Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cutaneous disease in lupus is clinically heterogeneous, and it is likely that mechanisms of disease are also heterogeneous. Nevertheless, in many cutaneous forms of lupus and in the systemic disease itself, there is compelling evidence that autoantibodies are involved. It is our belief that autoantibodies are of primary importance in the etiology of the cutaneous lupus lesions discussed in this chapter and that antibody specificities are critical in most cases in determining the clinical expression of disease. As discussed earlier, antibodies can effect tissue injury by several mechanisms. There is evidence that ADCC may be an important mechanism of keratinocyte cytotoxicity in cutaneous lesions characterized by antibody deposition and a mononuclear cell infiltrate. Vasculitic lesions that have an infiltrate of polymorphonuclear cells may be related to antibody- and complement-dependent neutrophil-mediated endothelial cytotoxicity. Ultraviolet light, sex steroids, and certain genes such as those of the major histocompatibility complex appear to be important modulating factors in lupus.
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PMID:Mechanisms of cutaneous tissue damage in lupus erythematosus. 248 64

Cytotoxic activity of polymorphonuclear leukocytes (PMN) in the peripheral blood of patients with various diseases was demonstrated to K562 cells (natural cytotoxicity, NC) and the antibody-coated P815 cells (antibody-dependent cellular cytotoxicity, ADCC), using a 51Cr-release method. The NC values of normal PMN were lower than those of normal lymphocytes with mean values of 5.0% and 30%, respectively. The NC values of patients' PMN were also lower in malignancy, chronic hepatitis and connective tissue diseases. The ADCC values of normal PMN were moderately high with a mean value of 16.0%, which was almost a half of normal lymphocytes. Higher ADCC values of PMN were found in patients with chronic hepatitis, SLE and Behcet's disease, and in these cases the ADCC values of their lymphocytes were extremely low. The supernatants of PMN mix-cultured with unlabeled K562 or the antibody-coated P815 cells were fairly cytotoxic to both cells, though the similar supernatants of lymphocytes were cytotoxic only to K562 cells, but not to the antibody-coated P815 cells.
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PMID:Natural and antibody-dependent cellular cytotoxicity of polymorphonuclear leukocytes. 622 11

To better understand potential antibody-dependent mechanisms of tissue damage in lupus erythematosus (LE), an examination of whether antibodies to nonhistone nuclear antigens in LE patients' sera can induce ADCC of cellular targets coated with the corresponding antigens was undertaken. With high titer anti-RNP sera, significant ADCC was seen with monocyte (P less than 0.01), T-lymphocyte (P less than 0.001), and low-density lymphocyte (P less than 0.001) effectors. Using monocyte effectors, significant ADCC was seen with anti-RNP (P less than 0.01), anti-Sm (P less than 0.01), and anti-SSA/Ro (P less than 0.01), with the most profound lysis being with the anti-SSA/Ro sera. Neutrophils were ineffective in any nuclear antigen-antibody system tested. The effective mononuclear cell-mediated ADCC seen with anti-RNP, anti-Sm, and anti-SSA antisera may be related to the mononuclear cell-associated tissue change seen in cutaneous lupus lesions.
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PMID:The role of RNP, Sm, and SS-A/Ro-specific antisera from patients with lupus erythematosus in inducing antibody-dependent cellular cytotoxicity (ADCC) of targets coated with nonhistone nuclear antigens. 660 40

An investigation of cell-mediated cytotoxicity in 22 patients with systemic lupus erythematosus (SLE), using both whole blood and purified peripheral blood mononuclear cells (PBM) to measure antibody-dependent (ADCC) and phytohaemagglutinin (PHA)-induced lymphocyte cytotoxicity for Chang liver cells, has revealed 2 distinct abnormalities in patients with active disease. PHA-induced cytotoxicity was found to be selectively reduced in whole blood assays only (P less than 0.05), whereas ADCC was impaired in both whole blood (P = 0.02) and PBM (P less than 0.05) assays, when comparison was made with 52 normal controls. The addition of patients' sera to corresponding assays utilizing control PBM confirmed that the impaired PHA-induced cytotoxicity resulted from circulating inhibitory serum factors. Surprisingly little effect, however, was exerted on ADCC assays. These findings suggest that there is a reduction in numbers and/or functional capacity of Fc-receptor cells in active SLE, which may have pathogenetic implications.
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PMID:Antibody-dependent and phytohaemagglutinin-induced lymphocyte cytotoxicity in systemic lupus erythematosus. 697 May 50

Antibodies against self-molecules play a significant role in the development and progression of Systemic Lupus Erythematosus, as well as a number of other autoimmune disorders. Immunosuppressive drugs have been used to control this process. However, they are normally not specific to the offending cell, and can actually suppress beneficial immune responses to pathogens. In this paper a genetically engineered targeting molecule is described, which has the capacity to target antigen-specific B cells for inhibition or elimination. The targeting molecule is a fusion of streptavidin subunit to the constant region of human IgG3 (IgG3-Av). It is demonstrated by ELISA and flow cytometry that IgG3-Av binds biotinylated antigen as well as human Fc gamma receptors present on myeloid cells. It is also shown by confocal microscopy and flow cytometry, that IgG3-Av can mediate Fc receptor-dependent phagocytosis of latex microspheres adsorbed with biotinylated antigen. Furthermore, the IgG3-Av construct can modulate Ca++ flux, characteristic of B cell inhibition as well as ADCC of B cells in an antigen-specific manner. In summary, these studies describe an approach, which has the potential to be used as a treatment to inhibit or remove antigen-specific (auto-reactive) B cells.
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PMID:Generation of a human IgG3-streptavidin fusion protein. Implications for the inhibition and elimination of auto-reactive B cells. 1464 36

B-cells play a major role in the immunopathogenesis of autoimmune diseases. Not only do they produce autoantibodies, but they regulate other cell types, secrete cytokines, and present antigens. They are thus potential targets for therapeutic intervention. CD20 is a B-cell specific cell surface molecule of uncertain function. An anti-CD20 chimeric mAb (rituximab) has been FDA approved for treatment of B-cell lymphomas since 1997. Rituximab also depletes normal B-cells by several mechanisms, including ADCC. Over the past seven years, it has shown promise in a number of autoimmune diseases in phase I trials and anecdotal reports. Efficacy in rheumatoid arthritis has already been demonstrated in randomized control trials (RCTs), and RCTs in SLE, inflammatory myositis, and ANCA associated vasculitis are under way. Safety does not appear to be a major problem, but continued vigilance is warranted. The increased use of rituximab, other anti-CD20 agents, and other B-cell targeting therapies holds great promise for substantial clinical benefits, as well as providing special opportunities to understand better disease pathogenesis.
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PMID:The therapeutic potential of anti-CD20 "what do B-cells do?". 1616 73