Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel mutation at the lpr (lymphoproliferation)(Fas) locus, lprcg, that can complement gld (generalized lymphoproliferative disease) in induction of lymphadenopathy was discovered in CBA/K1Jms mice. The lpr and lprcg mutations are a defective allele of the Fas locus that encodes an apoptosis-mediating receptor. The former does not express the receptor and the latter expresses the point-mutated nonfunctional receptor. The gld locus is hypothesized to encode a ligand for the receptor and the gld mutation to have a defect that leads to incompetent expression of the ligand. The absence and non-functioning of the receptor in lpr/lpr and lprcg/lprcg mice, respectively, and the lack of the ligand in gld/gld mice may arrest apoptosis of lymphoid cells in the thymus, resulting in the same type of lymphadenopathy characterized by expansion of unusual CD4-CD8- (DN) T cells. Less severe lymphadenopathy induced by complementarity between lprcg and gld may be explained by less efficient apoptosis resulting from competition for the ligand between the functional and nonfunctional receptors. Phenotypically, lpr and lprcg are different from gld in the function at bone marrow (BM) and lymph node (LN) levels: lpr/lpr and lprcg/lprcg BM cause atrophy but gld/gld BM hyperplasia of wild-type (+/+) LNs, and lpr/lpr and lprcg/lprcg LNs but not gld/gld LNs allow the homing of lpr- and lprcg-induced DN T cells. Lymphadenopathy is equally prominent in CBA-lprcg/lprcg and MRL-lprcg/lprcg mice. Hypergammaglobulinemia, autoantibodies and circulating immune complexes are detectable at significant levels in both lprcg/lprcg mice but at higher levels on the MRL background. Pathological signs like glomerulonephritis and vasculitis are clinically unimportant in CBA-lprcg/lprcg but strikingly severe in MRL-lprcg/lprcg mice. Noticeably, clinically significant glomerulonephritis and vasculitis also develop with slight but significant serological aberrations in MRL-lprcg/+ heterozygotes. Graft-vs.-host disease-like syndrome in the lprcg/lprcg BM-->+/+ chimera is minimal on the CBA but as severe as life-threatening on the MRL background as in the MRL-lpr/lpr BM-->MRL(-)+/+ chimera. Thus, autoimmune diseases induced by the lpr, lprcg and gld genes are actually indistinguishable in the clinical, serological and pathological aspects on the same strain background and the disease caused by the interaction between lprcg and gld is less severe in all the aspects, consistent with the receptor-ligand theory. The lprcg/lprcg mice with different strain backgrounds together with lpr/lpr and gld/gld mice will serve as a powerful tool for elucidation of the mechanism of development of single-gene autoimmune diseases at a molecular biological level.
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PMID:Autoimmunity in mice bearing lprcg: a novel mutant gene. 793 Aug 45

We established a T cell line, MV1, specific for rat vascular smooth muscle antigen from the regional lymph nodes of immunized MRL/Mp-+/+ mice. Adoptive transfer of MV1 T cells induced vasculitis lesions in the lungs of the syngeneic recipient mice pre-treated with cyclophosphamide. Flow cytometric analysis showed that MV1 was a CD4+ T cell line. The T cells proliferated in the presence of the vascular smooth muscle antigen and mitomycin C-treated syngeneic spleen cells. The cross experiments using an ovalbumin-specific T cell line demonstrated that MV1 was specific for vascular smooth muscle antigen. The antigen-specific proliferation of MV1 was CD4-dependent, which was consistent with the flow cytometric analysis. In addition, MV1 T cells, upon activation with anti-CD3 antibody or antigen-specific activation, killed A20.2J mouse B lymphoma cells. MV1 T cells also killed a CD95 (Fas)-transfected T lymphoma line, but not its parental Fas-negative cell line. These findings indicate that MV1 T cells killed target cells via a Fas ligand (FasL)/Fas pathway. The cytotoxicity of MV1 T cells may play an important role in the development of vasculitis in this model. Although the antigenic epitopes of MV1 and the lung specificity of vasculitis remain to be clarified, MV1-induced vasculitis should serve as an experimental model of human pulmonary vasculitis.
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PMID:A vascular smooth muscle-specific CD4+ T cell line that induces pulmonary vasculitis in MRL-+/+ mice. 869 25

