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)

We have developed a new, specific, and highly sensitive enzyme-linked immunosorbent assay (ELISA) which quantitates activation of the alternative pathway in human serum, plasma, or on the surface of activators. The ELISA detects the third component of complement (C3b), proteolytic fragment of complement Factor B (Bb), and properdin (P) complex or its derivative product, C3b,P. In the method, activator-plasma mixtures, plasma containing an activated alternative pathway, or other samples are added to the wells of microtitration plates precoated with antibody to P. C3b, Bb,P or C3b,P complexes which become bound are quantitated by subsequently added, enzyme-labeled, anti-C3. The resulting hydrolysis of the chromogenic substrate is expressed as nanograms of C3b by reference to a C3 standard curve. In addition to absolute specificity for activation of the pathway because of the nature of the complex detected by the assay, the ELISA is highly sensitive and able to reproducibly detect 10-20 ng/ml of C3b,P complexes in serum. This value corresponds to 0.0015% of the C3 in serum. In a series of studies to validate the parameters of the ELISA, reactivity was found to be dependent on the presence of alternative pathway proteins, the functional integrity of the pathway, and on the presence of magnesium. Sheep erythrocytes were converted to activators by treatment with neuraminidase. By using a variety of activators, the kinetics of activation and the numbers of bound C3b molecules quantitated by the ELISA were very similar to those measured by C3b deposition. The ELISA also detected identical activation kinetics when MgEGTA-serum and a mixture of the purified alternative pathway proteins were used as sources of the pathway. ELISA reaction kinetics also correlated with the restriction index, a measure of alternative pathway-activating ability. These studies cumulatively validate the ELISA as a direct and quantitative assay for alternative pathway activation. The sensitivity of the ELISA has permitted its use to detect direct alternative pathway activation by several viruses. The ELISA has also shown that certain classical pathway activators trigger the amplification loop of the alternative pathway while others do not. In addition, stable ELISA reactive complexes appeared in the supernatant of mixtures of serum with certain, but not other activators. The ability of the ELISA to detect activation which has already occurred and the stability of the reactive complexes permits studies of clinical sera. Normal human sera (20) contained low levels (5-20 ng/ml) of ELISA-reactive complexes. A proportion of sera from individuals with the adult respiratory distress syndrome (9-10), typhoid fever (8-10), malaria (3-5), gram-negative sepsis (9 of 47), acute trauma and shock (6 f 25), and systemic lupus erythematosus (3 of 29) showed elevated levels of complexes reactive in the alternative pathway ELISA. In contrast, nine sera from patients with circulating C3 nephritic factor were not reactive in the ELISA.
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PMID:Development and application of an enzyme-linked immunosorbent assay for the quantitation of alternative complement pathway activation in human serum. 641 67

Inherited deficiencies of the complement proteins are rare in unselected populations. Examination of patients with the clinical correlates of complement deficiency (autoimmune disease and certain bacterial infections) shows the frequency of inherited complement deficiency to rise enormously (5.9% of patients with systemic lupus erythematosus, 10 to 25% of adults with sporadic meningococcal disease). Autoimmune diseases of all types, but especially systemic lupus erythematosus, discoid lupus and glomerulonephritis, are seen in all categories of complement deficiency, most typically in those of the early classical pathway (C1, C4, C2). Pneumococcal infections are characteristic of deficiencies of the early classical pathway, as well. Deficiencies of C3 are associated with severe disease including autoimmune phenomena, pneumococcal and neisserial infections. C3-deficient patients become ill substantially earlier in life. Infections with N. meningitidis and N. gonorrhoeae are most typical of the late component deficiencies, with over 40% of homozygotes affected. Despite the presence of this deficiency from birth and the peak age-specific incidence of meningococcal disease in the general population at ages 3-8 months, the median age of first infection in the late component-deficient patients is 17 years. Relapse of infection is ten times more common in these patients, and discrete recurrences are seen in 45% of affected individuals. An unusual and unexplained predilection for infection with serogroup Y N. meningitidis exists. Despite an immune deficiency, and problems with ascertainment bias, it appears that persons with late component complement deficiency enjoy less mortality than normals who contract meningococcal disease. Attempts to explain the pathogenesis of neisserial infection in late component deficiencies have focused on the concept that normally non-pathogenic serum-sensitive bacteria are etiologic in the absence of serum bactericidal activity. Data to support this concept remain to be developed and contrary data exist. A separate mechanism may predispose properdin-deficient patients to meningococcal infection, since they appear to develop fulminant infections with high mortality.
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PMID:Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. 643 45

