Abstract

Rheumatoid arthritis (RA) is a common complex disease characterized by chronic inflammation which results in joint destruction and significant disability in those affected. According to the World Health Organisation, within 10 years of onset, at least 50% of patients in western countries are unable to sustain a full-time job bringing about detrimental consequences to patients as well as exorbitant societal costs. The cause of RA remains unknown. Human genetic studies have provided valuable insight with over 100 genetic risk factors identified to date. Genetic variants at the human leucocyte antigen (HLA) locus remain the most prominent genetic risk factor. Smoking is the best known environmental factor to date. Microbial triggers have also long been postulated in RA although specific microbes involved in disease pathogenesis remain to be identified.

The majority of RA patients (60–70%) harbors autoantibodies, including Rheumatoid factors (RF) and autoantibodies against modified self-antigens, commonly termed Anti-Modified Protein Antibodies (AMPA). A prominent example of AMPA are Anti-Citrullinated Protein Antibodies (ACPA). ACPA are highly disease-specific biomarkers of important diagnostic and prognostic value, with ACPA-positive patients being at risk for rapidly progressive, destructive and systemic disease. The strongest genetic risk factors for RA, the so-called HLA-shared epitope (SE) alleles, associate only with ACPA-positive-disease, indicating that ACPA define a specific disease entity within the complex group of symptoms clinically defined as RA. Current concepts of RA pathogenesis hold that a sequence of events leads to the development of ACPA-positive disease. Environmental factors are thought to cause an initial break of tolerance leading to the generation of ACPA. This initial development of auto-immunity appears to be independent of the disease-predisposing HLA-molecules. In most patients, this early event generates a polyclonal yet limited, mostly low-level autoantibody response that can be present for many years in the absence of clinical symptoms. Upon a putative second trigger, the ACPA epitope recognition repertoire broadens, more isotypes are being used, and ACPA serum levels rise. This is followed by precipitation of disease and is likely associated with the presence of the predisposing HLA-molecules. While the nature of this second trigger is presently unknown, the second event that initiates the broadening of the auto-immune response, in particular the citrulline-specific immune response, could mark a crucial moment upon which the auto-immune response becomes self-perpetuating and, potentially, irreversible.

Despite the many facets of ACPA revealed in the past two decades summarized above, it is not known how a breach of tolerance towards citrullinated proteins is mediated, or how ACPA-producing B-cells emerge.

Provision of T-cell help is crucial to convey the ability to B cells to modify the B cell receptor through somatic hypermutation. At present, it is unknown how ACPA- or other Anti-Modified Protein Antibody (AMPA)-producing B cells are “helped” by CD4+ Thelper cells, but it is often speculated that an auto-reactive T-cell response is crucial for their appearance. Our recent data show that such help could be provided by T-cells recognizing foreign proteins that have undergone a post-translational modification. In mice, AMPA-responses recognizing modified self-proteins are readily induced by immunization with modified proteins of non-selforigin. This is explained by the observation that the murine AMPA-response was, both at the monoclonal- and polyclonal level, highly cross-reactive towards multiple modified proteins, including proteins of self- and foreign origin. A similar observation was made analyzing the AMPA response in sera from RA patients. These data are important as the cross-reactive nature of AMPA could explain how autoreactive B-cell responses against PTM self-proteins can be induced by exposure to PTM foreign proteins thereby providing new insights on the breach of autoreactive B-cell tolerance.

Taken together, the analysis of the fine-specificity and recognition pattern of antibodies against modified proteins in RA during different phases of disease, together with detailed studies on the the identification, isolation and phenotypic characterization of auto-reactive B cells that express AMPA starts to shed light on the earliest phases of autoimmunity in RA.