Journal article
Latent Membrane Protein 1, the EBV-encoded oncogenic mimic of CD40, accelerates autoimmunity in B6.Sle1 mice
The Journal of immunology (1950), Vol.185(7), pp.4053-4062
10/01/2010
DOI: 10.4049/jimmunol.0904065
PMCID: PMC3048355
PMID: 20810985
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-LMP1tg) 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 to non-transgenic littermates. Anti-histone antibodies 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.
Details
- Title: Subtitle
- Latent Membrane Protein 1, the EBV-encoded oncogenic mimic of CD40, accelerates autoimmunity in B6.Sle1 mice
- Creators
- Anna L Peters - VA Medical Center, Iowa City, IA, 52242Laura L Stunz - VA Medical Center, Iowa City, IA, 52242David K Meyerholz - VA Medical Center, Iowa City, IA, 52242Chandra Mohan - VA Medical Center, Iowa City, IA, 52242Gail A Bishop - VA Medical Center, Iowa City, IA, 52242
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.185(7), pp.4053-4062
- DOI
- 10.4049/jimmunol.0904065
- PMID
- 20810985
- PMCID
- PMC3048355
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Language
- English
- Date published
- 10/01/2010
- Academic Unit
- Microbiology and Immunology; President; Pathology
- Record Identifier
- 9984001215502771
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