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

Isolated inherited deficiency states of almost every complement protein have been recognized. Almost all are autosomal recessive traits. Deficiency of the early-acting components C1, C4 and C2 is associated with increased risk of immune complex disease, particularly systemic lupus erythematosus. Patients with deficiency of C3, factor I or factor H have increased susceptibility to infection by pyogenic bacteria, whereas those with deficiencies of properdin, C5, C6, C7 or C8 are prone to systemic neisserial infection. Inherited deficiency of C1 inhibitor is transmitted as an autosomal dominant trait, is genetically heterogeneous, and is associated with attacks of angioedema and consumption of C4 and C2. There is evidence that a plasmin-modified fragment of C2 is responsible for the angioedema in this disorder. Administration of androgens tends to correct the biochemical abnormalities of hereditary angioedema and to prevent attacks.
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PMID:Inherited deficiencies of complement components in man. 357 Mar 60

The NH2-terminal amino acid sequences have been determined by automated Edman degradation for the heavy and light chains of five monoclonal IgM anti-DNA autoantibodies that were produced by human-human hybridomas derived from lymphocytes of two patients with systemic lupus erythematosus. Four of the antibodies were closely related to the idiotype system 16/6, whereas the fifth antibody was unrelated idiotypically. The light chains of the 16/6 idiotype-positive autoantibodies (HF2-1/13b, HF2-1/17, HF2-18/2, and HF3-16/6) had identical amino acid sequences from residues 1 to 40. Their framework structures were characteristic of VKI light chains. The light chain of the 16/6 idiotype-negative autoantibody HF6-21/28 was characteristic of the VKII subgroup. The heavy chains of the 16/6 idiotype-positive autoantibodies had nearly identical amino acid sequences from residues 1 to 40. The framework structures were characteristic of the VHIII subgroup. In contrast, the GM4672 fusion partner of the hybridoma produced small quantities of an IgG with a VHI heavy chain and a VKI light chain. The heavy chains of the lupus autoantibodies and the light chains of those autoantibodies that were idiotypically related to the 16/6 system had marked sequence homology with WEA, a Waldenstrom IgM that binds to Klebsiella polysaccharides and expresses the 16/6 idiotype. These results indicate a striking homology in the amino termini of the heavy and light chains of the lupus autoantibodies studied and suggest that the V regions of the heavy and light chains of the 16/6 idiotype-positive DNA-binding lupus auto-antibodies are each encoded by a single germ line gene.
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PMID:Homology of the NH2-terminal amino acid sequences of the heavy and light chains of human monoclonal lupus autoantibodies containing the dominant 16/6 idiotype. 392 67

The platelet binding properties of human monoclonal lupus autoantibodies have been studied. These IgM autoantibodies, produced by human X human hybridomas derived from lymphocytes of patients with systemic lupus erythematosus, are known to bind to single-stranded DNA. Four anti-DNA antibodies that express the dominant 16/6 idiotype--HF2-1/17, HF2-18/2, HF2-1/13b, and HF3-16/6--bound to glutaraldehyde-fixed platelets. In contrast, HF6-21/28, HF9-11/3, and polyclonal IgM bound poorly to platelets. [35S]Methionine was incorporated into HF2-1/17, and the interaction of the intrinsically radiolabeled HF2-1/17 with fixed platelets was evaluated in a solution phase radioimmunoassay. [35S]Methionine HF2-1/17 bound to fixed platelets and could be displaced by equivalent amounts of HF2-1/17, HF2-18/2, HF2-1/13b, and HF3-16/6. HF2-1/17 bound with greater affinity to fresh platelets and to thrombin-activated platelets than to glutaraldehyde-fixed platelets. Single-stranded DNA competed with platelets for the HF2-1/17 combining site. Treatment of fresh platelets with nuclease I, trypsin, chymotrypsin, and neuraminidase did not alter the binding of antibody to the platelet surface. No binding of antibody to phospholipid micelles was observed. Purified IgM autoantibodies did not inhibit platelet aggregation induced with ADP, thrombin, or ristocetin in platelet-rich plasma. These results indicate that the human IgM monoclonal anti-DNA autoantibodies that express the dominant 16/6 idiotype are polyspecific, bind to platelets, and interact with a platelet epitope that does not appear to involve DNA, protein, or sialic acid. These antibodies interact with platelets through the same sites responsible for antibody-DNA binding.
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PMID:Platelet binding properties of monoclonal lupus autoantibodies produced by human hybridomas. 406 19

