The defining cause of RA still remains elusive. Environmental factors like mechanical stress and cigarette smoking have been demonstrated to have a role in disease susceptibility . There have also been suggestions that RA may be initiated by bacterial or viral infections , but this has been a contentious issue. Attempts to identify which infectious pathogen is present in the inflamed joints of RA patients have continued to be unsuccessful and irreproducible. An alternative hypothesis that has become more favourable is disease initiation by endogenous antigens via loss of peripheral tolerance . They are equally as capable as exogenous infectious agents at eliciting an immune response and may prove to be a more likely stimulus to generate the inflammation of the early stages of RA (Fig. 3).
There is a genetic influence in RA, but the concordance in identical twins (15%)  is the lowest for all autoimmune diseases, suggesting that there is a role for other stimuli. Antigen presenting cells use major histocompatibility complex (MHC) class II antigens to present antigenic peptides to CD4+ T cells. In RA CD4+ T cells infiltrate the joint. MHC class II antigens have been associated with RA . In particular, the human leukocyte antigen (HLA)-DR molecule chains HLA-DRB1 *0404, *0401, *0405, *0101 and *1402 which all share a common epitope . This suggests that there may be antigen presentation of a viral/bacterial pathogen or endogenous proteins such as a citrullinated protein  or human cartilage glyco-protein 39 , in the initial immune response of RA.
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