RIG-I– and MDA5-Initiated Innate Immunity Linked With Adaptive Immunity Accelerates β-Cell Death in Fulminant Type 1 Diabetes

Abstract

OBJECTIVEThe contribution of innate immunity responsible for aggressive β-cell destruction in human fulminant type 1 diabetes is unclear.RESEARCH DESIGN AND METHODSIslet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid–inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes.RESULTSRIG-I was strongly expressed in β-cells in all three pancreata infected with enterovirus. Melanoma differentiation–associated gene-5 was hyperexpressed in islet cells, including β- and α-cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated islets. Interferon (IFN)-α and IFN-β were strongly expressed in islet cells. Major histocompatibility complex (MHC)-class I, IFN-γ, interleukin-18, and CXC motif ligand 10 were expressed and colocalized in affected islets. CD11c+ MHC-class II+ dendritic cells and macrophage subsets infiltrated most islets and showed remarkable features of phagocytosis of islet cell debris. CD4+ forkhead box P3+ regulatory T cells were not observed in and around the affected islets. Mononuclear cells expressed the Fas ligand and infiltrated most Fas-expressing islets. Retinoic acid–receptor responder 3 and activated caspases 8, 9, and 3 were preferentially expressed in β-cells. Serum levels of IFN-γ were markedly increased in patients with fulminant type 1 diabetes.CONCLUSIONSThese findings demonstrate the presence of specific innate immune responses to enterovirus infection connected with enhanced adoptive immune pathways responsible for aggressive β-cell toxicity in fulminant type 1 diabetes.

Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes [Review]

“…Studies of gene-deficient mice indicate that RLRs play an important role in antiviral response [22][23][24]. We have demonstrated significant hyper-expression of RLRs in islet cells of patients with fulminant type 1 diabetes [8,9]. MDA5 was strongly expressed in islet cells (including β-and α-cells) of fulminant type 1 diabetic pancreata.…”

“…The human TLR multigene family comprises 10 members, with TLR2, -3, -4, -7, and -8 considered to be of importance in the recognition of structural components of RNA viruses, including viral doublestranded RNA, single-stranded RNA, and surface glycoproteins [30]. We showed that both TLR3 and TLR4 were expressed in MNCs that had infiltrated islets of fulminant type 1 diabetic pancreata, but not SPIDDM patients or non-diabetic controls [8,9]. The frequencies of islets with infiltrating MNCs expressing TLR3 and TLR4 were 11.7% and 4.3%, respectively, although almost no islet with MNCs expressing TLR3 or TLR4 was recognized in pancreata of non-diabetic controls or SPIDDM patients.…”

“…NOD2 also recogfulminant type 1 diabetes [7][8][9]. A proportion of islet cells and acinar cells were positive for VP1.…”

“…Predominant phenotypes of MNCs in islets with insulitis were DCs, macrophages and CD8+ T cells in fulminant type 1 diabetic patients [7,8].…”

“…Endogenous insulin secretion is completely abolished over time and diabetic microangiopathies develop within a short duration [5,6]. Remarkable severe insulitis was recognized in autopsied pancreata of patients who died shortly after the onset of fulminant type 1 diabetes [3,[7][8][9][10]. The mechanisms underlying aggressive and rapid destruction of β-cells remain some of the key issues in question regarding this subtype of type 1 diabetes.…”