The complement system in Mediterranean spotted fever.
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Boutonneuse Fever↗
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Regulation of complement activity by vaccinia virus complement-control protein.
A major protein secreted by vaccinia virus-infected cells has structural similarity to the super-family of complement-control proteins. This vaccinia complement-control protein (VCP) was studied to determine how it regulates complement activation. VCP was bound by C4b and C3b and served as a cofactor with factor I in cleaving these two molecules. VCP inhibited the formation and accelerated the decay of the classical C3 convertase. It also accelerated decay of the alternative pathway convertase, although higher concentrations were apparently needed. In vitro, therefore, VCP interfered with the classical and alternative complement pathways at several steps. In vivo, this interference may increase the virulence of vaccinia virus by enabling it to escape attack by the host's complement system.
Complement Activation↗
Elevated levels of iC3b and C4d, but not Bb, complement fragments from plasma of persons infected with human T cell leukemia virus (HTLV) with HTLV-I-associated myelopathy/tropical spastic paraparesis.
Plasma levels of complement (C) fragments iC3b, C4d, and Bb from human T cell leukemia virus (HTLV)-positive subjects with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) were analyzed by EIA. Both iC3b and C4d levels were significantly elevated in persons with HAM/TSP. These levels were similar to those in patients with human immunodeficiency virus (HIV) infection or rheumatoid arthritis (RA), who are known to have increased C fragments. Bb levels in persons with HAM/TSP wer unaffected, suggesting that C activation occurred only via the classical pathway. This differed from findings in HIV-infected or RA patients, who had elevated levels of Bb. The results showed an increase in C activation in persons with HAM/TSP and activation via the classical pathway, likely mediated by virus or immune complexes. It is possible that the C activation observed in these subjects contributed to the inflammatory pathogenesis of HAM/TSP.
Arthritis, Rheumatoid↗
The excessive complement activation in fulminant meningococcal septicemia is predominantly caused by alternative pathway activation.
The relative contribution of the classical and alternative pathways in complement activation was quantified in 20 patients with systemic meningococcal disease. The activation products C4bc, C4bd, and Bb, indicating classical and alternative pathway activation, were measured with neoepitope-specific EIAs. Ten patients with persistent septic shock had significantly higher levels of Bb (P<.001), but not of C4bc (P=.43), than did 10 patients without septic shock. The Bb levels were significantly correlated with C3 activation products (C3bc; r= .72, P=.002), terminal SC5b-9 complement complex (TCC; r=.89, P<.001), and plasma lipopolysaccharides (LPS; r=.69, P= .01). There was no such association for C4bc versus C3bc, TCC, or LPS. Serially collected samples demonstrated activation of both pathways in patients with or without shock. Intervention strategies to stop the massive complement activation in fulminant meningococcal septicemia should include therapeutic principles that inhibit the alternative pathway.
Adult↗
Bgl II polymorphic site upstream to the human complement component C4A gene.
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Bacterial Proteins↗
Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection.
BACKGROUND: Capillary deposition of complement split product C4d has been suggested to be a valuable marker for humoral rejection. In this retrospective study we evaluated the clinical impact of C4d deposition in renal allografts with special emphasis on associations between C4d staining patterns and histological features of acute rejection. METHODS: One hundred and two allograft biopsies obtained from 61 kidney transplants (1-532 days after transplantation; median 14 days) were examined by immunohistochemistry on routine paraffin sections using a novel anti-C4d polyclonal antibody (C4dpAb). RESULTS: Fourty-two of 102 biopsies showed endothelial C4d deposits in peritubular capillaries (PTC). Histopathological analysis revealed a significantly lower frequency of positive C4d staining in biopsies with rather than in those without acute cellular rejection defined by the Banff grading schema (P<0.01). For clinical evaluation, patients were classified according to C4d staining in allografts (C4d(PTC) positive in at least one biopsy, n=31 vs C4d(PTC) negative in all biopsies, n=30). C4d(PTC) positive patients had significantly higher serum creatinine levels than C4d negative patients. Even in the absence of morphological evidence for rejection, differences in serum creatinine levels between C4d(PTC) positive and negative recipients were significant (6 months: 2.01+/-0.75 vs 1.41+/-0.27 mg/dl; 12 months: 1.95+/-0.60 vs 1.36+/- 0.34 mg/dl; 18 months: 1.98+/-0.50 vs 1.47+/-0.31 mg/dl; P<0.05). All patients with rejection resistant to conventional therapy (n=4) were in the C4d(PTC) positive subgroup. All recipients with panel reactive antibodies (PRA) >50% (n=8) were C4d(PTC) positive. CONCLUSIONS: Our data indicate that endothelial C4d deposition is associated with inferior graft outcome. We provide evidence that this immunohistochemical finding and its clinical impact are not associated with morphological signs of cellular rejection.
Biopsy↗
Effect of fish protein supplementation on aminoacid profile and nutritional status in haemodialysis patients.
