Schematic representation of tolerance mechanisms important in preventing PNS autoimmunity and pathogenic mechanisms that lead to CIDP. (A) In a physiologically healthy state, P0-reactive T cells undergo negative selection. In the thymus, AIRE controls expression of tissue-specific antigens, such as P0, and recognition of these antigens by developing T cells leads to their negative selection. In CIDP, loss of negative selection by decreased AIRE or ICAM1 expression in the thymus results in escape of autoreactive T cells into the periphery. (B) Peripheral tolerance mechanisms, including immunosuppressive Treg activity and PD-1/PDL-1 ligation, have also been implicated in preventing PNS autoimmunity. (C) T cell infiltration past the blood-nerve barrier causes an inflammatory environment in the peripheral nerves. CD4⁺ T cells secrete various cytokines (IFN-γ, IL-17) that are involved in the immunopathology of CIDP. Macrophage chemotaxis is promoted by POSTN expression by nerve-resident Schwann cells. Autoreactive antibodies produced by B cells are recognized by the Fc receptors on macrophages, which then cause nerve damage by demyelination. Autoantibodies targeted to paranodal proteins (e.g., NF-155) and nodal proteins (e.g., NF-140) are pathogenic in a distinct subset of atypical CIDP. Autoantibodies targeted to peripheral myelin proteins are also found in more generalized forms of CIDP. Illustrated by Rachel Davidowitz.