Involvement of the Fc gamma receptor in a chronic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of dopaminergic loss.

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Although there is growing evidence for a role of the innate immune response in Parkinson's disease, the nature of any humoral response in dopaminergic degeneration is uncertain. Here we report on a protracted N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of dopaminergic death that potentially allows a more full adaptive humoral response to develop. Rag2 mutant mice that lack the full adaptive response (deficient in both T and B cells) are resistant to dopaminergic death and behavioral deficiencies in this model. These mice are resensitized after reconstitution with WT splenocytes. To more directly provide evidence for humoral/IgG involvement, we show that deficiency of Fcγ receptors, which are critical for activation of macrophages/microglia by binding to IgGs, is also protective in this protracted model. FcγR-deficient mice display improved behavior and impaired microglial activation. Interestingly, however, Rag2 mutant but not FcγR-deficient mice are resistant to a more standard N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine paradigm where death is more rapid. Taken together, these data indicate that, provided sufficient time, the humoral arm of the adaptive immune system can play a critical functional role in modulating the microglial response to dopaminergic degeneration and suggest that this humoral component may participate in degeneration in Parkinson's disease.

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