title: EBV latent membrane protein 2A induces autoreactive B cell activation and TLR hypersensitivity.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.forename: Matilda W
authors.initials: MW
authors.lastname: Nicholas
authors.forename: Kara L
authors.initials: KL
authors.lastname: Conway
authors.forename: Pradip
authors.initials: P
authors.lastname: Sen
authors.forename: Ramiro
authors.initials: R
authors.lastname: Diz
authors.forename: Roland M
authors.initials: RM
authors.lastname: Tisch
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Clarke
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D006967:Hypersensitivity / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D012261:Ribonucleoproteins / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D012261:Ribonucleoproteins; D051193:Toll-Like Receptors; D014763:Viral Matrix Proteins