The spliceosomal autoantigen heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2) is a major T cell autoantigen in patients with systemic lupus erythematosus |
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Authors: | Ruth Fritsch-Stork Daniela Müllegger Karl Skriner Beatrice Jahn-Schmid Josef S Smolen Günter Steiner |
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Institution: | Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Austria. |
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Abstract: | A hallmark of systemic lupus erythematosus (SLE) is the appearance of autoantibodies to nuclear antigens, including autoantibodies
directed to the heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2), which occur in 20% to 30% of SLE patients as well as
in animal models of this disease. To investigate the underlying cellular reactivity and to gain further insight into the nature
and potential pathogenic role of this autoimmune response we characterized the T cell reactivity against hnRNP-A2 in patients
with SLE in comparison to healthy controls. Cellular proliferation of peripheral blood T cells to hnRNP-A2 was determined
by 3H]thymidine incorporation and T cell clones (TCCs) specific for hnRNP-A2 were grown by limiting dilution cloning; IFNγ,
IL-4 and IL-10 in culture supernatants were measured by ELISA. Bioactivity of culture supernatants was determined by incubation
of anti-CD3/anti-CD28 stimulated peripheral blood CD4+ T cells with supernatants of TCCs. Stimulation assays performed with
peripheral blood mononuclear cells of 35 SLE patients and 21 healthy controls revealed pronounced proliferative responses
in 66% of SLE patients and in 24% of the controls, which were significantly higher in SLE patients (p < 0.00002). Furthermore,
hnRNP-A2 specific TCCs generated from SLE patients (n = 22) contained a relatively high proportion of CD8+ clones and mostly lacked CD28 expression, in contrast to TCCs derived
from healthy controls (n = 12). All CD4+ TCCs of patients and all control TCCs secreted IFNγ and no IL-4. In contrast, CD8+ TCCs of patients secreted
very little IFNγ, while production of IL-10 did not significantly differ from other T cell subsets. Interestingly, all CD8+
clones producing IL-10 in large excess over IFNγ lacked expression of CD28. Functional assays showed a stimulatory effect
of the supernatants derived from these CD8+CD28- hnRNP-A2 specific TCCs that was similar to that of CD4+CD28+ clones. Taken
together, the pronounced peripheral T cell reactivity to hnRNP-A2 observed in the majority of SLE patients and the distinct
phenotype of patient-derived CD8+ TCCs suggest a role for these T cells in the pathogenesis of SLE. |
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