Modulation of the Alternative Pathway of Complement by Murine Factor H–Related Proteins

Antonioli, Alexandra H.; White, Janicé; Crawford, Frances; Renner, Brandon; Marchbank, Kevin J.; Hannan, Jonathan P.; Thurman, Joshua M.; Marrack, Philippa; Holers, V. Michael

doi:10.4049/jimmunol.1602017

Cited by 14 publications

(19 citation statements)

References 29 publications

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“…The authors concluded that mouse FHR-B similar to human FHR-1 and FHR-5 promoted complement activation via interaction with C3b and via competition with mouse FH ( 283 ). Similarly, it has been shown that mouse FHR-A and mouse FHR-B proteins antagonize the protective function of FH using sheep erythrocyte hemolytic assays and in two cell lines, kidney proximal tubular cell line and a human retinal pigment epithelial cell line (ARPE-19) ( 284 ). Lack of mouse FHR-C has been linked to an autoimmune disease ( 278 ).…”

Section: Mouse Models Of Human Rheumatoid Arthritismentioning

confidence: 96%

Complement in the Initiation and Evolution of Rheumatoid Arthritis

2018

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The complement system is a major component of the immune system and plays a central role in many protective immune processes, including circulating immune complex processing and clearance, recognition of foreign antigens, modulation of humoral and cellular immunity, removal of apoptotic and dead cells, and engagement of injury resolving and tissue regeneration processes. In stark contrast to these beneficial roles, however, inadequately controlled complement activation underlies the pathogenesis of human inflammatory and autoimmune diseases, including rheumatoid arthritis (RA) where the cartilage, bone, and synovium are targeted. Recent studies of this disease have demonstrated that the autoimmune response evolves over time in an asymptomatic preclinical phase that is associated with mucosal inflammation. Notably, experimental models of this disease have demonstrated that each of the three major complement activation pathways plays an important role in recognition of injured joint tissue, although the lectin and amplification pathways exhibit particularly impactful roles in the initiation and amplification of damage. Herein, we review the complement system and focus on its multi-factorial role in human patients with RA and experimental murine models. This understanding will be important to the successful integration of the emerging complement therapeutics pipeline into clinical care for patients with RA.

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Section: Mouse Models Of Human Rheumatoid Arthritismentioning

confidence: 96%

Complement in the Initiation and Evolution of Rheumatoid Arthritis

2018

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“…There was also no change in glomerular FHR staining. Little is known about the functions of the mouse FHR proteins, but they are able to interact with both C3b 27 , 28 and C3d. 27 In fact, the apparent affinity of both FHR-A and FHR-B for C3d is stronger than that of FH.…”

Section: Discussionmentioning

confidence: 99%

Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains

Gilmore

Zhang

Cook

et al. 2021

Kidney International

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C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh-/-) mice develop C3 glomerulopathy together with a reduction in plasma C3 levels. Using this model, we assessed the efficacy of two fusion proteins containing the factor H alternative pathway regulatory domains (FH 1-5) linked to either a non-targeting mouse immunoglobulin (IgG-FH1-5) or to an anti-mouse properdin antibody (Anti-P-FH 1-5). Both proteins increased plasma C3 and reduced glomerular C3 deposition to an equivalent extent, suggesting that properdin-targeting was not required for FH 1-5 to alter C3 activation in either plasma or glomeruli. Following IgGFH 1-5 administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels. Notably, the increases in plasma C5 and properdin levels persisted longer than the increases in C3 and factor B. In Cfh-/-mice IgG-FH 1-5 reduced kidney injury during accelerated serum nephrotoxic nephritis. Thus, our data demonstrate that IgG-FH 1-5 restored circulating alternative pathway activity and reduced glomerular C3 deposition in Cfh-/-mice and that plasma properdin levels are a sensitive marker of C5 convertase activity in factor H deficiency. The immunoglobulin conjugated FH 1-5 protein, through its comparatively long plasma half-life, may be a potential therapy for C3 glomerulopathy.

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“…In addition, some FHRs were reported to promote alternative pathway activation by binding C3b and serving as a platform for the assembly of the C3 convertase ( 27 , 32 , 33 ). Recent characterization of some of the mouse FHRs supports a role of these proteins as positive regulators in the modulation of complement activation ( 34 , 35 ).…”

Section: Introductionmentioning

confidence: 97%

Self-Damage Caused by Dysregulation of the Complement Alternative Pathway: Relevance of the Factor H Protein Family

et al. 2018

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The alternative pathway is a continuously active surveillance arm of the complement system, and it can also enhance complement activation initiated by the classical and the lectin pathways. Various membrane-bound and plasma regulatory proteins control the activation of the potentially deleterious complement system. Among the regulators, the plasma glycoprotein factor H (FH) is the main inhibitor of the alternative pathway and its powerful amplification loop. FH belongs to a protein family that also includes FH-like protein 1 and five factor H-related (FHR-1 to FHR-5) proteins. Genetic variants and abnormal rearrangements involving the FH protein family have been linked to numerous systemic and organ-specific diseases, including age-related macular degeneration, and the renal pathologies atypical hemolytic uremic syndrome, C3 glomerulopathies, and IgA nephropathy. This review covers the known and recently emerged ligands and interactions of the human FH family proteins associated with disease and discuss the very recent experimental data that suggest FH-antagonistic and complement-activating functions for the FHR proteins.

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Modulation of the Alternative Pathway of Complement by Murine Factor H–Related Proteins

Cited by 14 publications

References 29 publications

Complement in the Initiation and Evolution of Rheumatoid Arthritis

Complement in the Initiation and Evolution of Rheumatoid Arthritis

Complement activity is regulated in C3 glomerulopathy by IgG–factor H fusion proteins with and without properdin targeting domains

Self-Damage Caused by Dysregulation of the Complement Alternative Pathway: Relevance of the Factor H Protein Family

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