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)

The two types of human C4, C4A and C4B, differ in their amino acid sequence and in their capacity to bind to different acceptor sites. C4B is more efficient than C4A in haemolytic assays; by contrast C4A binds preferentially to immune complexes. In assays comparing haemolysis to processing of immune complexes the two types of C4 differ more than fivefold. Thus, the classical pathway is a duplicated system that allows the formation of a C3 convertase on various substrates: this duplication may be of vital importance to eliminate invading microorganisms. In addition, the clinical observation of an increased incidence of homozygous C4A null alleles in systemic lupus erythematosus may be explained in part by defective processing of immune complexes in the absence of C4A.
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PMID:Two isotypes of human C4, C4A and C4B have different structure and function. 265 Sep 88

Nephritic factor of the classical complement pathway (C4NeF) is an IgG antibody which stabilizes the C3 convertase (C4b2a) and has been detected in sera from patients with systemic lupus erythematosus (SLE) and acute postinfectious glomerulonephritis. In order to study the production of nephritic factor (NeF), mononuclear cells were isolated from the peripheral blood of patients with SLE and infected with Epstein-Barr virus (EBV) to establish active B lymphocyte cell lines. Supernatants from 15 established B cell lines, as well as from 10 B cell lines established from normal individuals, were investigated for their ability to conserve the classical and the alternative pathway C3 convertases as assessed by EAC3bBb and EAC14b2a stabilizing assays. Supernatants from 2 of 15 B cell lines from patients with SLE, but none from normal individuals, stabilized the classical C3 convertase without having any effect on the alternative pathway C3 convertase. Using anti-human Ig affinity chromatography, we showed that C4NeF activity resided in the IgG fraction; the IgG fraction containing C4NeF activity bound to the C4b2a complex, but not to C4b alone. On gel electrophoresis, following reduction, the heavy chains were slightly heavier than the heavy chains of normal IgG. We were able to isolate C4NeF from the sera of the 2 patients with SLE from whom the positive supernatants were derived, but were unable to detect any C4NeF activity in the sera of the other 13 patients and the 10 normal individuals. Serum and B cell line supernatant-derived C4NeF exhibited comparable characteristics. We conclude that C4NeF produced in vitro by EBV-transformed B cell lines derived from patients with SLE is functionally similar to the conventional C4NeF in serum. These studies confirm the production of autoantibodies by B cells with the ability to stabilize the classical pathway C3 convertase in certain patients with SLE; stabilization of the C4b2a enzyme in these patients is an apparent mechanism for the development of hypocomplementemia. Finally, preparation of homogeneous C4NeF in vitro should improve our understanding of the role of autoantibodies in complement metabolic disturbances in autoimmune diseases.
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PMID:Epstein-Barr virus transformed B cell lines derived from patients with systemic lupus erythematosus produce a nephritic factor of the classical complement pathway. 282 58

Rapid progress has been made recently on the elucidation of the structural components of the complement system by the application of recombinant DNA techniques. The derived amino acid sequences of most of the complement proteins are now available through cDNA cloning, and significant progress has been made in the discovery of the genetic organization of the corresponding genes. The linkage of some of the complement component genes has been established through the study of phenotypic genetics. Of particular interest has been the mapping of two clusters of genes which encode proteins involved in the activation of C3. C2, C4 and factor B, three of the structural components of the classical and alternative pathway C3 convertases, are encoded by genes which map to the MHC on human chromosome 6. The linkage of the genes with each other in a 100 kb segment of DNA has been established through the isolation of overlapping cosmid clones of genomic DNA, and PFGE has defined the molecular map position of these genes within the class III region of the MHC. The regulatory proteins factor H, C4BP, CR1 and DAF, which are involved in the control of C3 convertase activity, are encoded by closely-linked genes (termed the regulators of complement activation or RCA linkage group) that have been mapped to human chromosome 1. PFGE has defined the linkage of the CR1, C4BP and DAF genes, together with the CR2 gene in an 800 kb segment of DNA, and it is clear that this technique will eventually be applied to the molecular mapping of other complement genes in relation to their flanking loci. Polymorphism is a feature of many of the complement proteins, especially those encoded by genes in the MHC class III region. Of these, C4 is by far the most polymorphic, and differences in gene size and gene number, in addition to the functional and antigenic differences in the gene products, have been recognized. Null alleles at either of the C4 loci are rather common and may be important susceptibility factors in some HLA-associated diseases, particularly SLE. The molecular basis of complement deficiency states has begun to be elucidated. In many cases, the deficiency is not caused by a major gene deletion or rearrangement, and techniques which detect single point mutations in DNA (Cotton et al, 1988) will have to be applied to fully characterize the nature of the defect.
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PMID:The molecular genetics of components of the complement system. 306 64

