OBJECTIVEFulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated β-cell failure are unclear.RESEARCH DESIGN AND METHODSSubjects comprised three autopsied patients who died from diabetic ketoacidosis within 2–5 days after onset of fulminant type 1 diabetes. We examined islet cell status, including the presence of enterovirus and chemokine/cytokine/major histocompatibility complex (MHC) expressions in the pancreata using immunohistochemical analyses and RT-PCR.RESULTSImmunohistochemical analysis revealed the presence of enterovirus-capsid protein in all three affected pancreata. Extensive infiltration of CXCR3 receptor–bearing T-cells and macrophages into islets was observed. Dendritic cells were stained in and around the islets. Specifically, interferon-γ and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including β-cells and α-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyperexpression of MHC class I was observed in some islet cells.CONCLUSIONSThese results strongly suggest the presence of a circuit for the destruction of β-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates coexpression of interferon-γ and CXCL10 in β-cells. CXCL10 secreted from β-cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-γ in the islets, not only damaging β-cells but also accelerating CXCL10 generation in residual β-cells and thus further activating cell-mediated autoimmunity until all β-cells have been destroyed.

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.

OBJECTIVE-The pathogenesis of autoimmune pancreatitis (AIP) and fulminant type 1 diabetes remains unclear, although it is known that immune-mediated processes severely compromise the endocrine and exocrine functions in both diseases. RESEARCH DESIGN AND METHODS-We have screened aTriplEx2 human pancreas cDNA library with serum from a patient with AIP and obtained positive clones. Sequence analysis revealed that 7 of 10 clones were identical to human amylase ␣-2A. Using a recombinant COOH-terminal amylase ␣-2A protein, we developed an enzyme-linked immunosorbent assay system to detect autoantibodies against human amylase ␣-2A.RESULTS-All 15 serum samples from patients with AIP recognized the recombinant protein, whereas sera from 25 patients with chronic alcoholic pancreatitis and sera from 25 patients with a pancreas tumor did not. Interestingly, 88% (15/17) of patients with fulminant type 1 diabetes were positive for an autoantibody against amylase ␣-2A. These antibodies were detected in 21% of patients with acute-onset type 1 diabetes (9 of 42) and 6% of type 2 diabetic patients (4 of 67).CONCLUSIONS-These results suggest that an autoantibody against amylase ␣-2A is a novel diagnostic marker for both AIP and fulminant type 1 diabetes and that, clinically and immunologically, AIP and fulminant type 1 diabetes are closely related. Diabetes 58:732-737, 2009 R ecently, autoimmune pancreatitis (AIP), a unique form of chronic pancreatitis, has been reported as a discrete disease entity (1). It is characterized by 1) irregular narrowing of the main pancreatic duct and swelling of the pancreas, both of which are due to abundant lymphoplasmacytic inflammation to the exocrine pancreas (2); 2) the increased serum level of IgG and IgG4; 3) positive autoantibodies such as lactoferrin autoantibody or carbonic anhydrase II (CAII) autoantibody (3,4); and 4) a high prevalence of diabetes with complications (5).We recently reported that a high proportion of pancreatic islets and exocrine pancreatic tissues were infiltrated by CD4 ϩ or CD8 ϩ T-cells in the inflammatory process, which might induce diabetes in AIP (6). In addition, treatment with prednisolone improved insulin secretion and glycemic control in AIP patients (5). These data support the concept that autoimmune mechanism(s) plays a pivotal role in the destruction of the endocrine and exocrine pancreas in AIP patients with diabetes.Clinically, the most common initial symptom of AIP is jaundice, but in some patients, no symptoms or only mild symptoms, frequently without acute attacks of pancreatitis, may be present (7). It is difficult to distinguish AIP from other types of chronic pancreatitis or cancer of the pancreatic head (8). In such cases, detection of autoantibodies is useful for diagnosing AIP, but a proportion of patients with AIP are negative for autoantibodies against lactoferrin and CAII (3,4).We encountered an AIP patient whose serum IgG and IgG4 levels were 3,498 and 2,430 mg/dl, respectively. It has been reported that median levels (5th and 95th percentile...

In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1β levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD.

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