Plasmacytoid Dendritic Cells, Interferon Signaling, and FcγR Contribute to Pathogenesis and Therapeutic Response in Childhood Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disorder of childhood characterized by immune-mediated destruction of platelets. The mechanisms underlying the pathogenesis of ITP and the therapeutic efficacy of intravenous immunoglobulins (IVIG) in this disorder remain unclear. We show that monocytes from patients with ITP have a distinct gene expression profile, with increased expression of type I interferon response (IR) genes. Plasma from ITP patients had increased levels of several cytokines indicative of immune activation, including an increase in interferon-alpha. ITP patients also had an increase in plasmacytoid dendritic cells (pDCs) compared to healthy donors. Therapy-induced remission of ITP was associated with abrogation of the IR gene signature in monocytes without reduction in the levels of circulating interferon-alpha itself. IVIG altered the ratio of activating/inhibitory Fc gamma receptors (Fc gamma Rs) in vivo primarily by reducing Fc gamma RIII (CD16). The engagement of activating Fc gamma Rs was required for IVIG-mediated abrogation of monocyte response to exogenous interferon-alpha in culture. Moreover, plasma from ITP patients led to activation of monocytes and myeloid DCs in culture with an increase in T cell stimulatory capacity; this activation depended on the engagement of activating Fc gamma Rs and interferon-alpha receptor (IFNAR) and was inhibited by antibody-mediated blockade of these pathways. These data point to a central role of type I interferon in the pathogenesis of ITP and suggest targeting pDCs and blockade of IR as potential therapeutic approaches in this disorder. They also provide evidence for the capacity of IVIG to extinguish IR in vivo, which may contribute to its effects in autoimmunity.