Recently many studies have been done to identify complement pathway activation in renal tissue from patients with renal disease. We examined whether tissues obtained by renal biopsy from such patients would fix guinea pig complement. Nine out of 15 patients with systemic lupus erythematosus (SLE), 4 out of 7 patients with mesangiocapillary glomerulonephritis (MCGN), and 2 out of 7 cases with acute glomerulonephritis (AGN) fixed guinea pig C3. We found that tissues from 5 out of 9 guinea pig C3-positive SLE cases fixed guinea pig C4, while none of the guinea pig C3-positive tissues from patients with MCGN or AGN fixed guinea pig C4. These guinea pig C3-positive renal tissues were further studied for interaction with C4-deficient guinea pig serum, EDTA guinea pig serum, heated guinea pig serum, and EGTA Mg2+ guinea pig serum. The results indicated that activation of both the alternate and classical complement pathways occurred with tissues from patients with SLE, while activation of the alternate pathway occurred with MCGN and AGN. Results for tissues from AGN and MCGN patients indicated the presence of C3 convertase and protease which interacted with guinea pig C3.
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PMID:Guinea pig complement fixation by tissues from hypocomplementaemic renal diseases. 351 34

C3 nephritic factor (NEF), an IgG autoantibody to the alternative pathway C3 convertase, is usually measured by crossed immunoelectrophoresis (CI) but recently a reliable haemolytic assay (HA) was described by Rother (1982). This method is more specific than CI because it is negative in sera with immune complexes, SLE and sera incubated with IgG aggregates. The haemolytic assay is sensitive enough to detect NEF antibody in serum from patients with only slightly low C3 levels and NEF negatives by CI. The haemolytic assay is easy to perform and reproducible, the interassay coefficient of variation being 10.7% compared to 64% in the CI. The intra-assay coefficient of variation in CI was 28% compared to 5.5% in the haemolytic assay. The haemolytic method enabled us to study the kinetic effects of NEF on C3b.Bb bound to sheep erythrocytes, and the lysis mediated by ShE.C3b.Bb.NEF complex. Also the C and NEF binding to sheep erythrocytes was studied.
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PMID:C3 nephritic factor determination. A comparison between two methods. 355 14

A relationship was found between the sums of the component proteins of the classical pathway C3 convertase (C2 and C4) and their regulators (C4bp and 1) in 184 normal controls. The relationship was maintained in most patients with low levels of individual components resulting from congenital deficiency and urinary losses, as well as in most cord sera. On the other hand, classical pathway activation in membranoproliferative glomerulonephritis type I, systemic lupus erythematosus, hereditary angioneurotic edema, and bacteremia resulted in loss of this relationship. Patients with alternative pathway-mediated complement activation (membranoproliferative glomerulonephritis type II) had a normal relationship between the classical component and regulatory proteins. In situations in which classical pathway activation is suspected, simultaneous examination of C4, C2, C4bp, and I may be helpful.
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PMID:Relationship between the component and regulatory proteins of the classical pathway C3 convertase. 363 65

Factors with the ability to induce a minimum of 20% C3 conversion in normal human serum (NHS) were demonstrated in the sera of nine glomerulonephritis (GN) patients. The nature of these factors was heterogeneous allowing their division into at least three different groups. First, in three cases (membranoproliferative or acute GN) they exhibited the characteristics of C3 nephritic factor, an IgG autoantibody stabilizing the alternative pathway (AP) C3 convertase, C3bBb. Secondly, the serum of one patient (SLE like syndrome, mixed cryoglobulinaemia) with an activator of both pathways and profound hypocomplementaemia showed a temperature-dependent precipitation against autologous and homologous polyclonal IgG. Immunochemical analysis suggested this activity to be due to a monoclonal IgM kappa rheumatoid factor. By gel filtration the C3 converting activity was found in the high molecular weight fractions containing the cryoprecipitable IgM-IgG complexes. Finally, in five cases the exact nature of C-activating factors remained unknown. In four of these the factors were heat labile (30 min at 54 degrees C) C activators in association with post-streptococcal glomerulonephritis. The results suggest that the various C activating factors, possibly distinct from 'classical' immune complexes, are indicators of different types of pathogenetic mechanisms in certain forms of GN.
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PMID:Complement activation by circulating serum factors in human glomerulonephritis. 391 77

