A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis

Katschke, Kenneth J.; Helmy, Karim Y.; Steffek, Micah; Xi, Hongkang; Yin, Jianping; Lee, Wyne P.; Gribling, Peter; Barck, Kai; Carano, Richard A.D.; Taylor, Robin E.; Rangell, Linda; Diehl, Lauri; Hass, Philip E.; Wiesmann, Christian; Campagne, Menno van Lookeren

doi:10.1084/jem.20070432

Cited by 91 publications

(100 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In mouse models of arthritis clear evidence has been provided that the alternative pathway in particular, and not the classical pathway, is responsible for organ damage, based on experiments using complementdeficient animals (25,27) or a specific alternative pathway inhibitor (26). The present study provides evidence that human anti-CCP antibodies activate both the classical pathway and the alternative pathway and thereby mimic the results obtained from in vivo models.…”

Section: Discussionsupporting

confidence: 72%

“…C3 Ϫ/Ϫ , FB Ϫ/Ϫ , C5 Ϫ/Ϫ , and C5a receptor Ϫ/Ϫ mice are protected against induction of arthritis, whereas C1q Ϫ/Ϫ and MBL Ϫ/Ϫ mice are fully susceptible (25,26), indicating that in mouse models the alternative pathway is necessary and sufficient for disease induction (25,27,28). Now that ACPAs are increasingly recognized as major players in RA, it is of relevance to know if and how these antibodies activate complement.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Trouw¹,

Haisma²,

Levarht³

et al. 2009

Arthritis & Rheumatism

218

149

View full text Add to dashboard Cite

Objective. It has been suggested that anticitrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti-cyclic citrullinated peptide (anti-CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used.Methods. We set up novel assays to analyze complement activation by anti-CCP antibodies, using cyclic citrullinated peptide-coated plates, specific buffers, and normal and complement-deficient sera as a source of complement.Results. Anti-CCP antibodies activated complement in a dose-dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti-CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place.Conclusion. Our findings indicate that anti-CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement-mediated damage in RA.

show abstract

Section: Discussionsupporting

confidence: 72%

mentioning

confidence: 99%

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Trouw¹,

Haisma²,

Levarht³

et al. 2009

Arthritis & Rheumatism

218

149

View full text Add to dashboard Cite

show abstract

“…20 VSIG4 has been reported to regulate T-cell proliferation in vitro and in vivo, 21 and a soluble form of HsVSIG4 displays therapeutic potential in mouse models of arthritis by inhibiting autoreactive immune responses. 22 We have previously reported that VSIG4 signaling eliminates phagocytosed LMs by rapidly inducing CLIC3-dependent acidification of LM-containing phagosomes. 20 However, we also suspected that VSIG4 signaling might inhibit the intracellular growth of LMs that escaped into the macrophage cytosol, because some phagocytosed LMs manage to escape from phagosomes before VSIG4 was triggered and yet are eliminated.…”

Section: Introductionmentioning

confidence: 99%

Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy

et al. 2016

View full text Add to dashboard Cite

VSIG4/CRIg (V-set and immunoglobulin domain containing 4) is a transmembrane receptor of the immunoglobulin superfamily that is expressed specifically on macrophages and mature dendritic cells. VSIG4 signaling accelerates phagocytosis of C3-opsonized bacteria, thereby efficiently clearing pathogens within macrophages. We found that VSIG4 signaling triggered by C3-opsonized Listeria (opLM) or by agonistic anti-VSIG4 monoclonal antibody (mAb) induced macrophages to form autophagosomes. VSIG4-induced autophagosomes were selectively colocalized with the intracellular LM while starvation-induced autophagosomes were not. Consistent with these results, the frequency of autophagosomes induced by infection with opLM was lower in VSIG4-deficient bone marrow-derived macrophages (BMDMs) than in WT BMDMs. Furthermore, when VSIG4 molecules were overexpressed in HeLa cells, which are nonmacrophage cells, VSIG4 triggering led to efficient uptake of LM, autophagosome formation, and killing of the infected LM. These findings suggest that VSIG4 signaling not only promotes rapid phagocytosis and killing of C3-opsonized intracellular bacteria, as previously reported, but also induces autophagosome formation, eliminating the LM that have escaped from phagosomes. We conclude that VSIG4 signaling provides an anti-immune evasion mechanism that prevents the outgrowth of intracellular bacteria in macrophages.

show abstract

“…The authors therefore suggested, that this area may be involved in C3b-dimerization or C3-C3b binding, and that compstatin may interfere with these interactions . A similar mechanism has been proposed for another complement inhibitor, the physiological receptor CRIg, that binds C3b at the same face of the β-chain (although via domains MG3/MG6) and selectively inhibits the alternative pathway convertases (Katschke et al 2007;Wiesmann et al 2006). …”

mentioning

confidence: 62%

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Ricklin

Lambris²

2008

Advances in Experimental Medicine and Biology

118

166

View full text Add to dashboard Cite

Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic. Tackling Complement at its CoreTherapeutic intervention in the human complement system has long been recognized as a promising strategy for the treatment of a series of ischemic, inflammatory and autoimmune diseases (Lambris and Holers 2000;Ricklin and Lambris 2007a). In principle, the large network of soluble and cell-surface-bound proteins, which builds the base of the complement cascade, offers a variety of potential drug targets. However, the quest for complement-specific therapeutics proved to be much more challenging than initially anticipated. With the therapeutic antibody eculizumab (Soliris ® , Alexion Pharmaceuticals, Inc.) against paroxysmal nocturnal hemoglobinuria, the first drug with proven complement connectivity has been marketed only recently (Ricklin and Lambris 2007a;Rother et al. 2007). A second complement-associated compound, purified C1 esterase inhibitor (C1-INH), is available as a therapeutic option for the treatment of hereditary angioedema in several countries. However, its mechanism of action may be closer related to the bradykinin-kallikrein than the complement cascade (Davis 2006). Strikingly, both drugs cover relatively rare diseases and have been developed with the aid of orphan drug regulations. Yet, for many of the more common inflammatory or autoimmune conditions there are no complement drugs on the market. Any extension of the current complement-specific therapeutic arsenal is therefore highly desired.Part of the problem in complement-directed drug discovery is the selection of the right target (Ricklin and Lambris 2007a activation is considered to be the most promising approach in many cases. On a molecular level, inhibition at the level of C3, including the C3 convertases, is of particular interest since both the amplification of all initiation pathways and the generatio...

show abstract

A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis

Cited by 91 publications

References 28 publications

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Contact Info

Product

Resources

About