title: Plasmacytoid dendritic cells, interferon signaling, and FcγR contribute to pathogenesis and therapeutic response in childhood immune thrombocytopenia.
abstract: 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-α. 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-α itself. IVIG altered the ratio of activating/inhibitory Fcγ receptors (FcγRs) in vivo primarily by reducing FcγRIII (CD16). The engagement of activating FcγRs was required for IVIG-mediated abrogation of monocyte response to exogenous interferon-α 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 FcγRs and interferon-α 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.
authors.affiliation: Yale Cancer Center, Yale University, New Haven, CT 06519, USA.
authors.forename: Kartik
authors.initials: K
authors.lastname: Sehgal
authors.forename: Xiuyang
authors.initials: X
authors.lastname: Guo
authors.forename: Srinivas
authors.initials: S
authors.lastname: Koduru
authors.forename: Anumeha
authors.initials: A
authors.lastname: Shah
authors.forename: Aiping
authors.initials: A
authors.lastname: Lin
authors.forename: Xiting
authors.initials: X
authors.lastname: Yan
authors.forename: Kavita M
authors.initials: KM
authors.lastname: Dhodapkar
mesh_terms: D000293:Adolescent; D018925:Chemokines / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016898:Interferon-alpha / Q000097:blood / Q000378:metabolism; D007372:Interferons / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008297:Male; D009000:Monocytes / Q000378:metabolism; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014019:Tissue Donors; D055815:Young Adult
chemical_list: D018925:Chemokines; D016756:Immunoglobulins, Intravenous; D036341:Intercellular Signaling Peptides and Proteins; D016898:Interferon-alpha; D017452:Receptors, IgG; D007372:Interferons