CRP-mediated reduction of EAE severity is FcγRIIb dependent (167.18)

Abstract

Abstract Blood levels of human C-reactive protein (CRP), the prototypical acute phase protein, elevate in response to inflammatory stimuli. Previously, our lab has shown that elevation of transgene-expressed human CRP is protective in mice with experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). Specifically, EAE onset is delayed and its clinical severity reduced in human CRP transgenic mice (CRPTg) compared to wildtype mice. Since human CRP is known to bind human and mouse Fc receptors (FcR), we sought to determine which FcRs, if any, might be required for human CRP-mediated protection from EAE. To do so, we induced EAE in CRPTg mice with normal FcR expression versus CRPTg mice deficient in expression of FcγRI, FcγRIIb, or FcγRIII. Time of EAE onset and clinical severity of disease were monitored for 30 days. We observed that in CRPTg mice deficient in the excitatory Fc receptors, FcγRI and FcγRIII, CRP’s full protective effect was still manifest. In stark contrast, for CRPTg mice deficient in the inhibitory Fc receptor, FcγRIIb, no human CRP dependent protection was evident. Furthermore, in wildtype mice with established EAE subcutaneous administration of purified human CRP stalled disease progression, whereas the same treatment did not impede EAE progression in FcγRIIB deficient mice. These results suggest that a human CRP→mouse FcγRIIB axis is responsible for the observed protection of human in the CRPTg model.