Innate immunity, epigenetics and autoimmunity in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by the progressive and irreversible destruction of joints.

RA remains an incurable condition, although a new class of drugs, biologicals, have made a major breakthrough in targeting and/or eliminating the immune cells, including T cells, B cells and monocytes/macrophages from the joints. That we cannot (yet?) cure the disease is most likely due to the lack of therapeutic targeting the endogenously activated RA synovial fibroblasts (RASF).

Most interestingly, RASF express Toll-like receptors (TLRs) 1–6 rendering them prone to activation by exogenous and endogenous TLR ligands and resulting in the production of numerous powerful chemokines and cytokines. These factors are responsible for the repopulation of immune cells in the joints after ceasing cell depleting therapies.

To characterize the molecular mechanisms of synovial activation, a new approach studying the epigenetic characteristics of RASF has been recently undertaken. Thereby, the pattern of histone acetylation, DNA methylation and gene expression regulating microRNA are being explored.

Since auto-antibodies have the most predictive and diagnostic value for RA, it is challenging to study more comprehensively the contribution of auto-antibodies to the disease. A new screening technique, serological analysis of recombinant human cDNA expression library (SEREX), adapted from cancer research allowed for the identification of novel auto-antibodies in RA, including anti-serpin E2 auto-antibodies. The serpin E2 auto-antibodies were found to inhibit the activity of serpin E2 and have potentially a functional role in the disease. The recent findings in the field of innate immunity, epigenetics and autoimmunity related to the pathogenesis of RA are in the scope of this review.

Introduction

Rheumatoid arthritis is a chronic autoimmune disease of which the main characteristic is irreversible joint destruction (Harris et al., 1970). Even though it is known that persistent activation of the immune system in RA leads to autoimmunity, the trigger activating the immune response remains unclear (Goronzy and Weyand, 2005). Before the turn of the century it was taken as a fact from clinical studies that non-steroidal anti-inflammatory drugs (NSAIDs) as well as disease modifying anti-rheumatic drugs (DMARDs) did not result in long-term effectiveness in patients with RA. Most patients still suffered from functional decline, radiographic progression, work disability and premature mortality. Now, biological-response modifiers including recombinant inhibitors of TNFα (infliximab, etanercept, adalimumab), IL-1 (anakinra), T cell co-stimulation (abatacept) and B cell targeted antibodies (rituximab) are powerful drugs for the majority of patients. However, since not all patients respond to these therapies and the disease cannot be cured yet, research has focused on the cells at the site of joint destruction. More attention is now paid, for example, on targeting the bone resorbing osteoclasts (Bull et al., 2008, Herman et al., 2008). Surprisingly, no interest was raised so far on the notion that, next to the development of autoimmunity and activation of the cytokine driven pathway of joint destruction, a cytokine-independent pathway driven by intrinsically activated RASF is another important part in the pathogenesis of RA (Gay et al., 1993, Ospelt et al., 2004). In this review we focus on the stimulating work done in the past years on innate immunity, epigenetic modulations in synovial cells and autoimmunity in RA. These new results should be inspiring for the development of innovative strategies in the treatment of RA.