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)

Defective Fas-mediated apoptosis in mice, caused by the gld mutation in the fas ligand gene, results in the development of lupus-like autoantibodies and severe lymphoproliferation. We previously demonstrated ectopic expression of the costimulatory molecule B7-1 (CD80) on T lymphocytes in B6/gld mice. This report extends these observations by demonstrating similar results in B6/lpr mice, which possess a mutation in the gene encoding Fas. Additionally, we demonstrate that this phenomenon is age-dependent and occurs on multiple subsets of B6/gld T lymphocytes. B7-1 upregulation is observed on T cells from both conventionally housed and specific-pathogen-free B6/gld mice, suggesting that this is not a consequence of infection by pathogen. T cells from lpr and gld mice show increased binding of CTLA4-Ig fusion protein, suggesting that the upregulated B7-1 is functional. CD28, a receptor for B7-1 which activates T cells, is upregulated in B6/lpr and B6/gld mice, while CTLA4, a negative regulator of T cells which binds B7-1, is not. Our results suggest that ectopic expression of B7-1 on T cells of lpr and gld mice may be playing a role in exacerbation of lymphoproliferation and/or autoimmunity.
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PMID:Ectopic expression of B7-1 (CD80) on T lymphocytes in autoimmune lpr and gld mice. 1037 Mar 75

Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development requires cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accetuated apoptosis, are now demonstrated as central defects in diverse human and murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor CD95 (Fas) and its ligand CD95L (FasL) have been identified; these errors create a lymphoid system resistant to apoptosis. In contract, select lymphoid subpopulations of auto immune diabetic mice have accelerated apoptosis due to faulty activation of transcription factor NF-kappaB that normally protects against apoptotic death. The genetic basis of interrupted NF-kappaB in diabetes is a gene defect in an essential subunit of the proteasome. Although no specific gene in most common forms of human autoimmune disease has been identified, functional assays repeatedly demonstrate apoptotic defects in multiple cellular signaling pathways for cell death.
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PMID:Implications of altered apoptosis in diabetes mellitus and autoimmune disease. 1132 Oct 39

Cell death by apoptosis is exerted by the coordinated action of many different gene products. Mutations in some of them, acting at different levels in the apoptosis process, have been identified as cause or contributing factor for human diseases. Defects in the transmembrane tumor necrosis factor receptor 1 (TNF-R1) lead to the development of familial periodic fever syndromes. Mutations in the homologous receptor Fas (also named CD95; Apo-1) are observed in malignant lymphomas, solid tumors and the autoimmune lymphoproliferative syndrome type I (ALPS I). A mutation in the ligand for Fas (Fas ligand; CD95 ligand, Apo-1 ligand), which induces apoptosis upon binding to Fas, was described in a patient with systemic lupus erythematodes and lymphadenopathy. Perforin, an other cytotoxic protein employed by T- and NK-cells for target cell killing, is mutated in chromosome 10 linked cases of familial hemophagocytic lymphohistiocytosis. Caspase 10, a representative of the caspase family of proteases, which plays a central role in the execution of apoptosis, is defect in autoimmune lymphoproliferative syndrome type II (ALPS II). The intracellular pro-apoptotic molecule bcl-10 is frequently mutated in mucosa-associated lymphoid tissue (MALT) lymphomas and various non-hematologic malignancies. The p53, an executioner of DNA damage triggered apoptosis, and Bax, a pro-apoptotic molecule with the ability to perturb mitochondrial membrane integrity, are frequently mutated in malignant neoplasms. Anti-apoptotic proteins like bcl-2, cellular-inhibitor of apoptosis protein 2 (c-IAP2) and neuronal apoptosis inhibitory protein 1 (NAIP1) are often altered in follicular lymphomas, MALT lymphomas and spinal muscular atrophy (SMA), respectively. This article reviews the current knowledge on mutations of apoptosis genes involved in the pathogenesis of human diseases and summarises the gradual transformation of discoveries in apoptosis research into benefits for the clinical management of diseases.
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PMID:Mutations in apoptosis genes: a pathogenetic factor for human disease. 1139 50

Lymphocyte development, selection, and education are strictly controlled to prevent autoimmunity, with potentially autoreactive cells being removed by apoptosis. Dysregulation of apoptosis is a central defect in diverse murine autoimmune diseases. In murine models of autoimmune lupus, for example, mutations in the death receptor Fas (CD95) or in its ligand, FasL (CD95L), have been identified and shown to render lymphoid cells resistant to apoptosis. In contrast, select lymphoid subpopulations of mice with autoimmune diabetes manifest an increased susceptibility to apoptosis as a result of impaired activation of the transcription factor nuclear factor-kappa B (NF-kappaB), which normally protects cells against tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. The genetic basis of this defect in NF-kappaB activation is a mutation in the promoter-enhancer region of a gene that encodes an essential subunit (LMP2) of the proteasome. Although no specific genetic defects have been identified in most common forms of human autoimmune disease, functional assays consistently demonstrate heightened apoptosis attributable to multiple death signaling pathways.
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PMID:Role of defective apoptosis in type 1 diabetes and other autoimmune diseases. 1279 17

