TY - JOUR
T1 - Latent membrane protein 1, the EBV-encoded oncogenic mimic of CD40, accelerates autoimmunity in B6.Sle1 mice
AU - Peters, Anna L.
AU - Stunz, Laura L.
AU - Meyerholz, David K.
AU - Mohan, Chandra
AU - Bishop, Gail A.
PY - 2010/10/1
Y1 - 2010/10/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.0904065
DO - 10.4049/jimmunol.0904065
M3 - Article
C2 - 20810985
AN - SCOPUS:77958146282
SN - 0022-1767
VL - 185
SP - 4053
EP - 4062
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -