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* Division of Rheumatology, Department of Internal Medicine III, and Institutes of
Medical Biochemistry,
Pathophysiology, and
Histology, University of Vienna, Vienna, Austria;
¶ Ludwig Boltzmann Institute for Rheumatology and Balneology, Vienna, Austria; and
|| Department of Cell Biology and Anatomy, Mount Sinai School of Medicine, New York, NY 10029
The role of autoimmune reactions in the pathogenesis of rheumatoid
arthritis (RA) is poorly understood. To address this issue we have
investigated the spontaneous T cell response to two well-characterized
humoral autoantigens in RA patients and controls: 1) the heterogeneous
nuclear ribonucleoprotein A2, i.e., the RA33 Ag (A2/RA33), and 2)
filaggrin in unmodified and citrullinated forms. In stimulation assays
A2/RA33 induced proliferative responses in PBMC of almost 60% of the
RA patients but in only 20% of the controls (patients with
osteoarthritis or psoriatic arthritis and healthy individuals), with
substantially stronger responses in RA patients (p
< 0.00002). Furthermore, synovial T cells of seven RA patients
investigated were also clearly responsive. In contrast, responses to
filaggrin were rarely observed and did not differ between RA patients
and controls. Analysis of A2/RA33-induced cytokine secretion revealed
high IFN-
and low IL-4 production in both RA and control PBMC,
whereas IL-2 production was mainly observed in RA PBMC
(p < 0.03). Moreover, A2/RA33-specific T cell
clones from RA patients showed a strong Th1 phenotype and secreted
higher amounts of IFN- than Th1 clones from controls
(p < 0.04). Inhibition experiments performed with
mAbs against MHC class II molecules showed A2/RA33-induced T cell
responses to be largely HLA-DR restricted. Finally, immunohistochemical
analyses revealed pronounced overexpression of A2/RA33 in synovial
tissue of RA patients. Taken together, the presence of autoreactive
Th1-like cells in RA patients in conjunction with synovial
overexpression of A2/RA33 may indicate potential involvement of this
autoantigen in the pathogenesis of RA.
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