The C3b receptor of human erythrocytes, neutrophils, monocytes, all mature B cells, a subpopulation of T cells, and glomerular podocytes is a single chain glycoprotein that exists in two allotypic forms having Mr's of approximately 250,000 (F) and 260,000 (S). The number of receptors present on erythrocytes varies by eight-fold among different individuals and is genetically regulated by two codominant alleles that are distinct from the alleles determining the structural polymorphism. The number of receptors expressed by neutrophils is subject to rapid increases from 5000 per cell to 40,000 per cell by exposure to nanomolar concentrations of C5adesArg, in vitro, and a similar mechanism is probably the basis for observing increased receptor expression on neutrophils in patients undergoing hemodialysis. Cytoskeletal association of the C3b receptor on monocytes and neutrophils is suggested by experiments demonstrating receptor-mediated phagocytosis, adsorptive endocytosis through coated pits, and restricted lateral diffusion, and by the reciprocal co-redistribution of cross-linked C3b and Fc receptors, and the detergent-insolubility of cross-linked C3b receptors. The factor H-like cofactor activity of the C3b receptor promotes the cleavage of bound C3b to iC3b, C3c and C3d, g, reactions that may enhance the clearance of circulating immune complexes and the generation of ligands for CR2 and CR3. The inherited partial deficiency of erythrocyte C3b receptors in patients with SLE, and the absence of glomerular C3b receptors in these patients with proliferative glomerulonephritis may contribute to systemic and organ-specific abnormalities in the clearance of immune complexes that contribute to the pathogenesis of this disease.
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PMID:The human C3b receptor. 622 98

Thirty-two of 36 serum samples from 19 SLE patients showed reduced capacity to mediate complement-dependent solubilization of immune complexes (IC). SLE patients with nephritis exerted the lowest complement-mediated solubilization capacity (CMSC) whereas sera from patients with inactive disease gave the highest CMSC values, with three out of four samples within the normal reference range. Thirty-five of the 36 serum samples showed inhibition of CMSC in a newly developed CMSC inhibition assay. The strongest CMSC inhibition was exerted by sera from newly discovered cases of SLE who received no medical treatment and the lowest inhibition by sera from patients with inactive disease. There was a significant negative correlation between CMSC and CMSC inhibition (r = -0.67, P less than 0.001). Sera with low concentrations of C1q, C3, factor B or high C3d levels showed markedly reduced CMSC values. Pronounced CMSC inhibition was observed only in samples with normal or high factor H values. No significant correlation was found between CMSC or CMSC inhibition and circulating IC levels, but pronounced CMSC inhibition was registered only in strongly IC positive sera.
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PMID:Complement-mediated solubilization of immune complexes. Solubilization inhibition and complement factor levels in SLE patients. 623 Jan 82

The human C3b receptor (C3bR) is a glycoprotein that exists in two allotypic forms having Mr values of approximately 250,000 (F) and 260,000 (S). The number of receptors present on erythrocytes varies by eightfold among normal individuals and is genetically regulated by two codominant alleles that are distinct from the alleles determining the structural polymorphism. C5a and C5ades Arg induce rapid increases in the number of receptors expressed by neutrophils in vitro, and probably account for the increased receptor expression on neutrophils in patients undergoing hemodialysis. Cytoskeletal association of the C3bR on monocytes and neutrophils is suggested by experiments demonstrating receptor-mediated phagocytosis and adsorptive endocytosis through coated pits, and by the reciprocal coredistribution of cross-linked C3b and Fc receptors and the detergent insolubility of cross-linked C3bR. The factor H-like cofactor activity of the C3bR promotes the cleavage of bound C3b to iC3b, C3c, and C3d,g, which may enhance the clearance of circulating immune complexes and the generation of ligands for CR2 and CR3. The inherited partial deficiency of the erythrocyte C3bR in patients with systemic lupus erythematosus and the absence of glomerular C3bR in these patients with proliferative glomerulonephritis may contribute to systemic and organ-specific abnormalities in the clearance of immune complexes in this disease.
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PMID:Structure and function of the human C3b receptor. 623 86

