Environmental Factors and Autoantibody Expression in Rheumatoid Arthritis

Rheumatoid arthritis (RA) represents one of the most common forms of inflammatory arthritis
worldwide. Among U.S. veterans, RA is associated with substantial morbidity, accelerated
mortality, and rapidly rising treatment costs. Fortunately, there have been substantial recent
gains in our understanding of RA pathogenesis including insight into the role of antigen-specific
autoantibodies in disease propagation. Preliminary evidence from our group and others
suggest that select autoantibodies may serve as robust biomarkers for disease progression and
indeed may actually directly mediate the joint damage that characterizes RA. Moreover, our
preliminary data suggests that antigen-specific autoantibody responses in RA may be 'shaped'
by environmental factors including cigarette smoking and periodontitis (PD), modifiable factors
that could be targeted in future strategies of disease treatment and/or prevention. Supported
now by substantial preliminary data, our overarching hypothesis is that environmental factors
directly impact the formation of specific autoantigens and tolerance loss in RA, leading to
adaptive immune responses that in turn have profound implications in RA. We plan to test our
central hypothesis and, thereby, accomplish the objectives of this application by pursuing the
following three specific aims: Aim 1 will examine the associations of antigen-specific
autoantibody responses in RA with radiographic disease progression. Studies will initially be
conducted using data and serum samples already available for patients enrolled in the recently
completed multinational VA Cooperative Study Program (CSP) 551 Study. Analyses will be
replicated in an additional RA cohort to mitigate false positive findings. This aim will include
preliminary studies exploring whether select autoantibodies stimulate osteoclast function and
bone resorption, pathologic features of bony erosion in RA. Aim 2 will examine associations of
subgingival microbiome composition (altered in the context of PD) with RA risk. These analyses
will leverage data and biosamples available (including subgingival bacterial plaque samples) as
part of the largest case-control study ever conducted examining the association of PD with RA
risk led by the PI. Aim 3 will then examine to what extent environmental factors (both smoking
and PD) shape autoantibody responses in RA. Studies in this aim will include initial
explorations of whether select subgingival bacteria influence antigen-specific responses of
circulating T-cells, thus promoting systemic autoimmunity in RA.
The questions proposed in this study are highly significant; addressing scientific questions and
current gaps in our understanding that have a high probability of altering the way the RA is
approached in clinical management in addition to shaping a future research agenda.