A patient with herpes gestationis, 6 of 6 patients with bullous pemphigoid, and 5 of 25 patients with systemic lupus erythematosus were found to have properdin deposited along the skin basement membrane.The patient with herpes gestationis demonstrated by immunofluorescence basement membrane deposition of C3 and C5 in the absence of C1q, immunoglobulins, and light chains. A second patient with herpes gestationis had C3 deposition with no demonstrable immunoglobulins or light chains. A thermolabile humoral factor(s) capable of depositing C3 (without C1q or C4) on normal skin basement membrane was found in the sera of both patients with herpes gestationis. No anti-basement membrane antibodies could be demonstrated in the sera of these patients.The patients with systemic lupus erythematosus and bullous pemphigoid who manifested properdin deposition also showed skin basement membrane deposits of C1q, C4, C3, C5, and immunoglobulins. C3 proactivator (C3PA) was also found deposited along the skin basement membrane of three patients with systemic lupus erythematosus and all six bullous pemphigoid patients. This study provides suggestive evidence that activation of complement is occurring via the alternate pathway in herpes gestationis. In systemic lupus erythematosus and bullous pemphigoid, both the classical (antibody) mediated activation of complement as well as the alternate pathway may be operative.
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PMID:Evidence for complement activation via the alternate pathway in skin diseases, I. Herpes gestationis, systemic lupus erythematosus, and bullous pemphigoid. 435 64

The study of serum from a patient with C2 deficiency is described. The patient had an episode of pneumococcal meningitis at 5 mo of age with seizures and transient hemiparesis and apparent purpuric skin lesions. He was first admitted to the University of Minnesota Hospitals at 10 yr of age following the discovery of proteinuria accidentally by his mother. Since then he has been admitted repeatedly to this hospital with numerous clinical findings including arthralgia, recurrent abdominal pain, proteinuria, membranous nephropathy, malar butterfly rash, seizures, personality aberrations, and recurrent fever. In June 1971, the patient developed positive DNA and DNP antibodies and positive LE cells. When the C profile was studied before and after recognition of lupus, C1q, C1s, and C4 dropped. C3 levels were elevated as were C5, C6, and C7, C3 proactivator had been reduced in the patient even before he developed lupus. Also because of a traumatic renal biopsy leading to a perirenal hematoma, he required surgery and a blood transfusion. 1 h after blood transfusion, a C2 titer of 23 hemolytic units was detected. Almost immediately levels of C3, C5, C6, and C7 dropped, C8 and C9 remained elevated. The addition of C2 from normal blood permitted dramatic activation of C3. These findings support the view that the rare deficiency in production of C2 predisposes to serious susceptibility to infection, vascular and mesenchymal disease as well as to renal disease and a lupus syndrome.
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PMID:C2 deficiency. Development of lupus erythematosus. 457 55

Serological and immunopathological studies of human glomerulonephritis have suggested that alternate pathways of activation of the third component of complement may be important in some forms of glomerulonephritis. We have investigated the role of two alternate pathway proteins, properdin and C3 proactivator, in 22 patients with chronic membranoproliferative glomerulonephritis, 21 patients with systemic lupus erythematosus, 20 patients with acute poststreptococcal glomerulonephritis, and 19 patients with other forms of renal disease. C3 (measured at beta(1)A), properdin, and C3 proactivator were assayed by single radial immunodiffusion. In sera with low beta(1)A (< 2 SD), mean properdin was most significantly decreased in patients with acute poststreptococcal glomerulonephritis but was also significantly decreased in chronic membranoproliferative glomerulonephritis and in untreated systemic lupus erythematosus. Properdin levels in other renal disease, acute glomerulonephritis, and chronic membranoproliferative glomerulonephritis with normal beta(1)A levels were not significantly different from normal. A positive correlation between beta(1)A and properdin levels in individual sera was present in all diseases except systemic lupus erythematosus. Serum C3 proactivator was markedly decreased in active systemic lupus erythematosus and there was a positive correlation between beta(1)A and C3 proactivator levels in systemic lupus erythematosus and other renal diseases but not acute poststreptococcal glomerulonephritis. Properdin in fresh sera from four patients with systemic lupus erythematosus and five with chronic membranoproliferative glomerulonephritis showed increased migration toward the cathode on immunoelectrophoresis, suggesting in vivo change of the properdin molecule. The observation of reduced serum levels of properdin and C3 proactivator and altered electrophoretic migration of properdin in some patients with glomerulonephritis provide new evidence for participation of these alternate pathway proteins in glomerulonephritis.
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PMID:Properdin anc C3 proactivator: alternate pathway components in human glomerulonephritis. 463 Sep 81


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