Perturbation of the serum complement system in glomerulonephritis can be the result of classical pathway activation by immune complexes or of C3 activation by the C3-C5 convertase stabilized by the C3 nephritic factor. Low C3 levels can also be the result of diminished C3 synthesis and possibly, in certain circumstances, of C3 convertases deposited on capillary walls. In glomerulonephritis the complement profile is helpful in diagnosis, in following the course of therapy and in providing insights into pathogenesis. Complement profiles must be interpreted recognizing that a pattern resembling classical pathway activation can be produced by idiopathic nephrotic syndrome, that hypogammaglobulinemia can reduce Clq levels, and that a primary deficiency of factor H or I or both, will secondarily produce subnormal levels of C3 and factor B. With these caveats, the complement profiles typical of systemic lupus erythematosus, membranoproliferative glomerulonephritis, acute glomerulonephritis, acquired Cl inhibitor deficiency, and hypocomplementemic vasculitis syndrome are described.
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PMID:Complement activation in renal disease. 654 95

Human B-cell lines were derived by limiting dilutions of Epstein-Barr virus (EBV) transformed peripheral B cells from a patient with an autoantibody against glycoprotein (GP)Ia/IIa, and manifesting defective collagen-induced platelet aggregation and a bleeding problem. Antibody-producing clones were selected for their reactivity with whole platelets or with affinity-purified GPIa/IIa by enzyme-linked immunosorbent assay (ELISA). One of these cell lines, selected for further evaluation, produced an IgM (E3G6) that interfered with platelet aggregation responses. Polymerase chain reaction (PCR) amplifications with two different sets of primers specific for human kappa-chains resulted in the rescue of a unique and identical sequence. The same was true for the mu-chain, from which it was concluded that the cell line was monoclonal. Further analysis showed that the kappa variable domain sequence is similar to the germline gene A30, to 2E7, an anti-GPIIb human autoantibody, and to HF2-1/17, a systemic lupus erythematosus (SLE)-associated broad-specificity human autoantibody. Thus, the specificity of our antibody, E3G6, appears to be determined by the mu-chain, the sequence of which is encoded by a VHIII gene segment strongly homologous to the germline gene DP-77, by a D gene that is not homologous to any of the germline D genes reported to date, and by JH4 gene segment that is germline. All four mutations versus DP-77 are in CDRs, and result in amino acid substitutions, which implies that E3G6 may have been derived from an antigen-driven response.
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PMID:Production and nucleotide sequence of an inhibitory human IgM autoantibody directed against platelet glycoprotein Ia/IIa. 754 50

Factor H, a 150-kD protein, is an important down-regulating protein of the alternative pathway of the complement system. Presently, only 15 persons, representing seven families, have been described with homozygous factor H deficiency. Deficiency of this protein, inherited as an autosomal recessive trait and resulting in uncontrolled breakdown of C3, results in depletion of components of the alternative pathway (factor B, properdin) and of the terminal pathway (C5), and is associated with the onset of bacterial infections, glomerulonephritis and systemic lupus erythematosus (SLE). The proband of the family in this study suffered from subacute cutaneous lupus erythematosus and had had meningococcal meningitis due to serogroup X. She had a complete factor H deficiency at the protein level as determined by Western blotting. Among 21 relatives of the proband studied, encompassing three generations, 10 had low factor H levels, including the two children of the proband, indicating a heterozygous factor H deficiency state. In serum samples of the proband and 11 relatives prospectively studied, a strong correlation of factor H levels with C3, C3 haemolytic activity, factor B and properdin levels (P < 0.0001) was found. Alternative pathway protein levels were significantly lower (Mann-Whitney test; Z values 3.6-2.7) in sera from the four heterozygous relatives studied than in sera from the seven non-deficient relatives. In addition, a defect of the 37/42-kD H-related protein was found in the proband and two of 21 relatives, compared with four of 40 controls. A defect of the 24/29-kD H-related protein was present in one of 21 relatives studied and in none of the 40 controls.
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PMID:Heterozygous and homozygous factor H deficiency states in a Dutch family. 880 42

Anticardiolipin antibodies (aCL) found in sera from patients with antiphospholipid syndrome recognize a cryptic epitope that appears on the beta2-glycoprotein I (beta2-GPI) molecule when beta2-GPI interacts with a lipid membrane composed of negatively charged phospholipid or when beta2-GPI is adsorbed on a polyoxygenated polystyrene plate. A homology based model of beta2-GPI was constructed based on the NMR coordinates of sushi domains of human factor H. The conformation was like a cylinder consisting of five domains, its IV and V domains being glued by electrostatic interaction. We used phage-displayed random peptide libraries to search the epitopes of human aCL. Structures similar to consensus sequences selected by a biopanning method was found on domain IV of beta2-GPI.
Lupus 1998
PMID:Epitopes on beta2-GPI recognized by anticardiolipin antibodies. 981 65


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