Latent membrane protein 1, the EBV-encoded oncogenic mimic of CD40, accelerates autoimmunity in B6.Sle1 mice

Anna L. Peters, Laura L. Stunz, David K. Meyerholz, Chandra Mohan, Gail A. Bishop

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4053-4062
Number of pages10
JournalJournal of Immunology
Volume185
Issue number7
DOIs
StatePublished - Oct 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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