Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been postulated that the high levels of autoantibodies observed in systemic lupus erythematosus (SLE) patients could result from abnormal longevity of polyclonally activated B-cells. This increased survival could be due to dysfunction of apoptosis, the normal regulatory process governing their life span. The protein product of the bcl-2 gene can enhance lymphoid cell survival by interfering with apoptosis. Moreover, transgenic mice overexpressing bcl-2 in their B-cells developed an autoimmune syndrome resembling SLE. To determine whether overexpression of bcl-2 occurs in SLE patients, bcl-2 protein was measured in peripheral blood mononuclear cells from 73 SLE patients, 20 healthy individuals and 47 patients with other autoimmune diseases. Only three lupus patients had raised levels of bcl-2 and there were no statistically significant differences in the mean bcl-2 levels measured in SLE patients compared to controls. Bcl-2 levels did not correlate with overall disease activity in SLE patients.
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PMID:Bcl-2 expression is unaltered in unfractionated peripheral blood mononuclear cells in patients with systemic lupus erythematosus. 778 44

Programmed cell death, an essential function in all cells, plays a central role in maintaining immune system homeostasis and controlling autoimmune reactions. Cell death may be an essential element in disseminated lupus erythematosus: defective cell death could lead to the development of autoreactive lymphocyte clones and degradation products of cell death could be implicated in autoimmunity induction and onset of renal lesions. Anomalies in programmed cell death have been demonstrated in murine models of lupus: mutations of the fas and fas-ligand genes, which play a known role in programmed cell death, produce the lpr and gld phenotypes associating lymphoproliferation and lupus. Transgenic mice which express Bcl-2 (the product of Bcl-2 inhibits programmed cell death) on B lymphocytes develop a lupus-type autoimmune disease. The role of these types of anomalies in human disease is not yet elucidated. However, cell death, via the degradation fragments of chromatin, could play a role in inducing antibody production and development of renal lesions. The anti-DNA antibodies, with characteristic antigen-induced immune response (clone expansion, class computation and somatic mutations) could be induced by nucleosomes released during cell death. Several arguments favor this mechanism including cation residues of histone nucleosomes which would bind to anionic residues of sulfate heparan and lead to deposit of autoantibodies in the glomerulus. The dual role of cell death is not really contradictory in autoimmune disease controlled by several independent genes, but would be compatible with several different genetic backgrounds.
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PMID:[Cell death and lupus]. 909 57

Although cumulative evidence suggests that a genetic predisposition plays a major role in development of systemic lupus erythematosus (SLE) and/or lupus nephritis (LN), the susceptibility genes are mostly unknown. The difficulty in identifying susceptibility genes is due in part to multiple genes with variable genetic effects and the diverse genetic backgrounds of human populations. In human SLE, genes of early components of complements as well as many polymorphic genes (including the MHC class II and class III, FcgammaR, mannose-binding protein, IL-6, Bcl-2, and IL-10 genes) have been associated with SLE or LN by population-based case-control or within-case studies. The contribution of some of these disease-associated genes to the presence or absence of clinical manifestations has been further tested in mice with targeted disruption of the specific candidate gene. In addition to SLE susceptibility genes, there may be a separate set of nephropathy susceptibility genes predisposing to LN as suggested by the familial clustering of end-stage renal disease in African-Americans with LN. The availability of densely mapped genetic markers spanning the entire genome has enabled the identification of chromosomal regions linked to disease susceptibility genes without prior knowledge of the gene function. Our group has used known murine lupus susceptibility loci as a guide, and conducted linkage analysis of genetic markers located within a specific, possibly syntenic human chromosomal region. Evidence for linkage of a chromosome 1q41-42 region was observed in SLE-affected sib pairs from multiple ethnic groups. More recently, several groups have reported results of genome scans of SLE-affected sib pairs or pedigrees. These exciting recent developments in delineating the genetic basis of SLE or LN are summarized in this review.
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PMID:Genetic susceptibility to lupus nephritis. 988 94