Plasma concentrations of aminoacids, albumin, prealbumin, transferrin, C3 and C4 complement, and anthropometric measurements were determined before and after oral administration of a new preparation of fish protein in 19 haemodialysis patients participating in a randomised, double-blind, placebo-controlled crossover study lasting 6 months. Furthermore, plasma concentrations of aminoacids were measured in 24 control subjects. Before fish protein dietary supplementation, serine, threonine, tyrosine, valine, methionine, isoleucine, phenylalanine, leucine, and lysine were lower than in control subjects. Serine, histidine, valine, tyrosine, methionine, isoleucine, leucine, and lysine increased after treatment, and phenylalanine tended to increase. The ratios of essential: non-essential aminoacids and alanine:branched-chain aminoacids (BCAA) became normal, whereas valine: lycine and serine:glycine increased significantly and tyrosine:phenylalanine was unchanged. Plasma protein concentrations were unchanged after treatment. Serum transferrin, triceps and subscapular skinfolds, and bodyweight index were slightly reduced in the patients, whereas arm muscle circumference was normal. Bodyweight, weight index, and arm muscle circumference increased after active treatment. In conclusion, the increase in body weight and the return to normal of the plasma aminoacid profile and aminoacid ratios seem to indicate that the treatment with this new fish protein preparation may have beneficial effects on some of the nutrition-related abnormalities in haemodialysis patients.
Adult↗
Kidney transplants, antibodies and rejection: is C4d a magic marker?
The immunohistochemical detection of the complement degradation product C4d in renal allograft biopsies has gained considerable clinical interest in recent years. The accumulation of C4d along peritubular capillaries is generally regarded as a marker for an antibody-mediated allo-response and is associated with poor graft survival. The aim of this review is to discuss histological findings associated with the deposition of C4d. Emphasis is placed on diagnostic and therapeutic implications. Unanswered questions regarding C4d and graft injury are highlighted.
Biomarkers↗
Complement genetics in relation to HLA.
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Complement C2↗
Reiter's syndrome and amyloidosis.
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Adult↗
HLA-DRB genes and antiribosomal P antibodies in systemic lupus erythematosus.
Antibodies to the ribosomal P protein are specific for SLE but their prevalence varies in different ethnic groups. In a group of Chinese SLE patients from Malaysia who have a high prevalence of this antibody, we have found an increased frequency of an uncharacterized HLA-DRB gene allele, DR16X, in patients who are positive for anti-P antibodies compared to antibody negative patients (31.3% vs 3.2%, P < 0.01, Pcorr not significant, relative risk = 13.6). DR16X has only been found in south east Asian populations and may be a genetic factor which influences the high prevalence of anti-P antibodies in Chinese.
Alleles↗
TMEM176B is co-expressed with TMEM176A and upregulated in peripheral blood monocytes of patients with primary Sjögren's syndrome.
OBJECTIVES: This study aims to determine the role of acid‑sensitive nonspecific cation channels transmembrane protein 176A (TMEM176A) and TMEM176B in autoimmune diseases, with a focus on primary Sjögren's Syndrome (pSS). METHODS: We examined the expression patterns of TMEM176A and TMEM176B across tissues and cells utilizing bulk RNA-seq and scRNA-seq datasets. Immunophenotyping analysis was performed by flow cytometry to compare CD62L expression between TMEM176B⁺ and TMEM176B⁻ monocytes. The proportion of TMEM176B+ cells in monocytes was interrogated in both pSS patients and healthy controls. Clinical correlations of TMEM176B with anti‑SSB antibody and complement C4 levels were also evaluated. RESULTS: TMEM176A and TMEM176B showed conserved co‑expression and were significantly upregulated in autoimmune diseases. TMEM176B⁺ monocytes displayed higher CD62L positivity rate than TMEM176B- monocytes. In pSS patients, the proportion of TMEM176B⁺ monocytes was elevated in total monocytes, classical monocytes (cMo) and intermediate monocytes (iMo). The proportion of TMEM176B+ monocytes positively correlated with anti‑SSB levels, while several TMEM176B-associated monocyte subset markers inversely correlated with C4. CONCLUSION: TMEM176A and TMEM176B are highly correlated. TMEM176B expression in monocytes is linked to pSS and may serve as a novel auxiliary diagnostic biomarker.
Humans↗
Influence of host genes on HIV-1 disease progression.
The role of host genes in the course of HIV-1 infection has been examined in different populations and among all major risk groups. Two extended human lymphocyte antigen (HLA) haplotypes, HLA A1-Cw7-B8-DR3-DQ2 and HLA A11-Cw4-B35-DR1-DQ1, are found to be associated with a faster progression to AIDS. The complement C4 factor and tumor necrosis factor genes of the major histocompatibility complex, as well as the mannose binding protein gene, have also been suggested to influence the outcome of AIDS. The recent discovery that chemokine receptors could serve as cofactors for HIV-1 cell entry has prompted a search for polymorphisms in chemokine receptor genes. A 32 base pair inactivating deletion in the CCR5 gene and a point mutation within the CCR2b gene resulting in a conservative amino acid substitution have been examined and shown to be independently associated with delayed disease progression. Together, these observations strongly support a genetic component in AIDS pathogenesis. This article synthesizes the current state of knowledge about the influence of host genes on HIV-1 disease progression. It provides a summary of all significant association studies reported so far. The role of the allelic polymorphism in these genes is discussed with regard to the immunopathogenesis of AIDS.