In order to determine the clinical utility of the lupus band test, the presence of dermal-epidermal junction (DEJ) deposits of IgG, IgM, IgA, C3, C4, Clq, and properdin were studied in biopsies of clinically normal deltoid area skin from 102 patients with systemic lupus erythematosus (SLE) and 151 patients with other rheumatic diseases. One or more proteins were detected at the DEJ in 72.6% (74 of 102) of patients with SLE and in 36.4% (55 of 151) of the other patients, yielding a specificity of 64% and a predictive value of 57%. The predictive value for the diagnosis of SLE was greatest with C4 (100%), properdin (91.3%), and IgA (86.2%) and lowest with IgM (59%). Specificity and predictive value increased with the number of proteins detected at the DEJ. The results suggest that more rigid criteria are required before diagnostic significance is attached to a positive result on the lupus band test.
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PMID:The clinical utility of the lupus band test. 660 47

Antibodies to the nuclear antigen SM are specific for systemic lupus erythematosus in humans and mice. In order to study the cellular mechanisms of anti-Sm generation, a hemolytic plaque assay to identify and enumerate lymphocytes secreting anti-Sm has been developed by using SRBC coated with purified Sm by a modified carbodiimide technique. Anti-Sm-specific PFC were found in MRL/Mp-Ipr/Ipr and MLR/Mp- +/+ mice whose sera contained anti-Sm, but were never detected in anti-Sm-negative MRL mice or in normals. Spleen cells from anti-Sm-positive MRL/Mp-Ipr/Ipr mice generated anti-Sm PFC spontaneously after 4 days of in vitro culture, whereas cells from normal mice or anti-Sm-negative MRL mice were never observed to produce spontaneous anti-Sm, even when cultured in the presence of bacterial lipopolysaccharide. The generation of anti-Sm by MRL cells in vitro was found to be dependent on the presence of T cells, but the ability of cells from individual MRL mice to generate anti-Sm appeared to be limited by the availability of Sm-specific B cell precursors and not due to a relative absence of T cells capable of providing help for the anti-Sm response. Analysis at the cellular level of the in vitro generation of a disease-specific autoantibody by using the methods described should facilitate understanding of mechanisms of autoreactivity.
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PMID:Anti-Sm autoantibodies in MRL mice: in vitro detection and generation of antibody-forming cells. 698 38

C3 cleaving activity through alternate pathway, appreciated by native C3 antigen reduction in the presence of Mg EGTA, has been measured in sera of 40 controls and of 125 GN patients. The normal percentage of native C3 conversion ranged from 0 to 29 in controls (p less than 0.05). The number of positive samples is 0/30 in lupus GN (0%), 13/29 in acute GN (45%) and 26/66 in membranoproliferative GN (39%) with 7/8 in dense deposits subtype. The presence of alternate pathway activators of complement correlated with serum C3 level: their frequency is respectively 0, 0.32, and 0.48 if serum C3 is normal, low, and very low. Such activity correlated also well with alternate pathway C3 activation (low C3 and normal C4): the frequency of positive samples is respectively 0, 0.07, and 0.51 in the presence of No C3 activation, classical pathway activation (low C3 and low C4), and alternate pathway activation. The nature of such serum activators could be nephritic factor, bacterial polysaccharides, polymeric IgA, activated properdin, peculiar immune complexes, or other factors. Such measurement is an improvement immunopathological step in the investigation of human GN.
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PMID:[Specific measurement of alternate pathway activation of complement in human glomerulonephritides (GN): 125 cases (author's transl)]. 730 Oct 22

Anti-DNA antibodies were assessed in 33 patients with active systemic lupus erythematosus (SLE) by the immunofluorescence Crithidia luciliae (CL) and the Farr assays. Eleven patients demonstrated complement (C3) fixation in the CL assay. Although 6 out of 9 patients with active nephritis showed complement fixation, 6 patients without overt renal disease were also positive in this assay. The ability to fix C3 was strongly associated with the total amount of anti-DNA antibodies as determined by both the CL and Farr assays (P less than 0.001). IgM anti-DNA antibodies were detected only in sera with complement fixing anti-DNA antibodies. Isolated whole IgG, but not the F(ab')2 fragment containing anti-DNA activity, fixed C3 on the Crithidia substrate. In depletion and reconstitution studies with human complement components, it was established that anti-DNA antibodies fixed C3 through the classical complement pathway although factors B and D of the alternative pathway were effective in C3 amplification. Properdin was also detected on the antigen-antibody complex but did not appear to be essential for maximal C3 fixation. Anti-DNA antibodies therefore fix complement by their Fc portion, form a classical pathway convertase, and recruit factors B and D of the C3b amplification loop when they bind to a fixed antigen.
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PMID:Complement fixing properties of antibodies to double-stranded DNA in systemic lupus erythematosus. 733 85

