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Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, and
Rheumatologische Gemeinschaftspraxis, Erlangen, Germany; and
Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235
The chronic immune response in rheumatoid arthritis (RA) might be
driven by activated Th1 cells without sufficient Th2 cell
differentiation to down-modulate inflammation. To test whether
disordered memory T cell differentiation contributes to the typical
Th1-dominated chronic inflammation in RA we investigated
differentiation of resting CD4+ memory T cells in patients
with early (6 wk to 12 mo) untreated RA and in age- and sex-matched
healthy controls in vitro. No difference in cytokine secretion profiles
of freshly isolated memory T cells was detected between patients and
controls. A cell culture system was then employed that permitted the
differentiation of Th effectors from resting memory T cells by short
term priming. Marked differences were found in response to priming. Th2
cells could be induced in all healthy controls by priming with
anti-CD28 in the absence of TCR ligation. By contrast, priming
under those conditions resulted in Th2 differentiation in only 9 of 24
RA patients. Exogenous IL-4 could overcome the apparent Th2
differentiation defect in seven patients but was without effect in the
remaining eight patients. In all patients a marked decrease in
IL-2-producing cells and a significant increase in well-differentiated
Th1 cells that produced IFN-
but not IL-2 were evident after priming
with anti-CD3 and anti-CD28. The data suggest that
CD4+ memory T cells from patients with early untreated RA
manifest an intrinsic abnormality in their ability to differentiate
into specific cytokine-producing effector cells that might contribute
to the characteristic Th1-dominated chronic (auto)immune inflammation
in RA.
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