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)

We have used single and multiple site-directed mutagenesis, and molecular modeling, to identify critical residues in the DNA binding site of MAb 2C10, an IgG anti-dsDNA autoantibody from an MRL/lpr lupus mouse. Simultaneous replacement of four Arg residues in the CDR3H abolished binding activity. With one exception, replacement of any one of these Arg residues reduced the activity to 20-50% of the unmutated scFv activity. Arg to Asp replacements had a slightly greater effect than Arg to Ala replacements. In the one exceptional case, replacement of Arg99 with Ala actually increased DNA binding five-fold and replacement by Asp had little effect. Mutation of Phe32 and Asn35 to A1a in CDRIH decreased DNA binding, whereas replacement of Arg31 with A1a had negligible effect. Ala substitution of any one of a cluster of Asp residues in CDR1L increased DNA binding three to six-fold, confirming previous findings that the L-chain of MAb 2C10 is not favorable for DNA binding. The L-chain does participate in shaping the selectivity of antigen binding, and mutation of CDR3L residue Asp92 or Asn93 caused a decrease in DNA binding activity. Directed mutagenesis, consistent with a molecular model, indicates that: several CDR amino acids contribute to DNA binding, without one residue dominating; both VH and VL CDR3 domains contribute to specificity of binding whereas the CDR1L hinders DNA binding. The results suggest a significant role for electrostatics in the interaction of DNA with MAb 2C10.
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PMID:The structural basis for DNA binding by an anti-DNA autoantibody. 1019 94

Peptide-mediated immunotherapy has been studied in a number of experimental models of autoimmune diseases and has also been tested in human patients to a certain extent. Copolymer 1 is a synthetic amino acid copolymer that has been demonstrated to suppress experimental autoimmune encephalomyelitis (a model for multiple sclerosis) when administered parenterally. Some study results indicate that mucosal tolerance induced by appropriate recombinant peptide fragments of human AChR is effective in suppressing experimental autoimmune myasthenia gravis and might be considered as a therapeutic modality for patients with MG. A peptide of the heat-shock protein 60 molecule, designated peptide p277, was shown to be a target of T cells in autoimmune diabetes in NOD mice, and intraperitoneal injections of glutamic acid decarboxylase (GAD) peptide 524-543 delayed the onset of diabetes and significantly reduced its incidence. Experimental evidence has revealed that CDR-based peptides may be potential candidates for the therapy of systemic lupus erythematosus. The use of synthetic peptides that focus on neutralization of pathogenic anti-beta 2GPI antibodies represents a possible new therapeutic approach to antiphospholipid syndrome. Studies in both acute and chronic-relapsing experimental autoimmune uveoretinitis have indicated that oral administration of S-Ag, S-Ag-derived peptides, inter-photoreceptor retinoid binding protein or HLA-derived peptides before immunization can protect animals from the disease.
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PMID:Peptide immunotherapy in autoimmune diseases. 1293 33

Autoantibodies to a wide variety of antigens are associated with systemic lupus erythematosus (SLE). Antibodies to double-stranded DNA (anti-dsDNA) are thought to be particularly closely related to tissue damage and disease activity in SLE. Autoantibodies to histones, Sm and Ro are found in patients with SLE, but their role in pathogenesis is unclear. Using a transient expression system, we previously showed that particular sequence motifs in CDRs of light chains derived from the human Vlambda gene 2a2 are very important in determining their ability to form a DNA-binding site, when paired with the heavy chain of the human monoclonal anti-dsDNA antibody B3. These motifs are often sites of somatic mutation and/or contain arginine residues. In the experiments reported in this paper, the same expression system was used to show that these CDR motifs also affect binding to histones, Ro antigen and Sm antigen, but that binding to different antigens is affected in diverse ways by particular changes in the sequence of the CDRs. The heavy chain also plays a role in binding to these antigens. Pairing of the same range of 11 2a2 derived light chains with the heavy chain of a different anti-DNA antibody, 33.H11, gave reduced ability to bind DNA in comparison with the results obtained using the B3 heavy chain. Computer-generated models of the three-dimensional structures of these heavy/light chain combinations were used to define the positions occupied by the important sequence motifs at the binding sites of these antibodies, and to explain the different effects exerted by arginine residues at different positions in the light chains.
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PMID:Somatic mutations to arginine residues affect the binding of human monoclonal antibodies to DNA, histones, SmD and Ro antigen. 1468 32

