title: Concentration and activity of the soluble form of the interleukin-7 receptor α in type 1 diabetes identifies an interplay between hyperglycemia and immune function.
abstract: Soluble interleukin-7 (IL-7) receptor α (sCD127) is implicated in the pathogenesis of autoimmune diseases. We show that serum sCD127 concentrations are increased at the onset of type 1 diabetes (T1D; n = 390) as compared with concentrations in age-matched islet autoantibody-negative first-degree relatives of patients (n = 392; P = 0.00001). sCD127 concentration in patients was influenced by islet autoantibody status (P = 0.003) and genotype of the rs6897932 single nucleotide polymorphism within the IL-7RA gene (P = 0.006). Release of sCD127 in vitro was strongly upregulated by activation of T lymphocytes and affected by exposure to cytokines. sCD127 bound IL-7 and was antagonistic to IL-7 signaling and IL-7-mediated T-cell proliferation, suggesting a regulatory feedback mechanism on T-cell expansion. Remarkably, high glucose led to a glycated form of sCD127 that was ineffective as an IL-7 antagonist. The finding of glycated sCD127 in the circulation of patients at onset of T1D suggested that physiological regulation of IL-7-mediated T-cell survival and expansion by sCD127 may be compromised in T1D. The findings indicate that genetic, immunologic, and metabolic factors contribute to a dysregulation of the IL-7/IL-7 receptor pathway in T1D and identify a novel hyperglycemia-mediated interference of immune regulatory networks.
authors: San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy. paolo.monti@hsr.it
authors: Paolo
authors: P
authors: Monti
authors: Cristina
authors: C
authors: Brigatti
authors: Miriam
authors: M
authors: Krasmann
authors: Anette G
authors: AG
authors: Ziegler
authors: Ezio
authors: E
authors: Bonifacio
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D006943:Hyperglycemia / Q000276:immunology / Q000378:metabolism*; D007109:Immunity; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit