Type I IFN protects against antigen‐induced arthritis

Abstract

Autoimmune diseases including rheumatoid arthritis (RA) involve immune reactions against specific antigens. The type I IFN system is suspected to promote autoimmunity in systemic lupus erythematosus, but may also dampen immune reactions in e.g. inflammatory bowel disease. This prompted us to investigate the role of type I IFN in antigeninduced arthritis (AIA). The importance of type I IFN in methylated (m) BSA-induced arthritis was studied by using mice deficient for the type I IFN receptor (IFNAR) and by administration of the IFN-a activator viral double-stranded (ds) RNA or recombinant IFN-a at antigen sensitization. In IFNAR knock-out mice, arthritis severity was significantly higher than in WT mice. Administration of dsRNA at antigen sensitization protected WT but not IFNAR KO mice from arthritis. Also, addition of recombinant IFN-a during the immunization, but not the induction phase of arthritis, almost abolished arthritis. Protection mediated by IFN-a was accompanied by delayed and decreased antigen-specific proliferative responses, including impaired lymph node recall responses after intraarticular antigenic challenge.In conclusion, we demonstrate that type I IFN can prevent joint inflammation by downregulating antigen-specific cellular immunity.Keywords: Arthritis . Tolerance . Type I IFN IntroductionThe cause of autoimmunity remains unknown, but a better understanding of what determines whether encounter with an antigen results in immunological attack or tolerance should provide strategies for deviating an existing autoimmune response. The type I IFNs, initially discovered for their direct anti-viral activity [1], are pluripotent cytokines with bearing also on adaptive immune responses [2], especially humoral immunity [3]. The rapid onset of type I IFN production in response to viral infection has suggested type I IFNs as potential instigators of viral-induced autoimmunity [4], although the link is only circumstantial. Interestingly, a number of auto-antibody related diseases, in particular systemic lupus erythematosus are characterized by a type I IFN signature, i.e. elevated levels of type I IFNs and products regulated by type I IFNs [5]. This may represent pro-inflammatory properties of type I IFN on adaptive, humoral immune responses, which may contribute to autoimmunity [6]. However, the effects of type I IFNs on antigen-specific immunity cannot be clearly categorized as either pro-or antiinflammatory. In vaccine studies, e.g. both an enhancing [7] and a clear dampening effect [8] of type I IFN signalling on the antigen-specific immune response has been reported. Similarly, in experimental models of autoimmunity, type I IFN may either aggravate [9,10] or mitigate [11][12][13] inflammation. The underlying mechanism(s) explaining these apparent contradictory findings remain to be determined. In arthritis, viral infections are known to exacerbate or precipitate inflammation [14], and viral interferogenic double-stranded (ds)RNA and IFN-a can be found at the site of inflammation in rheumatoid arthriti...

Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine

“…In contrast, there was no direct antiinflammatory effect because treatment with IFN-α after the induction of arthritis did not affect the arthritis severity [111]. This protective effect of IFN-α was associated with higher serum TGF-β levels both in the sensitization phase and arthritis phase of AIA in IFN-α treated mice compared to controls [112].…”

“…This protective effect, mediated by dsRNA-induced type I IFN signalling, inhibited antigen-specific proliferation [111]. Moreover, endogenous IFN-α signalling mitigated arthritis development because mice lacking the type I IFN receptor (IFNAR KO) developed more severe arthritis than wild-type mice [111]. Thus in apparent contrast to the arthritogenic effect of dsRNA and IFN-α when present in the joint [103,104] , activation of type I IFN signalling during development of antigen-induced arthritis is clearly anti-inflammatory.…”

“…In our previous research paper, we have shown that protection conferred by IFN-α was associated with suppressed proliferation of leukocytes (splenocytes or LN cells) from IFN-α treated mice upon mBSA re-stimulation [111]. Next, we investigated if the IFN-α-induced inhibitory effect on leukocyte proliferation upon mBSA-restimulation was dependent on IDO1.…”

“…Treatment with recombinant IFN-β or IFN-β producing fibroblasts ameliorated CIA in mice [109,110]. Our group previously showed that treatment with dsRNA or IFN-α during development of antigen-specific adaptive immune response clearly protected mice against AIA [111]. and osteoclasts [109,112] and boosting production of IDO and TGF-β [113].…”

“…Administration of dsRNA during the development of immune responses against mBSA totally down modulated the development of arthritis. This protective effect, mediated by dsRNA-induced type I IFN signalling, inhibited antigen-specific proliferation [111]. Moreover, endogenous IFN-α signalling mitigated arthritis development because mice lacking the type I IFN receptor (IFNAR KO) developed more severe arthritis than wild-type mice [111].…”