A great many cardiovascular drugs (CVDs) have the potential to induce adverse reactions in the mouth. The prevalence of such reactions is not known, however, since many are asymptomatic and therefore are believed to go unreported. As more drugs are marketed and the population includes an increasing number of elderly, the number of drug prescriptions is also expected to increase. Accordingly, it can be predicted that the occurrence of adverse drug reactions (ADRs), including the oral ones (ODRs), will continue to increase. ODRs affect the oral mucous membrane, saliva production, and taste. The pathogenesis of these reactions, especially the mucosal ones, is largely unknown and appears to involve complex interactions among the drug in question, other medications, the patient's underlying disease, genetics, and life-style factors. Along this line, there is a growing interest in the association between pharmacogenetic polymorphism and ADRs. Research focusing on polymorphism of the cytochrome P450 system (CYPs) has become increasingly important and has highlighted the intra- and inter-individual responses to drug exposure. This system has recently been suggested to be an underlying candidate regarding the pathogenesis of ADRs in the oral mucous membrane. This review focuses on those CVDs reported to induce ODRs. In addition, it will provide data on specific drugs or drug classes, and outline and discuss recent research on possible mechanisms linking ADRs to drug metabolism patterns. Abbreviations used will be as follows: ACEI, ACE inhibitor; ADR, adverse drug reaction; ANA, antinuclear antigen; ARB, angiotensin II receptor blocker; BAB, beta-adrenergic blocker; CCB, calcium-channel blocker; CDR, cutaneous drug reaction; CVD, cardiovascular drug; CYP, cytochrome P450 enzyme; EM, erythema multiforme; FDE, fixed drug eruption; I, inhibitor of CYP isoform activity; HMG-CoA, hydroxymethyl-glutaryl coenzyme A; NAT, N-acetyltransferase; ODR, oral drug reaction; RDM, reactive drug metabolite; S, substrate for CYP isoform; SJS, Stevens-Johnson syndrome; SLE, systemic lupus erythematosus; and TEN, toxic epidermal necrolysis.
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PMID:ORAL ADVERSE DRUG REACTIONS TO CARDIOVASCULAR DRUGS. 1476 98

Systemic lupus erythematosus (SLE) can be induced in mice by immunizing them with a monoclonal human anti-DNA Ab that expresses a major Id, designated 16/6Id. In addition, a peptide based on the sequence of the CDR 1 (hCDR1) of the 16/6Id ameliorated the clinical manifestations of SLE in experimental models. In this study we examined the effects of treating mice with human complementary-determining region 1 (hCDR1) on the subsequent chemotaxis of T cells derived from 16/6Id-primed mice. First we demonstrated elevated levels of stromal cell-derived factor-1alpha (SDF-1alpha) in the sera of SLE-afflicted mice and in the sera and lymphoid tissues of 16/6Id-immunized BALB/c mice shortly after the immunization. We then found that administration of hCDR1 to 16/6Id-immunized mice specifically down-regulated SDF1alpha-induced T cell chemotaxis through fibronectin and collagen type I. This was accompanied by diminished SDF1-alpha-induced T cell adhesion and ERK phosphorylation. Treatment with hCDR1 up-regulated TGF-beta secretion, which, in turn, inhibited the murine T cell adhesion to and chemotaxis through fibronectin as well as their ERK phosphorylation. Thus, the secretion of TGF-beta after treatment of 16/6Id-immunized mice with hCDR1 plays an important role in the down-regulation of SDF-1alpha-mediated T cell activation and the interactions with extracellular matrix moieties observed in the present study.
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PMID:Down-regulation of stromal cell-derived factor-1alpha-induced T cell chemotaxis by a peptide based on the complementarity-determining region 1 of an anti-DNA autoantibody via up-regulation of TGF-beta secretion. 1561 Dec 53

