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

A relationship between lymphocytic activation and the overexpression of proto-oncogenes such as c-myb or c-myc has been demonstrated in human autoimmune disease. In autoimmune-prone MRL/l mice, which spontaneously develop lupus erythematosus (LE)-like lesions on the back, increased expression of myb RNA has been found in the lymphoid organs. We detected the overexpression of c-myb and c-myc proto-oncogenes in infiltrating cells in the cutaneous lesions of MRL/l mice by using in situ hybridization. No specific hybridization signals of either of the probes used were seen in the nonlesional skin of MRL/l mice or in the apparently normal skin of aged MRL/n and young MRL/l mice. These results suggest that the increased expression of myb and myc proto-oncogenes in the cutaneous LE-like lesions of MRL/l mice is related to a state of activation in the infiltrating cells and is involved in the development of these lesions.
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PMID:Histological detection of c-myb and c-myc proto-oncogene expression in infiltrating cells in cutaneous lupus erythematosus-like lesions of MRL/l mice by in situ hybridization. 172 75

The T cell-associated antigen CD5 has been shown to play an important role in the regulation of T cell activation. Monoclonal antibodies directed against CD5 upregulate helper function, and induce interleukin 2 (IL2) production by mature T cells as well as thymocytes. CD5 is also expressed on subsets of B cells associated with autoantibody production, and CD5+ B cells are present in increased numbers in patients with rheumatoid arthritis and systemic lupus erythematosis. More recently CD5 has been found to be present on human B lymphocytes following in vitro activation with phorbol myristate acetate. To date a similar functional role for CD5 has not to date been demonstrated for B cells. In this study we have shown that structurally similar CD5 molecules are present on activated B cells and T cells. In addition, CD5 on both stimulated B cells and T cells is phosphorylated, which may be important in the function of CD5 following activation. CD5 protein or mRNA was not detected on unstimulated splenic B cells depleted of any CD5+ cells. To investigate the control of CD5 expression, we examined a series of cytokines either alone or in combination for their effect on the induction of CD5. CD5 expression was specifically inhibited by IL4 but not by the other cytokines tested. This inhibition was very specific as IL4 did not inhibit the expression of other B cell activation antigens including CD25, B5, T9 and CD23 as well as the pan-B cell antigen CD20. The addition of other cytokines did not increase or reverse the inhibition of CD5 expression by IL4. This inhibition was demonstrated by immunofluorescence and flow cytometric analysis. Immunoprecipitation studies of 125I-labeled activated B cells demonstrated that there was a decrease in cell surface CD5 protein, and not simply inhibition of expression of a particular epitope. Northern blot analysis demonstrated that the expression of CD5 mRNA was markedly inhibited in the presence of IL4, whereas the induction of the protooncogene c-myb was unaffected. This suggests that IL4 inhibits CD5 protein expression on activated B cells by reducing the amount of CD5 mRNA transcription or increasing the degradation of CD5 mRNA. The role of the T cell-derived lymphokine IL4 in regulating CD5 expression may be important in the disease states characterized by increased numbers of CD5+ B cells.
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PMID:Expression and regulation of CD5 on in vitro activated human B cells. 247 77

Mice homozygous for the lpr gene spontaneously develop massive lymphoproliferation and an associated lupus-like autoimmune disease. In addition, the total lymphoid organs from these mice express high levels of mRNA for the c-myb proto-oncogene. Since enhanced c-myb mRNA is normally observed in immature thymic lymphocytes but not normal peripheral T cells, this may be indicative of the abnormal maturation state of lpr T lymphocytes. To determine whether the abnormal Lyt-2-, L3T4- (double negative) T lymphocytes in lpr mice express high c-myb, we purified this population by complement-mediated lysis with anti-L3T4 and Lyt-2 antibody from B6/lpr lymph nodes. We found that increased c-myb mRNA is expressed by this double-negative subset. To assess whether the high level of c-myb correlated with the aberrant undifferentiated state of these cells, we examined the effects of T cell differentiation inducers, phorbol ester and calcium ionophore, on c-myb expression. We found that c-myb levels were depressed after phorbol ester and calcium ionophore treatment. Concomitantly, transcriptional activation of the interleukin 2 receptor gene and progression of these cells through the cell cycle were observed. Thus, in B6/lpr double-negative T cells, the regulation of c-myb, interleukin 2 receptor, and cell proliferation may be interrelated. A combination of Northern hybridization and nuclear run-on transcription assays revealed two levels at which c-myb can be regulated in the double-negative T cell subset. The gene is transcriptionally regulated in untreated cells, but on induction with phorbol ester and calcium ionophore, the gene is negatively regulated via post-transcriptional mechanisms.
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PMID:The expression and regulation of c-myb transcription in B6/lpr Lyt-2-, L3T4-T lymphocytes. 311 95

MRL-lpr/lpr mice spontaneously develop massive T cell lymphadenopathy, autoantibodies, and immune-mediated pathology. These mice are thought to be models of various human autoimmune diseases, including systemic lupus, Sjogren's syndrome, and rheumatoid arthritis. We have used cyclosporin A (CS-A) treatment as a tool by which the mechanisms of immune-mediated pathology might be dissected. CS-A was used because of its known preferential inhibition of T cell function and the marked expansion in MRL-lpr/lpr mice of an unusual L3T4-, Lyt-2-, 6B2+ T cell population. CS-A prevented lymphadenopathy and expansion of L3T4-, Lyt-2-, 6B2+ T cells in the peripheral lymph nodes, and also in the thymus. The increased expression of the c-myb and T cell receptor beta-chain genes associated with these unusual cells was also corrected. The finding of increased numbers of L3T4-, Lyt-2-, 6B2+ thymocytes in untreated mice suggests abnormal intrathymic differentiation in lpr/lpr mice, a defect that was corrected by CS-A. Treated mice had a marked decrease in arthritis and glomerulonephritis and significantly prolonged survival. These beneficial effects of CS-A occurred despite a lack of reduction in antibodies reactive with DNA, circulating immune complexes, rheumatoid factor titers, or immunoglobulin concentrations. These results demonstrate that the B cell hyperactivity of MRL-lpr/lpr mice can proceed without the T cell proliferative disease.
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PMID:CS-A therapy in MRL-lpr/lpr mice: amelioration of immunopathology despite autoantibody production. 353 28

PBMC from patients with autoimmune diseases and from normal controls were studied for the expression of several cellular oncogenes. Gene expression was assessed by Northern blot analysis of poly(A)+ RNA obtained from leukapheresis samples. Patients with SLE expressed significantly more c-myc protooncogene RNA than did normal controls. Increased expression of the N-ras protooncogene was found in that subset of patients whose autoimmune disease was very active. Cells from individuals with SLE, but not from those with other autoimmune illnesses, showed significantly decreased levels of the c-myb and c-fos protooncogenes. To examine the implications of these findings, B and T cells were purified from apheresis samples donated by normal volunteers. When mitogen was used to activate the B cells in vitro, their pattern of protooncogene expression changed to resemble that found in freshly isolated cells from lupus patients. These results suggest that the differences detected in the expression of protooncogenes by patients with SLE may be due to the abnormal activation of their B cells in vivo. The pattern of protooncogene expression found in patients with other autoimmune illnesses is consistent with the activation of additional cell types in those diseases.
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PMID:Oncogene expression in autoimmune and normal peripheral blood mononuclear cells. 370 Dec 56