An MRL/Mp strain of mice bearing the Fas deletion mutant gene, lpr (MRL/lpr), spontaneously develop systemic vasculitis and glomerulone phritis in the same individual, and both have been thought to be associated with an increase in circulating immune complexes and autoantibodies. However, the genetic basis of these diseases is poorly understood. A novel recombinant congenic mouse strain, McH5-lpr/lpr, which was established by rearrangement of the genetic background of MRL/lpr mice by hybridization with C3H/HeJ-lpr/lpr mice, developed severe granulomatous polyarteritis, as did the MRL/lpr strain, but not glomerulonephritis. Serum levels of anti-DNA and anti-myeloperoxidase antibodies in these mice were significantly reduced, as compared with MRL/lpr mice, although rheumatoid factors were not. These results indicate that each of these two diseases, arteritis and glomerulonephritis, is under the control of different background gene(s), suggesting a different pathological basis of these diseases, and that anti-DNA and anti-myeloperoxidase autoantibodies appear to have a limited pathogenic role in granulomatous arteritis in the mouse strain described.
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PMID:Arteritis in a novel congenic strain of mice derived from MRL/Lpr lupus mice: genetic dissociation from glomerulonephritis and limited autoantibody production. 890 64

MRL/Mp-lpr/lpr (lpr) mice develop autoantibodies, vasculitis, and glomerulonephritis, which are similar to human systemic lupus erythematosus, and acquire a generalized, nonmalignant, lymphoproliferative disorder. CD4- CD8- CD3+ TCR alphabeta+ (double-negative, DN) T cells accumulate in spleen and lymph nodes, and become a major T cell population in vivo. These DN T cells, however, are refractory to various stimuli, including CD3, IL-2, CD28, PMA, and PHA. Recently, the lpr gene mutation has been identified as a mutant gene for Fas, resulting in expression defects of Fas Ag. It is still unclear, however, what kinds of mechanisms cause the dysfunction of lpr DN T cells. To elucidate the pathogenic mechanisms in abnormal DN T cells, biochemical analyses were conducted for the expression and tyrosine phosphorylation of the vav proto-oncogene product (Vav) in DN T cells from lpr mice. We demonstrated that Vav, a 95-kDa cytoplasmic protein, from lpr mice was constitutively tyrosine phosphorylated several times higher than in control +/+ mice, while expression of Vav protein in lpr and +/+ mice was equal. Additionally, in contrast with +/+ T cells, tyrosine phosphorylation of Vav, which normally increases within a minute of stimulation via TCR, did not increase in lpr DN T cells following PHA or Ab activation. Taken together with the suggested roles of Vav in multiple receptor-mediated signal transductions, our findings suggest that the functional abnormalities of lpr DN T cells may be related to Vav abnormal tyrosine phosphorylation, which could lead to impaired signaling between surface receptors and G proteins in this cell population.
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PMID:Constitutive tyrosine phosphorylation of the vav proto-oncogene product in MRL/Mp-lpr/lpr mice. 905 37

MRL/MpJ-Fas(lpr) (Fas(lpr)) mice develop a rapidly fatal form of systemic autoimmune disease characterized by glomerulonephritis and vasculitis similar to severe cases of systemic lupus erythematosus in humans. To evaluate the requirement for intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of tissue injury in this model, we created ICAM-1-deficient MRL/MpJ-Fas(lpr) (ICAM-1/Fas(lpr)) mice. ICAM-1 deficiency resulted in a striking improvement in the survival of Fas(lpr) mice (median +/- SEM survival of Fas(lpr) = 26 +/- 1.7 vs ICAM-1/Fas(lpr) = 47 +/- 2.4 wk, p < 0.0001) and the increased survival was associated with delayed elevations of blood urea nitrogen levels in the ICAM-1/Fas(lpr) mice. Histologic examination of the ICAM-1/Fas(lpr) mice revealed an overall reduction in glomerular disease and a significant reduction in vasculitis in the kidney, lung, skin, and salivary glands when compared with Fas(lpr). These findings indicate that ICAM-1 plays a major role in development of glomerular and vascular injury in Fas(lpr) mice.
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PMID:Intercellular adhesion molecule-1 deficiency protects MRL/MpJ-Fas(lpr) mice from early lethality. 925 74

