than what is seen in Lyn-deficient mice. Recently a gain of function mutation in CD45 that may enhance activity of Src family tyrosine kinases has also been found to cause autoimmune disease, suggesting that the level of Src family tyrosine kinase activity is an important determinant of immune tolerance. Finally, several studies suggest that there is a significant interaction between Src family tyrosine kinases and the Fas pathway that is important for self-tolerance. Although these studies are still at an early stage, it seems clear that alterations in regulators of antigen receptor signaling can contribute to autoimmunity.
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PMID:Signaling mutations and autoimmunity. 1240 47


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