Anti-dsDNA antibodies tend to be enriched for heavy chain complementarity determining region 3 (CDR-H3) intervals of above average length that contain an increased frequency of charged amino acids. It is unclear whether these types of CDR-H3s are more common in the primary B-cell repertoire of auto-immune prone strains or whether their increased prevalence in affected individuals reflects positive selection and expansion of atypical CDR-H3s in the pathogenic response to self-antigen. Here, we present evidence that when compared to C3H, a MRL/MpJ(2+) parental strain, CDR-H3 intervals from pre-B cells of adult lupus-prone MRL/MpJ(2+) mice are longer on average and are enriched for charged amino acids. The predicted prevalence of deformed loops per Shirai H3 criteria is also higher. In contrast, the frequency of charge, the distribution of length, and the pattern of predicted deformed loop structures did not differ in sequences obtained from neonates of the same two strains. These observations suggest that the mechanisms that serve to shape the initial CDR-H3 repertoire in adults, but not neonates, are being regulated differently in C3H versus MRL/MpJ(2+). Dysregulation of the adult pre-B CDR-H3 antibody repertoire could be a contributing factor for the development of florid auto-immune disease in MRL/MpJ(2+) mice.
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PMID:Adult lupus-prone MRL/MpJ2+ mice express a primary antibody repertoire that differs in CDR-H3 length distribution and hydrophobicity from that expressed in the C3H parental strain. 1582 67

Expansion of autoreactive T cells and their resistance to anergy was demonstrated in systemic lupus erythematosus (SLE). A pair of transcription factors, early growth response 2 (Egr-2) and 3 (Egr-3), are negative regulators of T cell activation that were shown to be important in anergy. A peptide (designated hCDR1 for human CDR1) based on the CDR-1 of an anti-DNA Ab ameliorated SLE in both induced and spontaneous lupus models. Our objectives were to determine the expression levels of Egr-2 and Egr-3 in autoreactive T cells following immunization with the lupus-inducing anti-DNA Ab that bears a common Id designated 16/6Id and also in a full-blown SLE and to determine the effect of hCDR1 on these transcription factors. We demonstrated diminished expression levels of Egr-2 and Egr-3 mRNA both early after immunization with the 16/6Id and in SLE-afflicted (NZB x NZW)F1 (New Zealand Black and New Zealand White) mice. Furthermore, by down-regulating Akt phosphorylation and up-regulating TGFbeta secretion, treatment with hCDR1 significantly up-regulated Egr-2 and Egr-3 expression. This was associated with an increased expression of the E3 ligase Cbl-b. Inhibition of Akt in T cells of immunized mice decreased, whereas silencing of the Egr-2 and Egr-3 in T cells of hCDR1-treated mice increased IFN-gamma secretion. Thus, hCDR1 down-regulates Akt phosphorylation, which leads to up-regulated expression of T cell Egr-2 and Egr-3, resulting in the inhibition of IFN-gamma secretion that is required for the maintenance of SLE.
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PMID:A peptide that ameliorates lupus up-regulates the diminished expression of early growth response factors 2 and 3. 1820 54

