High anti-collagen type-II antibody levels and induction of proinflammatory cytokines by anti-collagen antibody-containing immune complexes in vitro characterise a distinct rheumatoid arthritis phenotype associated with acute inflammation at the time of disease onset

Mullazehi, Mohammed; Mathsson, Linda; Lampa, Jon; Rönnelid, Johan

doi:10.1136/ard.2006.064782

Cited by 62 publications

(108 citation statements)

References 13 publications

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“…In retrospect, the lack of success regarding oral tolerance induction with CII in RA is not surprising, since autoimmunity to CII does not seem to be the clue to RA aetiopathogenesis. Anti-CII antibodies have low diagnostic specificity for RA and occur in a minority of RA patients, which are predominantly ACPA-negative and have a favourable prognosis (Mullazehi et al 2007;Raza et al 2008). Yet, systemic immunisation against citrullinated CII may be relevant in relation to RA pathogenesis (Lundberg et al 2005;Uysal et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis

Svärd

Kastbom

Sommarin³

et al. 2013

Immunobiology

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Section: Discussionmentioning

confidence: 99%

Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis

Svärd

Kastbom

Sommarin³

et al. 2013

Immunobiology

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“…Several of these autoantibodies have emerged as potential arthritogenic factors. For example, anti-glucose-6 phosphate isomerase and anti-type II collagen antibodies, both of which are highly arthritogenic in mice, can be detected in patients with RA (Schaller et al, 2005;Mullazehi et al, 2007). In addition, anticitrullinated protein autoantibodies, the most prevalent in RA, can bind citrullinated fibrinogen in RA joints to form immune complexes (Zhao et al, 2008), which stimulate macrophages to produce inflammatory cytokines such as TNF␣ (Clavel et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

RN486, a Selective Bruton's Tyrosine Kinase Inhibitor, Abrogates Immune Hypersensitivity Responses and Arthritis in Rodents

Kim²,

Postelnek³

et al. 2012

J Pharmacol Exp Ther

131

119

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Genetic mutation and pharmacological inhibition of Bruton's tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopro-, in vitro and in rodent models of immune hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell types, blocking Fc receptor cross-linking-induced degranulation in mast cells (IC 50 ϭ 2.9 nM), Fc␥ receptor engagement-mediated tumor necrosis factor ␣ production in monocytes (IC 50 ϭ 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC 50 ϭ 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing type I and type III hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and boneprotective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases.

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“…Antibodies against CII are detectable in the sera and synovial fluid of about 5 to 70% of RA patients [11,27,28] and is highly conserved between species [12]. Recognition of the C1 epitope is significant compared with other arthritis susceptible B-cell epitopes [29].…”

Section: Discussionmentioning

confidence: 99%

“…Earlier we reported the nature of the CII antibody response as germ line-encoded, but pathogenic [13], and the pathogenicity was enhanced if antibodies binding to several CII epitopes were present in the animals [25]. Antibodies against CII are detectable in the sera and synovial fluid of about 5 to 70% of RA patients [11,27,28] and is highly conserved between species [12]. Recognition of the C1 epitope is significant compared with other arthritis susceptible B-cell epitopes [29].…”

mentioning

confidence: 99%

B‐cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production

et al. 2015

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Autoantibody-mediated inflammation contributes to the development of rheumatoid arthritis (RA), and anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients. We had previously generated and characterized knockin mice expressing a germline-encoded, CII-specific IgH (B10Q.ACB), which demonstrated positive selection of self-reactive B cells. Here, we show that despite the spontaneous production of CII-specific autoantibodies, B10Q.ACB mice are protected from collageninduced arthritis. Introducing a mutation in the Ncf1 gene, leading to ROS deficiency, breaks this strong arthritis resistance. Disease development in Ncf1-mutated B10Q.ACB mice is associated with an enhanced germinal center formation but without somatic mutations of the auto-reactive B cells, increased T-cell responses and intramolecular epitope-spreading. Thus, ROS-mediated B-cell tolerance to a self-antigen could operate by limiting the expansion of the auto-reactive B-cell repertoire, which has important implications for the understanding of epitope spreading phenomena in rheumatoid arthritis and other autoimmune diseases.Keywords: Auto-reactive B cells r Autoantibodies r Arthritis r Epitope spreading r ROS Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAutoimmune diseases affect 5% of the worldwide population, and often involve autoantibody-mediated tissue inflammation. The development of rheumatoid arthritis (RA) involves autoantibodies such as rheumatoid factor and antibodies to citrullinated protein antigens. These antibodies appear in the blood of RA patients, many years before the onset of clinical symptoms [1,2], and durCorrespondence: Dr. Rikard Holmdahl e-mail: rikard.holmdahl@ki.se ing the preclinical phase epitope spreading of the antibodies to citrullinated protein antigens occurs [3,4].Anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients [5,6]. These are directed to both native triple helical (approx. 10% of the patients) and modified citrullinated (approx. 40% of the patients) epitopes [7,8]. The triple helical CII-directed antibodies are detected during the early joint inflammatory phase of RA [9,10]. Interestingly, the identification of the CII epitopes showed that they are highly conserved between mammals [11,12]. Functional analysis of single chain variable fragment antibody [13] Numerous studies identified the prototypes of different pathogenic autoimmune diseases, where the production of hightiter, high affinity autoantibodies to the proposed antigens is generated in germinal centers (GC). GCs in the secondary lymphoid organs are the sites of intense B-cell proliferation and support somatic hyper mutation and the subsequent selection of high affinity B cells. Extra-follicular (non-GC) origin of the autoantibodies was described in many mouse models of autoimmune diseases [19]. We have previously found that Ncf1 polymorphism leads to a lower oxid...

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High anti-collagen type-II antibody levels and induction of proinflammatory cytokines by anti-collagen antibody-containing immune complexes in vitro characterise a distinct rheumatoid arthritis phenotype associated with acute inflammation at the time of disease onset

Cited by 62 publications

References 13 publications

Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis

Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis

RN486, a Selective Bruton's Tyrosine Kinase Inhibitor, Abrogates Immune Hypersensitivity Responses and Arthritis in Rodents

B‐cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production

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