Since the ligand for the death factor CD95 (CD95L) was identified almost a decade ago, it has been established that this molecule (CD95L, FasL, Apo-1L, CD178, TNFSF6, APT1LG1) has multiple immunoregulatory and pathophysiologically relevant functions. CD95L does not only act as a death factor when externalized with secretory lysosomes on cytotoxic T and NK cells or when expressed on CD4(+) T cells in the course of activation-induced cell death, it is also a key molecule for the establishment of immune privilege or tumor cell survival and may serve as a costimulatory molecule during T cell activation. Moreover, alterations of expression or shedding of different forms of CD95L are associated with many diseases including various malignancies, HIV infection, autoimmune disorders (systemic lupus erythematodes, rheumatoid arthritis), acute myocardial infarction, traumatic injury and many others. In most cases, however, the physiological link between altered CD95L expression and pathophysiology is unknown. Given the potency of the molecule to regulate death and survival of many different cell types, the control of CD95L production, transport, storage, shedding and release is of tremendous biological and clinical interest. This commentary aims at briefly summarizing the current knowledge, hypotheses and controversies about CD95L as a multifunctional ligand and receptor. It touches upon the complex networks of intracellular dynamics of protein transport and trafficking and the potential bidirectional signal transduction capacity of CD95L with a focus on molecular interactions that have been worked out over the past years.
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PMID:Slowly getting a clue on CD95 ligand biology. 1455 16

Goal of this study was to monitor levels of serum neopterin and soluble interleukin-2 receptor (sIL-2r) and to evaluate their importance in monitoring activity of systemic lupus erythematodes (SLE). Levels of serum neopterin, anti-dsDNA antibodies, C3, C4 complement components, nucleosomes antibodies, IL-10, fas ligand, soluble thrombomodulin, sVCAM-1, and sICAM-1 were measured in a group of 52 patients with SLE. Positive correlations were proved between neopterin concentrations and disease activity (ECLAM), levels of sVCAM-1, sICAM-1, sIL-2r and thrombomodulin, further between sIL-2r level and disease activity (ECLAM), and concentrations sVCAM-1, sICAM-1 and neopterin. Higher values of neopterin and sIL-2r levels were identified in patients with lupus nephritis compared to patients without kidney impairment. Statistically significant differences were identified in levels of neopterin between a subgroup (A) with minimum disease activity and a subgroup (B) with increasing disease activity (p = 0.01) and a subgroup (C) with decreasing disease activity (p = 0.003 ) and a subgroup (LN) with lupus nephritis (0.007) during the first and the third series of measurements. sIL2r levels which had in all subgroups very varied values were the lowest in the subgroup A with minimum disease activity during the whole time of monitoring. The highest levels reached the free receptor IL-2 in the subgroup B with increasing disease activity and in the subgroup with lupus nephritis. Statistically significant differences in values were identified between the subgroup A (non-active) and the subgroup LN (lupus nephritis) with p = 0.01 during the first set of the measurements. Fluctuation of sIL-2r levels in individual subgroups during the time of monitoring did not reach statistically important levels. In conclusion it could be said that potential practical utilization of the measurement of concentrations of the two mentioned molecules should be seen especially in monitoring disease activity because they don't contribute to SLE with needed information. Their always low values have favourable prognostic impact in monitoring patients with SLE and vise versa.
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PMID:[Neopterin and a soluble interleukin-2 receptor in patients with systemic lupus erythematodes]. 1534 34

Lpr/lpr mice develop a lymphoproliferative, autoimmune, lupus-like disease. These mice lack functional Fas (CD95) expression and are resistant to Fas ligand (CD178)-mediated apoptosis, a critical mechanism for the maintenance of peripheral tolerance. In this study, we show that noradrenaline (NA), the main sympathetic neurotransmitter, can induce apoptosis of lymphoid cells independently of functional Fas. Based on this finding, we used lpr/lpr mice as model to study the role of noradrenergic nerves in the expression of a lymphoproliferative disease. Early in ontogeny, the concentration of NA was significantly increased in the spleen of lpr/lpr mice, compared with normal littermates. However, splenic sympathetic innervation gradually declined as the disease progressed, and IgM blood levels and splenic NA concentration inversely correlated when the disease was overtly manifested. When the loss of noradrenergic fibers that occurred naturally during adult life in lpr/lpr mice was experimentally advanced by neonatal sympathectomy, the concentration of IgM and IgG2a in blood was markedly higher than that of control lpr/lpr mice, and the appearance of lymphadenopathy was accelerated. Furthermore, although neonatal denervation did not affect the life span of normal animals, it shortened significantly the survival time of lpr/lpr mice. These data show that, in addition to defects in the Fas pathway, an altered sympathetic innervation in lpr/lpr mice also contributes to the pathogenesis of the autoimmune disease, and strongly support the hypothesis that the sympathetic nervous system can modulate the expression of lymphoproliferative diseases.
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PMID:The role of noradrenergic nerves in the development of the lymphoproliferative disease in Fas-deficient, lpr/lpr mice. 1670 70