Chronic inflammation promotes the formation of ectopic lymphoid tissue morphologically resembling secondary lymphoid tissues, though it is unclear whether this is a location where Ag-specific immune responses develop or merely a site of lymphocyte accumulation. Ectopic lymphoid tissue formation is associated with many humoral autoimmune diseases, including lupus induced by tetramethylpecadentane in mice. We examined whether an immune response to 4-hydroxy-3-nitrophenyl acetyl-keyhole limpet hemocyanin (NP-KLH) and NP-OVA develops within ectopic lymphoid tissue ("lipogranulomas") induced by tetramethylpecadentane in C57BL/6 mice. Following primary immunization, NP-specific B cells bearing V186.2 and related heavy chains as well as lambda-light chains accumulated within ectopic lymphoid tissue. The number of anti-NP-secreting B cells in the ectopic lymphoid tissue was greatly enhanced by immunization with NP-KLH. Remarkably, the H chain sequences isolated from individual lipogranulomas from these mice were diverse before immunization, whereas individual lipogranulomas from single immunized mice had unique oligo- or monoclonal populations of presumptive NP-specific B cells. H chain CDR sequences bore numerous replacement mutations, consistent with an Ag-driven and T cell-mediated response. In mice adoptively transferred with OT-II or DO11 T cells, there was a striking accumulation of OVA-specific T cells in lipogranulomas after s.c. immunization with NP-OVA. The selective colocalization of proliferating, Ag-specific T and B lymphocytes in lipogranulomas from tetramethylpecadentane-treated mice undergoing primary immunization implicates ectopic lymphoid tissue as a site where Ag-specific humoral immune responses can develop. This has implications for understanding the strong association of humoral autoimmunity with lymphoid neogenesis, which may be associated with deficient censoring of autoreactive cells.
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PMID:Colocalization of antigen-specific B and T cells within ectopic lymphoid tissue following immunization with exogenous antigen. 1871 97

Internalization of autoantibodies against double-stranded DNA (anti-dsDNA) is crucial to the pathogenesis of systemic lupus erythematosus. Anti-dsDNA may bind to cell-surface targets in order to facilitate the subsequent cell penetration of the anti-dsDNA. In this study, we observed that the 9D7 monoclonal anti-dsDNA autoantibody (9D7 mAb) penetrates into Jurkat cells via a novel alternative pathway. Endocytosis inhibitors or a lipid-raft inhibitor did not significantly change the penetration of 9D7 mAb into the Jurkat cells. However, heparin sulfate, chondroitin sulfate B, decaarginine and chondroitinase ABC significantly suppressed the internalization and the 9D7 mAb inhibited the internalization of Tat-GFP. Moreover, the penetration of the 9D7 mAb was significantly reduced in proteoglycan-deficient cells (pgs A-745). Positively charged amino acids including arginine are commonly found in the CDR of the 9D7 mAb. Point mutations to the arginine residues in the CDR of the H chain of the recombinant 9D7 mAb significantly attenuated its DNA-binding and cell-penetration abilities. These findings indicate that cell penetration of anti-dsDNA is due to the electrostatic interactions of arginine residues in the CDR with the negatively charged sulfated polysaccharides on the cell surface.
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PMID:Arginines in the CDR of anti-dsDNA autoantibodies facilitate cell internalization via electrostatic interactions. 1899 Dec 92

Enhanced cell death and deficient clearance of cellular debris are thought to contribute to increased self-antigen exposure in systemic autoimmune disease. To investigate the characteristics of early humoral autoimmune responses, six monoclonal antibodies were generated from two autoimmune prone strains of mice. All antibodies specifically bound the surface of late-stage apoptotic cells. Similar antibody reactivities were present in the sera of patients with systemic lupus erythematosus. While IgM antibodies significantly reduced the phagocytic uptake of apoptotic thymocytes, IgG antibodies enhanced uptake. Poly-reactivity was demonstrated in the recognition of ribonucleoproteins and lipids. An antibody reactive towards lysophosphatidylcholine reversed lysophosphatidylcholine-mediated inhibition of LPS-induced TNF-alpha production and adversely affected the transmigration of phagocytes towards an apoptotic stimulus. In several instances, CDR were characterized by the accumulation of somatic mutations. Anti-idiotypic antibodies generated upon immunization bound distinct cellular moieties and self-antigens. Poly-specific, apoptotic cell-reactive autoantibodies can therefore directly impact upon the course of disease by influencing phagocytic uptake of apoptotic cells, by inducing a pro-inflammatory environment through neutralization of bioactive lipids, by blinding phagocytes to the presence of dying cells through the negation of lipidic chemotactic signals, and by mediating diversification of the humoral autoimmune response via the idiotypic network.
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PMID:Endogenous humoral autoreactive immune responses to apoptotic cells: Effects on phagocytic uptake, chemotactic migration and antigenic spread. 1901 23


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