Keratinocyte apoptosis may be induced by ultraviolet-B radiation and represents a potential source of fragmented autoantigens in autoimmune diseases. This study investigates whether excessive keratinocyte apoptosis occurs in the skin lesions of cutaneous lupus (CLE) and dermatomyositis (DM) and the potential mechanisms responsible for this phenomenon. Skin biopsies have been studied from 19 patients with CLE and DM, eight with scleroderma, and five healthy controls. Apoptosis was detected by in situ end-labelling of fragmented DNA. The expression of Bcl-2, PCNA, p53, and Ki-67 proteins was studied by immunohistochemistry. In DM and CLE skin, the number of apoptotic keratinocytes was significantly increased (p=0.008) compared with normal skin. In both diseases, a large accumulation of apoptotic keratinocytes and apoptotic bodies was present in the disrupted basal zone. Unlike normal skin, a large number of keratinocytes, particularly those morphologically apoptotic, expressed p53 protein. A significant increase in the number of proliferating Ki-67 positive (p=0.0007) and PCNA-positive (p=0.0008) nuclei was also observed. In both CLE and DM, exaggerated and inappropriate keratinocyte apoptosis occurs. It is associated with increased expression of p53 and PCNA. This suggests that normal solar radiation alone or in combination with additional local factors induces DNA damage and excessive keratinocyte apoptosis in these autoimmune diseases of the skin. Apoptosis can mediate the severe epidermal lesions observed in both diseases and the release of fragmented autoantigens into the dermis.
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PMID:Keratinocyte apoptosis and p53 expression in cutaneous lupus and dermatomyositis. 1039 42

Sex hormones are presumed to contribute to sexual dimorphism in the immune system. Estrogen, in particular, has been suggested to predispose women to systemic lupus erythematosus. We report here that estradiol (E(2)) can break B cell tolerance and induce a lupus-like phenotype in nonautoimmune mice transgenic for the heavy chain of a pathogenic anti-DNA antibody. E(2) treatment resulted in a rise in anti-DNA serum titers and in Ig deposition in renal glomeruli. ELISPOT analysis confirmed a significant increase in the number of high-affinity anti-DNA antibody-secreting B cells in the spleens of E(2)-treated mice. Hybridomas generated from E(2)-treated mice express high-affinity, unmutated anti-DNA antibodies, indicating that naive B cells that are normally deleted or anergized are rescued from tolerance induction. Finally, immunohistochemical studies revealed increased Bcl-2 expression in splenic B cells of E(2)-treated mice. These data demonstrate that estrogen interferes with tolerance induction of naive autoreactive B cells and that the presence of these B cells in the periphery is associated with up-regulation of Bcl-2.
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PMID:Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. 1069 76

Estrogen can modulate autoimmunity in certain models of systemic lupus erythematosus. Recently, we have shown that it can mediate survival and activation of anti-DNA B cells in a mouse transgenic for the heavy chain of a pathogenic anti-DNA antibody. To identify whether estrogen effects reflect increased prolactin secretion, we characterized B-cell autoreactivity in transgenic mice given both bromocriptine (an inhibitor of prolactin secretion) and estradiol. Treatment of mice with estradiol plus bromocriptine led to reduced titers of anti-DNA antibodies and diminished IgG deposition in kidneys compared with treatment with estradiol alone. However, mice treated with estradiol plus bromocriptine showed an expansion of transgene-expressing B cells and enhanced Bcl-2 expression, similar to those of estradiol-treated mice. We identified anergic high-affinity anti-DNA B cells in mice treated with estradiol plus bromocriptine, and we showed by molecular analysis of anti-DNA hybridomas that their B cells derive from a naive repertoire. Thus, the estradiol-induced breakdown in B-cell tolerance can be abrogated by bromocriptine, which induces anergy in the high-affinity DNA-reactive B cells. These studies demonstrate that some of the effects of estrogen on naive autoreactive B cells require the presence of prolactin and, thus, suggest potential therapeutic interventions in lupus.
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PMID:Bromocriptine restores tolerance in estrogen-treated mice. 1110 90

