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

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.

Experimental allergic encephalomyelitis is inhibited in transgenic mice expressing human C-reactive protein.

We show here using a transgenic model that human C-reactive protein (CRP) protects against experimental allergic encephalomyelitis (EAE) in C57BL/6 mice. In transgenic compared with wild-type females, the duration of the human CRP acute phase response that accompanies the inductive phase of active EAE correlates with a delay in disease onset. In transgenic males, which have higher human CRP expression than females do, EAE is delayed, and its severity is reduced relative to same-sex controls. Furthermore, in male transgenics, there is little or no infiltration of the spinal cord by CD3(+) T cells and CD11b(+) monocytes and macrophages, and EAE is sometimes prevented altogether. CRP transgenics also resist EAE induced passively by transfer of encephalitogenic T cells from wild-type donors. Human CRP has three effects on cultured encephalitogenic cells that could contribute to the protective effect observed in vivo: 1) CRP inhibits encephalitogenic peptide-induced proliferation of T cells; 2) CRP inhibits production of inflammatory cytokines (TNF-alpha, IFN-gamma) and chemokines (macrophage-inflammatory protein-1alpha, RANTES, monocyte chemoattractant protein-1); and 3) CRP increases IL-10 production. All three of these actions are realized in vitro only in the presence of high concentrations of human CRP. The combined data suggest that during the acute phase of inflammation accompanying EAE, the high level of circulating human CRP that is achieved in CRP-transgenic mice inhibits the damaging action of inflammatory cells and/or T cells that otherwise support onset and development of EAE.