Inhibition of Experimental Autoimmune Encephalomyelitis in Human C-Reactive Protein Transgenic Mice Is FcRIIB Dependent

Xian-Zhen Hu,Mark A Mccrory,Alexander J Szalai,Theresa N Ramos,Tyler T Wright,Gregory A Skibinski,Scott R Barnum,Nicholas R Jones

doi:10.4061/2011/484936

Abstract

We showed earlier that experimental autoimmune encephalomyelitis (EAE) in human C-reactive protein (CRP) transgenic mice (CRPtg) has delayed onset and reduced severity compared to wild-type mice. Since human CRP is known to engage Fc receptors and Fc receptors are known to play a role in EAE in the mouse, we sought to determine if FcγRI, FcγRIIb, or FcγRIII was needed to manifest human CRP-mediated protection of CRPtg. We report here that in CRPtg lacking either of the two activating receptors, FcγRI and FcγRIII, the beneficial effects of human CRP are still observed. In contrast, if CRPtg lack expression of the inhibitory receptor FcγRIIB, then the beneficial effect of human CRP is abrogated. Also, subcutaneous administration of purified human CRP stalled progression of ongoing EAE in wild-type mice, but similar treatment failed to impede EAE progression in mice lacking FcγRIIB. The results reveal that a CRP → FcγRIIB axis is responsible for protection against EAE in the CRPtg model.

Highlights

C-reactive protein (CRP) is a widely used blood marker of inflammation [1], but it is increasingly apparent that the protein plays a causal role in host defense against microbial pathogens [2] and in cardiovascular disease [3]
Binds both human and mouse Fc receptors [7,8,9,10] and because there is growing evidence that Fc receptors play a major role in controlling the emergence of EAE and other autoimmune diseases [11,12,13,14,15], we sought to determine if FcγRs were required for human CRP-mediated protection against EAE in the mouse
As we reported previously in [6], onset of EAE was delayed by ∼1 week for CRP transgenic mice (CRPtg) compared to wild type mice (Figure 2(a) and Table 1; P < .001, t-test), and this delay led to reduced cumulative disease index (Table 1; 32.8 versus 46.55) even though average disease severity was not significantly lowered (Table 1 and Figure 2(a))

Summary

Introduction

C-reactive protein (CRP) is a widely used blood marker of inflammation [1], but it is increasingly apparent that the protein plays a causal role in host defense against microbial pathogens [2] and in cardiovascular disease [3]. We showed that human CRP transgenic mice (CRPtg) are resistant to experimental autoimmune encephalomyelitis (EAE) [6], an animal model of multiple sclerosis (MS). In CRPtg compared to wild-type mice, EAE onset was delayed, its severity was attenuated, and infiltration of encephalitogenic T-cells and monocytes/macrophages into the CNS was prevented [6]. Since human CRP binds both human and mouse Fc receptors [7,8,9,10] and because there is growing evidence that Fc receptors play a major role in controlling the emergence of EAE and other autoimmune diseases [11,12,13,14,15], we sought to determine if FcγRs were required for human CRP-mediated protection against EAE in the mouse

Methods

Results

Conclusion