Apoptosis is an inducible suicide program that occurs in all phases of multicellular as well as in protozoa life and gains more and more importance in all medical disciplines. It is required for normal ontogenesis, organ and tissue remodeling, function of the immune system, prevention of inappropriate cellular proliferation and of survival of inappropriate mutations. Thereby apoptosis represents the key event which guarantees differentiation and maintenance of homeostasis. Terminal differentiation seems to be a special form of apoptosis. Dysregulated apoptosis is associated with various pathological conditions, including inflammation, and cancer. Acanthosis, the hallmark of psoriatic skin, is an example for diminished epidermal apoptosis. Defects in termination of inflammatory reactions occur in atopic dermatitis. Lupus erythematosus may arise due to disturbed apoptosis on several check points of the apoptosis cascade. Experimental evidence suggests a role for Bcl-2 and CD95L in the inhibition of programmed cell death in UV-induced skin cancer or malignant melanoma cells. Thus, it leads to survival of malignant cell clones. The slow growth of basal cell carcinomas is due to an increased apoptosis to mitosis ratio. Spontaneous regression of tumors is associated with increased apoptotic rates. Malignant melanoma cells characteristically show different anti-apoptotic strategies which underscore its aggressive behavior and its refractory towards classic therapeutic regimens. Additionally, induction of apoptosis in tumor infiltrating immune cells seems to be a strategy by which the tumor escapes from an immunological attack (tumor counter-attack). Since apoptosis is either absent or altered under pathological conditions therapeutic procedures should correct this. Established therapies like dithranol, vitanin-D3 analogs, low-dose methotrexate, induce apoptosis. Future treatment regimens like vaccine and gene therapy are designed to selectively induce apoptosis. Therefore, pharmacological agents and therapeutic strategies interfering with disrupted apoptosis regulation could improve the therapeutic arsenal in the future.
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PMID:Apoptosis in physiological and pathological skin: implications for therapy. 1690 Jun 61

The source of IgA and the mechanism for deposition of IgA in the mesangium remain unknown for primary IgA nephropathy. Because CD19(+)CD5(+) B cells are important producers of IgA and contribute to several autoimmune diseases, they may play an important role in IgA nephropathy. In this study, flow cytometry, quantitative PCR, and confocal microscopy were used to assess the frequency, distribution, Ig production, CD phenotypes, cytokine production, and sensitivity to apoptosis of CD19(+)CD5(+) B cells in the peripheral blood, peritoneal fluid, and kidney biopsies of 36 patients with primary IgA nephropathy. All patients with IgA nephropathy were significantly more likely to have CD19(+)CD5(+) B cells in the peripheral blood, peritoneal fluid, and kidney biopsies than were five control subjects and 10 patients with active systemic lupus erythematosus. The 33 patients who had IgA nephropathy and responded to treatment demonstrated a significant decrease in CD19(+)CD5(+) B cells in the peripheral blood, peritoneal fluid, and kidney (all P < 0.01). In the three patients who had IgA nephropathy and did not respond to treatment, the frequency of CD19(+)CD5(+) B cells did not change. CD19(+)CD5(+) B cells isolated from patients with untreated IgA nephropathy expressed higher levels of IgA, produced more IFN-gamma, and were more resistant to CD95L-induced apoptosis than cells isolated from control subjects and patients with lupus; these properties reversed with effective treatment of IgA nephropathy. In conclusion, these results strongly suggest that CD19(+)CD5(+) B cells play a prominent role in the pathogenesis of primary IgA nephropathy.
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PMID:CD19+CD5+ B cells in primary IgA nephropathy. 1865 Apr 80

FAS/FASL system plays a central role in maintaining peripheral immune tolerance. Human Systematic Lupus Erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by expansion of autoreactive lymphocytes. It remains unclear whether a defective FAS/FASL system is involved in the pathogenesis of SLE. In this study, we have discovered a novel nucleotide insertion in FAS mRNA. We demonstrate that this novel FAS mutation occurs at mRNA levels, likely through a site-specific mRNA editing process. The mRNA editing mutation is unique for human FAS because the similar mRNA editing event is absent in other human TNF receptor (TNFR) family genes with death domains (DR5, DR6, and TNFR1) and in murine FAS. The adenine insertion mutation in the coding region message causes the alteration of human FAS mRNA reading frame. Functionally, cells expressing the edited FAS (edFAS) were refractory to FAS-mediated apoptosis. Surprisingly, cells from SLE patients produced significantly more edFAS products compared to cells from normal healthy controls. Additionally, we demonstrated that persistent engagement of T-cell receptor increases human FAS mRNA editing in human T cells. Our data suggest that the site-specific FAS mRNA editing mutation may play a critical role in human immune responses and in the pathogenesis of human chronic inflammatory diseases.
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PMID:FAS mRNA editing in Human Systemic Lupus Erythematosus. 2200 62


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