Estrogen is believed to contribute to the development of the autoimmune disorder systemic lupus erythematosus (SLE) (lupus) in women. We hypothesized that estrogen might promote the development of lupus by altering apoptosis of bone marrow cells, perhaps through regulation of the apoptotic proteins Bax and Bcl-2. We compared the effects of estrogen (E2) and thrombopoietin (TPO) on the expression of Bax or Bcl-2 in bone marrow cells isolated from female non-lupus (NZW or NZB parental strains) or lupus-prone (NZB and NZW cross; NZB/W) mice. We report that the basal level of Bax in parental bone marrow cells was significantly greater than that of cells from NZB/W animals. Treatment of NZB or NZW marrow cells with E2 resulted in a significant decrease in Bax expression, which was completely reversed upon co-treatment with TPO. Bax expression was not significantly altered by E2 and/or TPO in NZB/W cells. Bcl-2 levels did not differ between murine strains under basal or hormone-treated conditions. Lower basal expression of Bax protein was associated with significantly less apoptosis for NZB/W marrow cells. In addition, there were significantly greater numbers of cells in bone marrow of lupus-susceptible animals. Our results indicate that bone marrow cells of NZB/W animals differ physiologically from those of NZW or NZB mice, and suggest that decreased expression of Bax in bone marrow precursors may lead to decreased apoptosis of mature blood cells in lupus-susceptible mice.
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PMID:Altered Bax expression and decreased apoptosis in bone marrow cells of lupus-susceptible NZB/W mice. 1178 88

Systemic lupus erythematosus is a multisystemic autoimmune disease. The immunopathogenesis is characterized by the loss of tolerance to self. While many abnormalities in the immune system have been detected, genetic factors play a central role in the pathogenesis. The event proximate to target organ involvement appears to be autoantigen-driven, T cell-mediated, B cell activation. High levels of autoantibodies are produced. However, not all autoantibodies are pathogenic to the kidney (i.e. 'nephritogenic'). These nephritogenic autoantibodies appear to share specific physiochemical features that correlate well with patterns of renal injury. While DNA was initially regarded as the inciting autoantigen, this view does not appear to be supported by the prevailing evidence. Nucleosomes, which are structures comprising histones and DNA, have emerged as the more likely candidate autoantigen. Autoantibodies directed against nucleosomes that cross-react with nucleosomal epitopes have been identified. Furthermore, evidence suggests that immunoglobulin-nucleosomal complexes may be important in target organ immune deposition. In-vivo generation of nucleosomes requires apoptosis; in fact, there are several examples of aberrant apoptotic processes that present with autoimmunity. Aberrant apoptosis may also be critical in lupus immunopathogenesis. Indeed, studies on Fas/FasL and Bcl-2 in animal models and in humans have underscored the importance of apoptosis as an etiological factor in lupus. Cytokines, hormonal, infectious and environmental factors have also been found to be important in the pathogenesis of systemic lupus erythematosus. Overall, much progress has been made in elucidating the etiological agents and pathogenic mechanisms by which lupus develops. However, there is still some way to go before arriving at a unifying hypothesis. The reward for a better understanding of lupus immunopathogenesis will be the development of more specific targets for treatment, and the introduction of better and safer treatment modalities.
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PMID:Immunopathogenesis of lupus and lupus nephritis: recent insights. 1198 Dec 56

A characteristic feature of systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G1-arrested cells express high levels of cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation and apoptosis, and produce large amounts of proinflammatory cytokines. Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction. Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential. Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax. Proliferation and apoptosis of B cells were also increased in p21-/- lupus mice. Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate systemic autoimmunity.
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PMID:Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity. 1497 Jan 81

The presence of rheumatoid factors (RF) is a characteristic feature of patients with rheumatoid arthritis, but not systemic lupus erythematosus. In this study, we have explored the role of the anti-apoptotic Bcl-2 protein and the Y-linked autoimmune acceleration (Yaa) mutation in the production of IgG RF in comparison with IgG anti-DNA autoimmune responses. Analysis in C57BL/6 mice, in their F1 hybrids with lupus-prone NZW mice, and in bone marrow chimeras containing mixtures of C57BL/6 bcl-2-transgenic and BXSB non-transgenic cells demonstrated that an enforced Bcl-2 expression in B cells promoted the induction of IgG anti-DNA production in these mice, while significant IgG RF responses were observed only in mice developing high levels of gp70-anti-gp70 immune complexes and lethal glomerulonephritis. Moreover, in contrast to a synergistic interaction between the Yaa mutation and Bcl-2 overexpression on IgG anti-DNA production, the Yaa mutation failed to enhance the production of IgG RF induced in bcl-2-transgenic mice. Our results reveal that defects in the regulation of B cell apoptosis play a critical role in the production of IgG RF, and that the Yaa mutation differentially modulates RF and anti-DNA autoimmune responses, likely related to the nature of autoantigens involved in each autoimmune response.
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PMID:Enforced Bcl-2 expression in B lymphocytes induces rheumatoid factor and anti-DNA production, but the Yaa mutation promotes only anti-DNA production. 1504 18


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