Carrier Proteins↗
Clinical applications of complement measurements in rheumatic diseases.
There is now convincing evidence that the complement system is involved in the pathogenesis of at least some of the manifestations of human rheumatic diseases. Complement measurements in serum and/or pathologic fluids from patients with these disorders not only reflect this involvement but also may provide important clues regarding the activity and extent of the disease processes. Future studies should provide additional information concerning the usefulness of such measurements for predicting the outcome of specific therapeutic regimens, and perhaps also be the basis for the evolution of new and more rational forms of therapy.
Antigen-Antibody Reactions↗
Poststreptococcal reactive arthritis in adults: long-term follow-up.
BACKGROUND: Poststreptococcal reactive arthritis (PSReA) is a recognized inflammatory articular syndrome that follows group A streptococcal infection in persons not fulfilling the Jones criteria for the diagnosis of acute rheumatic fever. Characteristic features include nonmigratory arthritis, lack of response to aspirin or nonsteroidal anti-inflammatory agents, and the presence of extra-articular manifestations, including vasculitis and glomerulonephritis. Whether or not patients with PSReA develop carditis is a point of contention. METHODS: We analyzed the clinical features, laboratory findings, response to therapy, and outcome in patients diagnosed with PSReA between 1983 and 1998 and observed through April 2000. All patients were contacted, reexamined, and repeat antistreptolysin, rheumatoid factor, C3 and C4 complement components, and echocardiograms were performed. RESULTS: Seventeen patients (4 men and 13 women) were included. All were of low socioeconomic status. All patients had acute severe arthritis that began shortly after a sore throat episode. Extra-articular involvement including tenosynovitis, vasculitis, and glomerulonephritis was relatively common. More importantly, none exhibited clinical and/or echocardiographic evidence of cardiac involvement. Longterm antibiotic therapy was not given. CONCLUSION: Cardiac involvement did not occur in this group of patients with PSReA. Prolonged prophylactic antibiotic therapy may not be required for adult patients presenting with PSReA.
Adolescent↗
C5a and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin.
The authors conducted a study in humans to determine the mediators associated with acute pulmonary vaso- and broncho-constriction occurring episodically with protamine reversal of heparin anticoagulation. Of 48 adult patients investigated prospectively after termination of cardiopulmonary bypass, two presented a sudden increase of airway pressure, acute pulmonary hypertension, and systemic hypotension 1-3 min after right atrial protamine injection. In these two subjects, plasma levels of C5a increased from 0.7 and 2.2 to 9.8 and 9.9 ng/ml, respectively, and thromboxane B2 increased from 0.26 and 0.34 to 7.5 and 16.2 ng/ml 1 minute after drug injection. A third subject not identified prospectively had an identical reaction and mediator profile (C5a, 10.2 ng/ml; TxB2, 18.6 ng/ml at 1 min). The plasma levels of these mediators were unchanged in the remaining patients (C5a, 0.7 +/- 1.1 [x +/- S.D.] to 0.6 +/- 0.9 ng/ml; TxB2, 0.16 +/- 0.12 to 0.15 +/- 0.07 ng/ml). Plasma histamine was not involved in this type of reaction, but increased from 0.7-10.4 ng/ml in a fourth patient who became hypotensive without acute pulmonary hypertension, bronchoconstriction, or elevation of C5a or TxB2. The authors' data indicate that the generation of high plasma levels of C5a anaphylatoxins and thromboxane is associated with pulmonary vaso- and broncho-constriction induced by protamine reversal of heparin in humans.
Adult↗
The frequency of C4B variants of complement in familial and sporadic Alzheimer disease.
A previous study reported an unexpected increased frequency of the uncommon C4B2 allele of complement in a group of patients with senile dementia of the Alzheimer type. We compared the frequency of various C4B types in 25 patients with familial Alzheimer dementia (AD), 22 patients with sporadic AD, and 360 control individuals. Neither Alzheimer group showed any significant increase or decrease in the frequency of C4B alleles compared with controls. We were unable to confirm any association between AD and the C4B2 allele.
Adult↗
Rapid activation of the alternative pathway of complement by extracorporeal membrane oxygenation.
Extracorporeal membrane oxygenation (ECMO) is an effective therapy for patients with severe respiratory distress syndromes. However, an inflammatory response has been observed with the use of this therapy. We measured complement activation in vivo in two adults receiving ECMO for acute respiratory distress syndrome (ARDS). Production of complement activation fragments C4d, Bb, iC3b, and SC5b-9 was determined using commercial ELISA kits. In both patients there was intense activation of complement that peaked 1 hour (mean SC5b-9 increase to 1135% of baseline) after the start of ECMO and occurred predominantly via the alternative pathway (Bb production). Early and acute complement activation may be responsible for the initiation of the inflammatory response that has been observed in patients treated with ECMO.
Adult↗