The complement system in systemic autoimmune disease

Chen, Min; Daha, Mohamed R.; Kallenberg, Cees G. M.

doi:10.1016/j.jaut.2009.11.014

Cited by 290 publications

(206 citation statements)

References 115 publications

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“…Here, we show that in children with LN, the alternative complement pathway is indeed activated during renal flares, indicating its pathogenic significance and diagnostic value. The major cause of complement activation in SLE although is thought to be the formation of immune complexes that in turn activate complement via the classical pathway [49]. In children with active LN we found high levels of circulating C3d fixing CIC.…”

Section: Discussionmentioning

confidence: 68%

Markers of childhood lupus nephritis indicating disease activity

et al. 2010

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Current treatment regimens for childhood lupus nephritis (LN) are associated with significant side-effects and toxicity in vulnerable phases of growth and development. The paucity of biomarkers particularly in childhood impedes the appropriate clinical management and the development of new therapeutics. We analyzed markers of immune system (BAFF, RANTES), complement (Bb, C1q, C3d-CIC, C5a) and endothelial cell activation (sVCAM-1) in children with LN (n=22, mean age 14.8±4.7 years), nephrotic syndrome (n =13) and age-matched healthy controls (n=20) to define parameters that correlate with LN activity. Complement fragments of the alternative (Bb, p=0.0004) classical (C3d-CIC, p<0.0001) and common pathway (C5a, p<0.0001) and the levels of BAFF (p< 0.0001), RANTES (p=0.0002) and sVCAM-1 (p=0.0004) were significantly higher in active compared to inactive LN. Activation of complement was associated with the occurrence of anti-C1q antibodies and reduced complement

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Section: Discussionmentioning

confidence: 68%

Markers of childhood lupus nephritis indicating disease activity

et al. 2010

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“…26 In many systemic autoimmune diseases, activation of the complement system is involved in pathogenesis. 27 In recent years, it has become more apparent that IgAN is an autoimmune disease, in which IgA1-containing immune complexes initiate glomerular injury. 28 As in other autoimmune diseases, complement activation has also been reported in IgAN.…”

Section: Discussionmentioning

confidence: 99%

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Zhu

Zhai

Wang

et al. 2015

Journal of the American Society of Nephrology

130

108

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Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q32 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1Δ) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations. Group 1 included 1178 subjects with IgAN and available genome-wide association study data. Group 2 included 365 subjects with IgAN and available clinical follow-up data. In group 1, rs6677604 was associated with mesangial C3 deposition by genotype-phenotype correlation analysis. In group 2, we detected a linkage between the rs6677604-A allele and CFHR3-1Δ and found that the rs6677604-A allele was associated with higher serum levels of CFH and lower levels of the complement activation split product C3a. Furthermore, CFH levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition. Moreover, serum levels of the pathogenic galactose-deficient glycoform of IgA1 were also associated with the degree of mesangial C3 deposition in patients with IgAN. Our findings suggest that genetic variants in CFH, CFHR3, and CFHR1 affect complement activation and thereby, predispose patients to develop IgAN.

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“…Complement component 4 (C4) is a component of both the classical and lectin pathways, whereas factor B is the integral component of the alternative pathway (19 -21). Complement activation via these pathways is under strict control of complement regulatory proteins; disruption of the balance between complement activation and regulation can result in deleterious effects on the host and contributes to several diseases (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Recently we have reported that suppression of complement activation by recombinant complement regulatory protein inhibits EAAU (15).…”

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confidence: 99%

Inhibition of Complement Alternative Pathway Suppresses Experimental Autoimmune Anterior Uveitis by Modulating T Cell Responses

Manickam

Jha

Matta

et al. 2011

Journal of Biological Chemistry

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The objective of the current study was to delineate the pathway of complement activation that is crucial for the induction of experimental autoimmune anterior uveitis (EAAU). We studied the development of EAAU in melanin-associated antigen (MAA)-sensitized Lewis rats treated with antibody against C4 or factor B. Control animals received isotype IgG control. Antibody against C4 had no effect on EAAU, and all of the animals developed EAAU similar to those injected with control IgG. Uveitis, a vision-threatening intraocular inflammatory disease is one of the leading causes of vision loss worldwide. Anterior uveitis (AU) 2 refers to the inflammation of the anterior segment of the eye, which includes the iris and the ciliary body (CB). Idiopathic AU is the most common form of intraocular inflammation in humans (1-3). Experimental autoimmune anterior uveitis (EAAU) is an organ-specific autoimmune disease of the eye that serves as an animal model of noninfectious autoimmune idiopathic AU (4 -15). The EAAU model has been extensively used in our laboratory to understand the underlying mechanisms involved in the pathogenesis of idiopathic AU (5-15). In this experimental model, inbred Lewis rats are subcutaneously immunized in the footpad with melanin-associated antigen (MAA) isolated from the iris and the CB, and EAAU is induced in these animals by an antigen-specific CD4 ϩ T cell response to MAA (5-15). The hallmark pathologic features of EAAU include lymphocytic infiltration in the iris, the CB, and the anterior segment of the eye with no inflammation of the retina (5-15). Antigen-specific CD4 ϩ T cells can adoptively transfer disease into naïve syngenic recipients (7,8,13) and are the predominant inflammatory cells within the uvea (5-15).Previous reports from our laboratory have established a critical role of complement in EAAU (9, 10). Complement has been recognized as a key innate immune defense system that plays an important role in fighting infections and modulating various immune and inflammatory responses by bridging the innate immunity with adaptive immune responses (16 -21). The complement systems consist of more than 35 proteins circulating in blood and expressed on cell membranes. These proteins interact with one another in three distinctive activation cascades: the classical, the lectin, and the alternative, which can be triggered by different stimuli. Complement component 4 (C4) is a component of both the classical and lectin pathways, whereas factor B is the integral component of the alternative pathway (19 -21). Complement activation via these pathways is under strict control of complement regulatory proteins; disruption of the balance between complement activation and regulation can result in deleterious effects on the host and contributes to several diseases (22-36). Recently we have reported that suppression of complement activation by recombinant complement regulatory protein inhibits EAAU (15). However, the contribution of each complement activation pathway in EAAU has not yet been described. In this...

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The complement system in systemic autoimmune disease

Cited by 290 publications

References 115 publications

Markers of childhood lupus nephritis indicating disease activity

Markers of childhood lupus nephritis indicating disease activity

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Inhibition of Complement Alternative Pathway Suppresses Experimental Autoimmune Anterior Uveitis by Modulating T Cell Responses

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