Immune function in SLE is paradoxically characterized by active T cell help for autoantibody production, along with impaired T cell proliferative and cytokine responses in vitro. To reconcile these observations, we investigated the possibility that the accelerated spontaneous cell death of SLE lymphocytes in vitro is caused by an activation-induced cell death process initiated in vivo. 27 SLE patients, three patients with systemic vasculitis, seven patients with arthritis, and 14 healthy subjects were studied. Patients with clinically active SLE or systemic vasculitis had accelerated spontaneous death of PBMC with features of apoptosis at day 5 of culture. A prominent role for IL-10 in the induction of apoptosis was observed, as neutralizing anti-IL-10 mAb markedly reduced cell death in the active SLE patients by 50%, from 22.3 +/- 5.2% to 11.2 +/- 2.8%, and the addition of IL-10 decreased viability in the active SLE group, but not in the control group, by 38%. In addition, apoptosis was shown to be actively induced through the Fas pathway. The potential clinical relevance of T cell apoptosis in active SLE is supported by the correlation of increased apoptosis and IL-10 levels in vitro with low lymphocyte counts in vivo. We conclude that the spontaneous cell death observed in vitro in lymphocytes from patients with SLE and other systemic autoimmune disorders results from in vivo T cell activation, is actively induced by IL-10 and Fas ligand, and reflects pathophysiologically important events in vivo. Activation-induced cell death in vivo provides a pathogenic link between the aberrant T helper cell activation and impaired T cell function that are characteristic features of the immune system of patients with SLE.
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PMID:Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand. 936 78

Aspects of pathogenesis of primary systemic vasculitis are highlighted in this review. The cause of these entities is still obscure, although new information on the possible role of infections has emerged. Success of antimicrobial treatment to ameliorate systemic vasculitis, for which proof was recently provided, adds to the new information. Apart from new data that point to a precipitating role for environmental toxins the background for development of these diseases is most likely genetic predisposition. Reports on hereditary alpha 1-antitrypsin deficiency, the link between systemic vasculitis and human leukocyte antigen molecules, and an animal model of spontaneous granulomatous arteritis in mice with a hereditary deficit in Fas-mediated apoptosis, are some of the new data that strongly favor genetic predisposition. Progress has been made in the process of identification of the agonists and antagonists in the front line of vasculitic inflammation. The interaction of blood cells (e.g., neutrophils and monocytes) with vascular endothelium has become more evident as have the signals for the release of harmful proteolytic enzymes. Antineutrophil cytoplasmic antibodies, which are important markers of disease, may be actively involved in these processes.
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PMID:New developments in pathogenesis of systemic vasculitis. 944 84

There is compelling animal and human experimental evidence that leukocytoclastic vasculitis is a hypersensitivity vasculitis, similar in nature to the experimental Arthus reaction. The immune complexes formed in antigen excess circulate until some event occurs that cause deposition in blood vessel walls. Adhesion molecules and cytokines released by endothelial cells and activated neutrophils represent a key factor in this process. The membrane attack complex of complement plays a significant role in altering the endothelial cell membrane integrity. Activated neutrophils release proteolytic enzymes, especially collagenases and elastases, along with free oxygen radicals that damage the vessel walls and the surrounding tissues. It remains uncertain whether antineutrophilic cytoplasmic antibodies, anti-endothelial antibodies and anti-cardiolipin antibodies are epiphenomena or are directly involved in the disease process. Apoptotic cell death mediated by the Fas/Bc12 system is a feature of leucocytoclastic vasculitis. In conclusion, the post-capillary venule is the active orchestrator of neutrophils in leukocytoclastic vasculitis which mediate a complex series of endothelial/leukocyte interactions.
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PMID:Pathogenesis of leukocytoclastic vasculitis. 964 7

