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Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599
EBV is associated with systemic lupus erythematosus (SLE), but how it might contribute to the etiology is not clear. Since EBV-encoded latent membrane protein 2A (LMP2A) interferes with normal B cell differentiation and function, we sought to determine its effect on B cell tolerance. Mice transgenic for both LMP2A and the Ig transgene 2-12H specific for the ribonucleoprotein Smith (Sm), a target of the immune system in SLE, develop a spontaneous anti-Sm response. LMP2A allows anti-Sm B cells to overcome the regulatory checkpoint at the early preplasma cell stage by a self-Ag-dependent mechanism. LMP2A induces a heightened sensitivity to TLR ligand stimulation, resulting in increased proliferation or Ab-secreting cell differentiation or both. Thus, we propose a model whereby LMP2A induces hypersensitivity to TLR stimulation, leading to activation of anti-Sm B cells through the BCR/TLR pathway. These data further implicate TLRs in the etiology of SLE and suggest a mechanistic link between EBV infection and SLE.
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 was supported by National Institutes of Health Grants AI29576 and AI43587 and a grant from the Arthritis Foundation (to S.H.C.).
2 Current address: Laboratory of Immunopathology, National Institute of Allergy and Infectious Disease, National Institutes of Health, 5640 Fishers Lane, Rockville, MD 20852.
3 Address correspondence and reprint requests to Dr. Stephen H. Clarke, Department of Microbiology and Immunology, CB#7290, 804 Mary Ellen Jones Building, University of North Carolina, Chapel Hill NC 27599. E-mail address: shl{at}med.unc.edu
4 Abbreviations used in this paper: SLE, systemic lupus erythematosus; ASC, Ab-secreting cell; Blimp-1, B lymphocyte-induced maturation protein-1; FO, follicular; HPRT, hypoxanthine phosphoribosyltransferase; LMP, latent membrane protein; MZ, marginal zone; ODN, oligonucleotide; PC, plasma cell; Sm, Smith; Tg, transgenic; XBP-1, X-box binding protein 1.
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