title: Latent membrane protein 1, the EBV-encoded oncogenic mimic of CD40, accelerates autoimmunity in B6.Sle1 mice.
abstract: EBV infection is associated with development of the autoimmune disease systemic lupus erythematosus (SLE), and EBV can reactivate during SLE flares. Latent membrane protein 1 (LMP1) is an EBV-encoded oncogenic mimic of CD40 that can be re-expressed in PBMCs during SLE flares, as >90% of humans are latently EBV-infected. Whether LMP1 signaling exacerbates SLE is unknown. The phenotype of mice expressing a chimeric molecule with the mouse CD40 extracellular domain and the LMP1 intracellular signaling regions (mCD40-LMP1 transgenic [tg]) includes enhanced autoreactivity, yet these mice do not develop fatal autoimmune disease. We hypothesized that LMP1-mediated activation signals cooperate with and/or amplify events that predispose individuals to development of autoimmunity. To determine which aspects of autoimmunity may be exacerbated by LMP1, we bred mCD40-LMP1tg mice to two lupus-prone strains, B6.Sle1 and B6.Sle3, and analyzed autoimmunity parameters. LMP1(+)Sle1(+/+) mice developed enlarged lymphoid organs containing increased frequencies of germinal center, B cells, CD86(+) B cells, and activated and memory T cells compared with non-tg littermates. Anti-histone Abs were elevated in serum of LMP1(+)Sle1(+/+) mice, and they had signs of kidney pathology. LMP1(+)Sle1(+/+) B cells produced increased IL-6 and upregulated CD86 to a higher degree following CD40 stimulation in vitro, suggesting that the in vivo autoimmune exacerbation is B cell intrinsic. In contrast, the LMP1 transgene has no additional effects on autoimmunity on the B6.Sle3 background. These data indicate that LMP1-induced effects can cooperate with distinct subsets of host genes that predispose to autoimmunity and can thus be an exacerbating factor in autoimmune disease via multiple mechanisms.
authors.affiliation: Immunology Graduate Program, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Peters
authors.forename: Laura L
authors.initials: LL
authors.lastname: Stunz
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D002469:Cell Separation; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D051940:B7-2 Antigen; D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D015850:Interleukin-6; D014763:Viral Matrix Proteins
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