title: The spliceosomal autoantigen heterogeneous nuclear ribonucleoprotein A2 (hnRNP-A2) is a major T cell autoantigen in patients with systemic lupus erythematosus.
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; IFNgamma, 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 IFNgamma and no IL-4. In contrast, CD8+ TCCs of patients secreted very little IFNgamma, 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 IFNgamma 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.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
authors.forename: Ruth
authors.initials: R
authors.lastname: Fritsch-Stork
authors.forename: Daniela
authors.initials: D
authors.lastname: Müllegger
authors.forename: Karl
authors.initials: K
authors.lastname: Skriner
authors.forename: Beatrice
authors.initials: B
authors.lastname: Jahn-Schmid
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001324:Autoantigens / Q000097:blood*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D002457:Cell Extracts / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells / Q000473:pathology; D005260:Female; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008297:Male; D017381:Spliceosomes / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D018106:CD28 Antigens; D017252:CD3 Complex; D002457:Cell Extracts; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C439768:hnRNP A2