To elucidate the clinicopathological features of cutaneous allergic (leukocytoclastic) vasculitis (CAV), biopsied skin tissues of 32 patients with CAV were examined immunohistopathologically and compared with the main clinical features. Additionally, to obtain some clues to better understand the roles of infiltrating cells, particularly neutrophils in CAV, apoptosis and related antigens were investigated in vivo. The 32 patients with CAV were divided into two groups based on their clinical course: (i) non-recurrent (group I; nine cases); and (ii) recurrent (group II; 23 cases). Immunohistopathologically, group I was characterized by stereotypical necrotizing changes of CAV with fibrin exudation of small blood vessels in the upper cutis, and group II was characterized by CAV and fibrous thickening of the vascular walls with significant infiltration of CD3+, UCHL-1+ T cells. Group II was subdivided further: groups IIa (15 cases) and IIb (eight cases); that is, the former was notable for necrotizing changes of CAV, which tended to spread into the proper corium down to the lower cutis; whereas the latter exhibited considerably less marked histological changes of CAV without any spread to the lower cutis. In a comparison of the clinical data among the three groups, there were considerable differences in age, clinical course, localization of purpura and associated disease. In particular, group II showed a high frequency of connective tissue diseases. The presence of apoptosis was seen in a considerable number of neutrophils, and some nuclear debris turned out to be apoptotic bodies by the in situ terminal deoxytransferase (TdT)-catalyzed DNA nick end-labeling (TUNEL) method and electron microscopy. By combining immunohistochemistry with TUNEL, the majority of apoptotic neutrophils and nuclear debris was seen to be ingested by macrophages. In immunohistochemical examinations for apoptosis-related bcl-2 protein and Fas antigen, bcl-2 was recognized only in the cytoplasm of infiltrating T cells, and Fas was positively stained on the cellular membranes of infiltrating T cells and neutrophils in a scattered fashion. Thus, a novel method for neutrophil disposal in CAV was suggested.
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PMID:Cutaneous allergic vasculitis: clinicopathological characterization and identification of apoptosis. 977 9

MRL-lpr/lpr (MRL/lpr) mice are a model of human autoimmune disease. They exhibit a number of characteristics of systemic lupus erythematosus, including anti-DNA Abs, anti-cardiolipin Abs, immune complex-mediated vasculitis, lymphadenopathy, and severe glomerulonephritis. Although the autoimmune disorder is mediated primarily by mutation of the Fas gene (lpr), which interferes with lymphocyte apoptosis, MRL/lpr mice also have other predisposing genetic factors. In an effort to identify these additional factors, we have applied quantitative trait locus (QTL) mapping using an intercross between MRL/lpr mice and the nonautoimmune inbred strain BALB/cJ. A complete linkage map spanning the entire genome was constructed for 189 intercross progeny, and genetic loci contributing to features of the autoimmunity were identified using statistical analytic procedures. As expected, the primary genetic determinant of autoimmune disease in this cross was the Fas gene on mouse chromosome 19, exhibiting a lod score of 60. In addition, two novel loci, one on chromosome 2 (lod score, 4.3) and one on chromosome 11 (lod score, 3.1), were found to contribute to levels of anti-DNA Abs. Interestingly, the chromosome 19 and chromosome 11 QTLs, but not the chromosome 2 QTL, also exhibited associations with anti-cardiolipin Abs (lod scores, 38.4 and 2.6). We further examined the effects of these QTLs on the development of coronary vasculitis in the F2 mice. Our results indicate that the QTLs on chromosomes 11 and 19 also control the development of vasculitis, demonstrating common genetic determinants of autoantibody levels and vasculitis.
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PMID:Genetic determinants of autoimmune disease and coronary vasculitis in the MRL-lpr/lpr mouse model of systemic lupus erythematosus. 986 36


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