Clustering activity for neutrophil granulocytes was generated in pooled normal human serum (NHS) by incubation of the serum with preformed IgG aggregates, but not in heat-treated NHS (56 degrees C, 30 min), indicating that the function was complement-dependent. Judging from results of experiments with complement-deficient sera, and serum depleted of C1q, factor D and properdin, recruitment of the complement system beyond C1 was not required for induction of the activity. Zymosan treatment of NHS resulted in some neutrophil clustering activity, but recombinant C5a had a limited effect. C1q added to heat-treated NHS in conjunction with performed IgG aggregates supported neutrophil clustering in a dose-dependent manner. The serum C1q inhibitor, a chondroitin 4-sulphate proteoglycan known to interact with the collagenous part of C1q, clearly reduced neutrophil clustering in heat-treated NHS supplemented with C1q and IgG aggregates. The C1q inhibitor also reduced the inherent neutrophil clustering activity of some sera from patients with systemic lupus erythematosus (SLE). Neutrophil clustering activity in SLE serum was earlier shown to be inversely related to the number of circulating neutrophils in vivo. Although the precise mechanisms remain unclear, we propose that C1q-containing immunoglobulin complexes mediate neutrophil clustering through C1q receptors, and that this might contribute to pathogenesis of immune complex diseases such as SLE.
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PMID:Clustering of neutrophil leucocytes in serum: possible role of C1q-containing immune complexes. 834 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

Chronic deficiencies in the complement pathway proteins are associated with an increased risk of meningococcal disease. Such deficiencies are caused by primary congenital immunodeficiency of a complement protein, properdin or mannose binding lectin, or are secondary to consumption of complement by systemic lupus erythematosus (SLE) or membranoproliferative glomerulonephritis (MPGN). Whatever the cause, the complement deficiency is always chronic. Here we report a case of meningococcal disease (MCD) in a child with a transient complement deficiency (CD), caused by post-streptococcal glomerulonephritis (PSGN).
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PMID:Meningococcal disease associated with an acute post-streptococcal complement deficiency. 1729 26

Recurrent miscarriage, fetal growth restriction and intrauterine fetal death are frequently occurring complications of pregnancy in patients with systemic lupus erythaematosus (SLE) and antiphospholipid syndrome (APS). Murine models show that complement activation plays a pivotal role in antiphospholipid antibody-mediated pregnancy morbidity, but the exact pathways of complement activation and their potential role in human pregnancy are insufficiently understood. We hypothesized that the classical pathway would play a major role in inducing fetal loss. Pregnant C57BL/6 mice and mice deficient in C1q and factor D were injected with antiphospholipid antibodies or normal human IgG. Mouse placentas were subsequently stained with an anti-C4 antibody and anti-normal human IgG to determine the presence of classical complement activation and IgG binding. Findings in mice were validated in 88 human placentae from 83 women (SLE and APS cases versus controls), which were immunohistochemically stained for C4d, C1q, properdin and MBL. Staining patterns were compared to pregnancy outcome. In murine placentae of mice pretreated with antiphospholipid antibodies, increased C4 deposition was observed, which was associated with adverse fetal outcome but not with IgG binding. In humans, diffuse C4d staining at the feto-maternal interface was present almost exclusively in patients with SLE and/or APS (p < 0.001) and was related to intrauterine fetal death (p = 0.03). Our data show that presence of C4d in murine and human placentae is strongly related to adverse fetal outcome in the setting of SLE and APS. The excessive deposition of C4d supports the concept of severe autoantibody-mediated injury at the fetal-maternal interface. We suggest C4d as a potential biomarker of autoantibody-mediated fetal loss in SLE and APS.
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PMID:Classical complement activation as a footprint for murine and human antiphospholipid antibody-induced fetal loss. 2168 69


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