The Devil in the Details: The Emerging Role of Anticitrulline Autoimmunity in Rheumatoid Arthritis

Breakdown in immunological self tolerance, leading to autoimmune diseases such as multiple sclerosis, might arise from immune recognition of self proteins that have undergone heightened posttranslational modification under pathophysiological conditions. A posttranslational modification of particular interest is the deimination of Arg to citrulline, catalyzed by peptidylarginyl deiminase (PAD) enzymes. As a CD4+ T cell-driven model of multiple sclerosis, we used experimental autoimmune encephalomyelitis (EAE) induced with the immunodominant 35–55 peptide of myelin oligodendrocyte glycoprotein (pMOG) in C57BL/6 mice to test whether citrullination of a T cell epitope can contribute to disease etiopathology. Immunization with an altered peptide ligand (APL) of pMOG with an Arg→citrulline conversion at a TCR contact (residue 41) led to the activation of two populations of APL-responsive T cells that either did, or did not cross-react with the native pMOG peptide. This APL could induce EAE. However, this reflected the activation of T cells that cross-reacted with the native pMOG epitope, because prior tolerization of these T cells using pMOG prevented APL-induced EAE. Using a passive transfer model, we found that T cells that responded specifically to the citrullinated form of pMOG were neither necessary, nor sufficient to initiate the EAE lesion. Nevertheless, these cells could provoke exacerbation of pathology if transferred into mice with ongoing EAE. The PAD2 and PAD4 enzymes were markedly upregulated in the inflamed CNS. Therefore, once inflammation is established, citrullination of target autoantigens can allow an expanded repertoire of T cells to contribute to CNS pathology.

Section: Discussionmentioning

confidence: 99%

Contribution of Myelin Autoantigen Citrullination to T Cell Autoaggression in the Central Nervous System

Carrillo-Vico

Leech

Anderton

2010

“…It is proposed that anti-CCP Ab are involved in inflammatory arthritis at two levels: firstly, forming soluble IC which facilitate entrance of the anti-CCP Ab into the joint, and secondly binding to citrullinated epitopes on the cartilage to create adIC (57). Soluble CCP-anti-CCP IC have not yet been described in the sera of patients with RA, but their possible existence may provide a mechanism of localized vascular leakage in the joint.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic Complement Activation in Collagen Antibody- Induced Arthritis in Mice Requires Amplification by the Alternative Pathway

Banda

Takahashi

Wood

et al. 2007

104

126

Immune complex-induced inflammation can be mediated by the classical pathway of complement. However, using mice genetically deficient in factor B or C4, we have shown that the collagen Ab-induced model of arthritis requires the alternative pathway of complement and is not dependent on the classical pathway. We now demonstrate that collagen Ab-induced arthritis is not altered in mice genetically deficient in either C1q or mannose-binding lectins A and C, or in both C1q and mannose-binding lectins. These in vivo results prove the ability of the alternative pathway to carry out pathologic complement activation in the combined absence of intact classical and lectin pathways. C3 activation was also examined in vitro by adherent collagen-anti-collagen immune complexes using sera from normal or complement-deficient mice. These results confirm the ability of the alternative pathway to mediate immune complex-induced C3 activation when C4 or C1q, or both C1q and mannose-binding lectins, are absent. However, when all three activation pathways of complement are intact, initiation by immune complexes occurs primarily by the classical pathway. These results indicate that the alternative pathway amplification loop, with its ability to greatly enhance C3 activation, is necessary to mediate inflammatory arthritis induced by adherent immune complexes.

“…It is very likely that anti-cyclic citrullinated peptide Abs are pathogenic at some point during the disease course (5). How these autoantibodies develop early in the disease course and whether they are then able to induce joint inflammation and ultimately lead to joint destruction is a matter of ongoing study (6).…”

mentioning

confidence: 99%

Alternative Complement Pathway Activation Is Essential for Inflammation and Joint Destruction in the Passive Transfer Model of Collagen-Induced Arthritis

Banda

Thurman

Kraus

et al. 2006

138

166

Activation of each complement initiation pathway (classical, alternative, and lectin) can lead to the generation of bioactive fragments with resulting inflammation in target organs. The objective of the current study was to determine the role of specific complement activation pathways in the pathogenesis of experimental anti-type II collagen mAb-passive transfer arthritis. C57BL/6 mice were used that were genetically deficient in either the alternative pathway protein factor B (Bf−/−) or in the classical pathway component C4 (C4−/−). Clinical disease activity was markedly decreased in Bf−/− compared with wild-type (WT) mice (0.5 ± 0.22 (n = 6) in Bf−/− vs 8.83 ± 0.41 (n = 6) in WT mice (p < 0.0001)). Disease activity scores were not different between C4−/− and WT mice. Analyses of joints showed that C3 deposition, inflammation, pannus, cartilage, and bone damage scores were all significantly less in Bf−/− as compared with WT mice. There were significant decreases in mRNA levels of C3, C4, CR2, CR3, C3aR, and C5aR in the knees of Bf−/− as compared with C4−/− and WT mice with arthritis; mRNA levels for complement regulatory proteins did not differ between the three strains. These results indicate that the alternative pathway is absolutely required for the induction of arthritis following injection of anti-collagen Abs. The mechanisms by which these target organ-specific mAbs bypass the requirements for engagement of the classical pathway remain to be defined but do not appear to involve a lack of alternative pathway regulatory proteins.