Rheumatoid arthritis (RA) is a chronic joint disease of unknown aetiology. The autoimmune nature of RA is underlined by abundant generation of rheumatoid factor (RF) autoantibodies to IgG1 Fc, and anti-citrullinated protein antibodies (ACPA) to citrullinated autoantigens such as fibrinogen. Although RA pathogenesis has not been elucidated, genetic predisposition, environmental insults and viral pathogens are considered contributory factors. Human endogenous retrovirus K10 (HERV-K10) is one such virus as it retained the capacity to produce viral particles in RA synovium. This study set out to explore how HERV-K10 Gag matrix region could contribute to RA pathogenesis and perpetuation, with particular emphasis on its ability to mimic host autoantigens. We showed that Gag region exhibits high levels of sequence and structural homology to IgG1 Fc and it could provide a key epitope important for auto-reactivity in RA.
Analysis of how HERV-K10 may evoke immune responses in RA was broadened by investigation of serological cross-reactivity of novel anti-K10 polyclonal antibody (PAbMAG) with IgG1 Fc. We showed that PAbMAG cross-reacted with linear and conformational epitopes on IgG1 Fc. In a further development, we showed a significantly elevated mean IgG response to HERV-K10 epitopes in serum samples from RA patients when compared to other arthritides. These data suggest that molecular mimicry between viral and host proteins has the potential to lead to antigen-driven high-affinity RF IgG immunological reactivity in RA.
Finally, we broadened our study of mimicry in RA by the investigation of citrullinated autoantigens. Structural studies demonstrated high levels of homology between citrullinated fibrinogen, IgG1 Fc and HERV. We further explored how protein citrullination affects the cross-reactivity of autoantibody responses in RA. These experiments revealed that generation of neoepitopes through citrullination of HERV-K10 and autoantigens IgG1 Fc and fibrinogen enhanced the reactivity of RA sera to these targets. Moreover, we showed that RF autoantibodies could mediate responses to a classical ACPA target fibrinogen, only when it is citrullinated, in the absence of ACPAs. These data provide a new insight into the initiation and propagation of immunological responses in RA and how viral/host molecular mimics and citrullination could modulate serum cross-reactivity profiles in RA.South Staffordshire Medical Foundation, Rotha Abraham Bequest, The Royal Wolverhampton Hospital Charity, New Cross Kidney Patients Association, James Beattie Charitable Trust.A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosoph
