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Heightened Interferon‐α/β Response Causes Myeloid Cell Dysfunction and Promotes T1D Pathogenesis in NOD Mice
Author(s) -
PENG RUI HUA,
PAEK EDWARD,
XIA CHANQING Q.,
TENNYSON NATHAN,
CLARESALZLER MICHAEL J.
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1375.013
Subject(s) - nod , nod mice , biology , immunology , immune system , innate immune system , interferon , cytokine , insulitis , autoimmunity , endocrinology , diabetes mellitus
Increasing attention is drawn to the contributions of abnormalities in both innate and acquired immune responses to the pathogenesis of autoimmune diseases, such as type 1 diabetes (T1D). Dendritic cells (DC) are critical immune cells linking innate and acquired immune responses and previous studies in NOD mice suggest abnormalities in these cells.To address DC dysregulation we examined kinetic global gene expression in NOD and B6 GM‐CSF/IL‐4‐induced bone marrow‐derived DC following lipopolysaccharide (LPS)‐stimulation. We identified expression differences in over 300 genes including a cluster of 16 interferon (IFN‐α/β) target genes overexpressed in NOD DC. Mechanistically, heightened IFN‐α/β responses were not due to increased production of this cytokine, IFN‐γ priming or increased Syk kinase activity. We found, however, heightened responses to IFN‐α/β in NOD versus B6 as demonstrated by increased type 1 IFN target gene expression, for example, IRF‐7, in NOD DC and macrophages. Analysis of multiple congenic strains demonstrated that the Idd5 susceptibility region largely governed heightened IFN‐α responses. Of interest, heightened IFN‐α/β response in NOD mice was not confined to hematopoietic cells but was also seen in the pancreas and β cells. Compounding the IFN‐α response defect, NOD mice harbor significantly more PDC in spleen in comparison to B6 and produce four‐ to sixfold more IFN‐α when stimulated with CpG. Finally, treatment of NOD mice with IFN‐α inducing agents, for example, high‐dose poly I:C accelerates diabetes in both female and male mice. The abnormalities in the IFN‐α/β axis appear to play a significant role in T1D pathogenesis.