EBV latent membrane protein 2A induces autoreactive B cell activation and TLR hypersensitivity.
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.
Wang
Hongsheng
H
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
Nicholas
Matilda W
MW
Conway
Kara L
KL
Sen
Pradip
P
Diz
Ramiro
R
Tisch
Roland M
RM
Clarke
Stephen H
SH
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*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D012261:Ribonucleoproteins; D051193:Toll-Like Receptors; D014763:Viral Matrix Proteins