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Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathies
Jolien Wolbert, … , Gerd Meyer zu Horste, Maureen A. Su
Jolien Wolbert, … , Gerd Meyer zu Horste, Maureen A. Su
Published February 13, 2020
Citation Information: JCI Insight. 2020;5(3):e132411. https://doi.org/10.1172/jci.insight.132411.
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Review

Deciphering immune mechanisms in chronic inflammatory demyelinating polyneuropathies

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Abstract

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nerves that presents with either chronic progression or relapsing disease. Recent studies in samples from patients with CIDP and mouse models have delineated how defects in central (thymic) and peripheral (extrathymic) immune tolerance mechanisms can cause PNS autoimmunity. Notably, nerve parenchymal cells actively contribute to local autoimmunity and also control disease outcome. Here, we outline how emerging technologies increasingly enable an integrated view of how immune cells and PNS parenchymal cells communicate in CIDP. We also relate the known heterogeneity of clinical presentation with specific underlying mechanisms. For example, a severe subtype of CIDP with tremor is associated with pathogenic IgG4 autoantibodies against nodal and paranodal proteins. An improved understanding of pathogenic mechanisms in CIDP will form the basis for more effective mechanism-based therapies.

Authors

Jolien Wolbert, Mandy I. Cheng, Gerd Meyer zu Horste, Maureen A. Su

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Figure 1

CIDP pathogenesis.

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CIDP pathogenesis.
Schematic representation of tolerance mechanisms impo...
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.

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