The role of collagen antibodies in mediating arthritis

Rowley, Merrill J.; Nandakumar, Kutty Selva; Holmdahl, Rikard

doi:10.1007/s10165-008-0080-x

Cited by 49 publications

(33 citation statements)

References 133 publications

(160 reference statements)

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“…Additionally, because collagen IX molecules are localized on the surface of collagen II-containing fibrils (26,27), their loss will render naked collagen II fibrils more accessible for MMPs, which can induce the cascade of events leading to arthritis (25). In the case of rheumatoid arthritis, a role of collagen II fragments in generating the autoimmune response is well established (28). Moreover, patients with recent onset rheumatoid arthritis have significantly elevated levels of autoantibodies to collagen IX (29), possibly indicating the antigenicity of degraded collagen IX fragments as well.…”

Section: Discussionmentioning

confidence: 99%

The NC2 Domain of Collagen IX Provides Chain Selection and Heterotrimerization

Boudko

Zientek

Vance

et al. 2010

Journal of Biological Chemistry

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The mechanism of chain selection and trimerization of fibrilassociated collagens with interrupted triple helices (FACITs) differs from that of fibrillar collagens that have special C-propeptides. We recently showed that the second carboxylterminal non-collagenous domain (NC2) of homotrimeric collagen XIX forms a stable trimer and substantially stabilizes a collagen triple helix attached to either end. We then hypothesized a general trimerizing role for the NC2 domain in other FACITs. Here we analyzed the NC2 domain of human heterotrimeric collagen IX, the only member of FACITs with all three chains encoded by distinct genes. Upon oxidative folding of equimolar amounts of the ␣1, ␣2, and ␣3 chains of NC2, a stable heterotrimer with a disulfide bridge between ␣1 and ␣3 chains is formed. Our experiments show that this heterotrimerization domain can stabilize a short triple helix attached at the carboxylterminal end and allows for the proper oxidation of the cystine knot of type III collagen after the short triple helix.The fibril-associated collagens with interrupted triple helices (FACITs) 2 include types IX, XII, XIV, XVI, XIX, XX, XXI, and XXII. Collagen IX is a heterotrimer composed of three distinct ␣ chains, and all others are homotrimers whose ␣ chains are characterized by short collagenous domains (COL) interrupted by several non-collagenous domains (NC) (1, 2). Unlike the fibril-forming collagens, the FACITs have significantly shorter NC1 domains (the carboxyl-terminal NC domains) (75 residues for human collagen XII, fewer than 30 residues for human collagen IX, and even fewer than 20 residues for human collagen XIX), whereas those of fibrillar collagens are of a different type and comprise about 260 residues. The FACITs share a remarkable sequence homology at their COL1/NC1 junctions by having two strictly conserved cysteine residues separated by four residues in the NC1 domain. These cysteines form interchain disulfide bonds, a so-called cystine knot, but only after the triple helix is formed (3-6). In other words, the NC1 domain cannot trimerize itself and requires exogenous alignment of three chains. It has been suggested that the NC2 domain in all FACITs is able to form an ␣-helical coiled coil, thus bearing an ability to trimerize those collagens (7). Experimental evidence for that was recently reported by us for the NC2 domain of collagen XIX (6).Collagen IX contains three collagenous domains (COL1-COL3) and four noncollagenous domains (NC1-NC4) (Fig. 1). The molecule is covalently associated with the surface of interstitial collagen fibrils in cartilage (8), where it plays a role in maintaining the long term structural integrity of this tissue (9). Loss of collagen IX is associated with such diseases as osteoarthritis, rheumatoid arthritis, intervertebrate disk degeneration, ocular defects, loss of hearing, and others (9 -13).Collagen IX is the most intriguing FACIT collagen in terms of its chain selection and heterotrimerization properties. Several attempts were made to decipher its code. Reasso...

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Section: Discussionmentioning

confidence: 99%

The NC2 Domain of Collagen IX Provides Chain Selection and Heterotrimerization

Boudko

Zientek

Vance

et al. 2010

Journal of Biological Chemistry

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“…CII is the predominant cartilage collagen and a known autoantigen [23, 31, 32]. The human joint contains abundant CII and collagen-induced arthritis is the common experimental animal model of RA [33, 34].…”

Section: Introductionmentioning

confidence: 99%

“…The human joint contains abundant CII and collagen-induced arthritis is the common experimental animal model of RA [33, 34]. Thus, antibodies to CII should be of highest relevance in RA [32]. Nevertheless, antinative CII antibodies occur only in 3–27% of patients with RA [29, 35–37] and, as such, it has been difficult to substantiate the role of autoimmunity to CII in the pathogenesis of RA.…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies to Posttranslational Modifications in Rheumatoid Arthritis

Burska

Hunt

Boissinot

et al. 2014

Mediators of Inflammation

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Autoantibodies have been associated with human pathologies for a long time, particularly with autoimmune diseases (AIDs). Rheumatoid factor (RF) is known since the late 1930s to be associated with rheumatoid arthritis (RA). The discovery of anticitrullinated protein antibodies in the last century has changed this and other posttranslational modifications (PTM) relevant to RA have since been described. Such PTM introduce neoepitopes in proteins that can generate novel autoantibody specificities. The recent recognition of these novel specificities in RA provides a unique opportunity to understand human B-cell development in vivo. In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation. With the advancement of research methodologies it should be expected that other autoantibodies against PTM proteins could be discovered in patients with autoimmune diseases. Many of such autoantibodies may provide significant biomarker potential.

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“…In mouse models of arthritis, the synthesized immune complexes bind to “inflammatory” Fc-receptors on intra-articular cells and then activate complement protein (Rowley et al, 2008). Complement fragments bound to immune complexes induce tissue injury, and FcR stimulation cumulatively activates mononuclear cells in situ , causing the activated cells to release pro-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Regulatory T Cell-Mediated Control of Autoantibody-Induced Inflammation

Fujio¹,

Okamura²,

Sumitomo³

et al. 2012

Front. Immun.

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Autoimmune inflammation including autoantibody-induced inflammation is responsible for the lethal organ damage. Autoantibody-induced inflammation can be separated in two components, autoantibody production, and local inflammatory responses. Accumulating evidence has suggested that regulatory T cells (Treg) control both antibody production and the numbers and functions of effector cells such as innate cells and T helper cells. Autoantibodies are produced by both the follicular and extrafollicular pathways. Recently, follicular regulatory T cells (TFR) and Qa-1 restricted CD8+ Treg were identified as populations that are capable of suppressing follicular T helper cell (TFH)-mediated antibody production. In local inflammation, CD4+CD25+Foxp3+ Treg have the capacity to control inflammation by suppressing cytokine production in T helper cells. Although complement proteins contribute to autoantibody-induced local inflammation by activating innate cells, Treg including CD4+CD25+Foxp3+ Treg are able to suppress innate cells, chiefly via IL-10 production. IL-10-secreting T cells such as T regulatory type I (Tr1) and Tr1-like cells might also play roles in the control of Th17 and innate cells. Therefore, several kinds of Tregs have the potential to control autoimmune inflammation by suppressing both autoantibody production and the local inflammatory responses induced by autoantibodies.

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The role of collagen antibodies in mediating arthritis

Cited by 49 publications

References 133 publications

The NC2 Domain of Collagen IX Provides Chain Selection and Heterotrimerization

The NC2 Domain of Collagen IX Provides Chain Selection and Heterotrimerization

Autoantibodies to Posttranslational Modifications in Rheumatoid Arthritis

Regulatory T Cell-Mediated Control of Autoantibody-Induced Inflammation

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