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A SmD Peptide Induces Better Antibody Responses to Other Proteins within the Small Nuclear Ribonucleoprotein Complex than to SmD Protein via Intermolecular Epitope Spreading¹

Specialized Center of Research on Systemic Lupus Erythematosus, Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908

Autoantibody response against the small nuclear ribonucleoprotein (snRNP) complex is a characteristic feature of systemic lupus erythematosus. The current investigation was undertaken to determine whether activation of SmD-reactive T cells by synthetic peptides harboring T cell epitopes can initiate a B cell epitope spreading cascade within the snRNP complex. T cell epitopes on SmD were mapped in A/J mice and were localized to three regions on SmD, within aa 26–55, 52–69, and 86–115. Immunization with synthetic peptides SmD_31–45, SmD_52–66, and SmD_91–110 induced T and B cell responses to the peptides, with SmD_31–45 inducing the strongest response. However, only SmD_52–66 immunization induced T cells capable of reacting with SmD. Analysis of sera by immunoprecipitation assays showed that intermolecular B cell epitope spreading to U1RNA-associated A ribonucleoprotein and SmB was consistently observed only in the SmD_52–66-immunized mice. Surprisingly, in these mice, Ab responses to SmD were at low levels and transient. In addition, the sera did not react with other regions on SmD, indicating a lack of intramolecular B cell epitope spreading within SmD. Our study demonstrates that T cell responses to dominant epitope on a protein within a multiantigenic complex are capable of inducing B cell responses to other proteins within the complex. This effect can happen without generating a good Ab response to the protein from which the T epitope was derived. Thus caution must be taken in the identification of Ags responsible for initiating autoimmune responses based solely on serological analysis of patients and animals with systemic autoimmune disorders.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported in part by the American Heart Association, the Lupus Research Institute, and by National Institutes of Health Grants KO1 AR051391 (to U.S.D.), KO1 DK063065 (to H.B.), and R01 AI043248 and P50 AR45222 (to S.M.F.).

² Address correspondence and reprint requests to Dr. Umesh S. Deshmukh, Division of Rheumatology and Immunology, Department of Internal Medicine, University of Virginia, Health Sciences Center, Box 800412, Charlottesville, VA 22908. E-mail address: usd7w{at}virginia.edu

³ Abbreviations used in this paper: snRNP, small nuclear ribonucleoprotein; A-RNP, U1RNA-associated A ribonucleoprotein; SLE, systemic lupus erythematosus; LNC, lymph node cell.

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