Human C-reactive protein is an acute phase protein whose blood concentrations rise dramatically in response to inflammatory insults. Though CRP is primarily of hepatic origin, it is also produced by neurons during times of CNS inflammation. CRP's contribution to CNS inflammation and the biological importance of neuronal CRP are unknown. Published work from our lab shows that mice containing the human CRP transgene (CRPtg) are protected from myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE), a rodent model of Multiple Sclerosis (MS). Human CRP, expressed transgenically or administered by injection, delays onset and reduces severity of EAE, and these effects rely on expression of Fc?RIIB. We showed that transgenic or injected human CRP is unable to ameliorate EAE in Fc?RIIB-/- mice. The Fc?RIIB-expressing cell that responds to human CRP remains unknown. The goals of this research project are (1) to determine the Fc?RIIB expressing cell through which CRP exerts protection against EAE and (2) to determine if CNS specific expression of human CRP is sufficient to protect mice from EAE. I hypothesize that CRP mediated amelioration of EAE is manifest via CRP binding to Fc?RIIB on dendritic cells (DCs), and that local CNS expression of CRP is sufficient to achieve this benefit. Utilizing purified human CRP, I will analyze bone marrow derived DCs from mice either sufficient or deficient for Fc?RIIB to determine if CRP alters their activation status in viro and if any CRP driven effect depends upon Fc?RIIB. Since EAE/MS is considered to be a T cell mediated disease, I will examine CRP's effect on DCs'ability to stimulate T cell proliferation and polarization in vitro in DC:T cell co-cultures using wildtype versus Fc?RIIB deficient DCs as antigen (MOG) presenting cells. I will also induce EAE in humanized mice (mice that express human CRP and express human Fc?RIIB exclusively on DCs, but no mouse Fc?RIIB) to investigate if the Fc?RIIB->DC axis is sufficient for CRP mediated amelioration of EAE. To assess the requirement of DCs, I will induce EAE in CRPtg in which DCs have been selectively depleted. Finally, using mice wherein human CRP expression is limited to neurons I will determine if exclusively CNS expression of human CRP is sufficient to protect mice from EAE. I will induce EAE in nCRPtg and compare their disease to CRPtg and WT mice. Successful pursuit of the work described herein will identify the effector cell by which CRP exerts protection in EAE, confirm that a human CRP->human Fc?RIIB axis operates in vivo, and elucidate the source of protective CRP. This will pave the way for development of new therapies that will benefit the ~350,000 U.S. citizens with MS.

Public Health Relevance

The goal of my project is to determine how C-reactive protein (CRP) protects mice from Experimental Autoimmune Encephalomyeltis (EAE), a Multiple Sclerosis (MS) like disease. In order to determine the mechanism of protection, including the cell types responsible, I will use various genetically altered mice to clarify how CRP interacts with various cells of the immune and nervous systems. This project is important because it presents a possible therapeutic avenue for MS, but also because it provides insight into the role of the immune system in central nervous system disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Utz, Ursula
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Jimenez, Rachel V; Wright, Tyler T; Jones, Nicholas R et al. (2018) C-Reactive Protein Impairs Dendritic Cell Development, Maturation, and Function: Implications for Peripheral Tolerance. Front Immunol 9:372
Wright, Tyler T; Jimenez, Rachel V; Morgan, Todd E et al. (2015) Hepatic but Not CNS-Expressed Human C-Reactive Protein Inhibits Experimental Autoimmune Encephalomyelitis in Transgenic Mice. Autoimmune Dis 2015:640171
Zhang, Lin; Liu, Shan-Hui; Wright, Tyler T et al. (2015) C-reactive protein directly suppresses Th1 cell differentiation and alleviates experimental autoimmune encephalomyelitis. J Immunol 194:5243-52