A polymorphism in human CD40 confers functional differences in B cell activation
CD40 is a TNF-receptor family member present on B cells, macrophages, and dendritic cells. My project focuses on the contribution of two molecules to the development of autoimmune disease: (1) LMP1, an EBV-encoded mimic of CD40, which transforms B cells and (2) a naturally-occurring mutation in CD40, P227A, which appears to have some LMP1-like properties. LMP1 is expressed upon EBV reactivation, which is latent in >90% of the human population. Reactivation of EBV is associated with SLE flares, and LMP1 transgenic mice generated in the lab have an autoimmune phenotype. Although CD40-P227A is not associated with incidence of SLE, this allele is highly enriched in individuals of Mexican and South American descent. This skewed population distribution is interesting because Hispanics with SLE have a much more severe and rapidly progressive disease course than other ethnic groups. Through the use of a variety of experimental approaches, I hope to understand more about how LMP1 and CD40-P227A contribute to aberrant immune system activation and autoimmunity.
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Peters , A.L., Plenge, R.M., Graham, R.R., Altshuler, D.M., Moser, K.L., Gaffney, P.M., Bishop, G.A. A novel polymorphism of the human CD40 receptor with enhanced function. Blood. 2008 Sep 1;112(5):1863-71. Epub 2008 Jun 30. PMID: 18591382 [PubMed - indexed for MEDLINE]
Peters , A.L., Stunz, L.L., Bishop, G.A. CD40 and autoimmunity: the dark side of a great activator. Semin Immunol. 2009 Oct;21(5):293-300.
PMID: 19595612 [PubMed - in process]
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