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Roger Williams - One of the best experts on this subject based on the ideXlab platform.
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Tumour necrosis factor production in Fulminant hepatic failure: relation to aetiology and superimposed microbial infection.
Clinical and Experimental Immunology, 2008Co-Authors: M Mata, N. Rolando, H. M. Daniels, Kayhan T. Nouri-aria, A. K. J. Goka, Adrian L. W. F. Eddleston, G J Alexander, Anthony Meager, Roger WilliamsAbstract:SUMMARY Tumour necrosis factor-alpha (TNF-α), a cytokine derived from macrophages, is considered to bean important endogenous mediator of endotoxic shock. Patients with Fulminant hepatic failure are particularly susceptible to infection and the development of multi-organ failure and similarities to endotoxic shock suggest a possible pathogenetic role for TNF in Fulminant hepatic failure. In vitro TNF production was therefore investigated serially in 21 consecutive patients with Fulminant hepatic failure and in 21 healthy controls. Spontaneous and lipopolysaccharide-stimulated TNF production were elevated in viral-induced Fulminant hepatic failure, compared with healthy controls (P < 0.05 and P
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Plasma Inhibitory Activity against Tumour Necrosis Factor in Fulminant Hepatic Failure
Clinical Science, 1996Co-Authors: Helen M. Keane, Nick Sheron, J. Goka, Robin D Hughes, Roger WilliamsAbstract:1. Soluble tumour necrosis factor receptors released into the circulation inhibit the effects of excess tumour necrosis factor-alpha and represent an important protective response. 2. In this study we have measured the levels of tumour necrosis factor and soluble tumour necrosis factor receptors p55 and p75 in the plasma of 10 patients with Fulminant hepatic failure and 10 healthy control subjects. The capacity of the plasmas at varying dilutions to inhibit the biological activity of 1000 pg/ml of recombinant tumour necrosis factor in a tumour necrosis factor cytotoxicity assay in vitro was also determined. 3. The mean plasma levels of tumour necrosis factor in patients with Fulminant hepatic failure (48.4 +/- 10.9 pg/ml) were significantly increased compared with normal control subjects (6.1 +/- 1.04 pg/ml, P < 0.01). Plasma soluble tumour necrosis factor receptors p55 and p75 were also significantly elevated in patients with Fulminant hepatic failure (18.16 +/- 9.94 ng/ml and 16.06 +/- 9.93 ng/ml respectively) when compared with normal control subjects (1.28 +/- 0.24 ng/ml and 1.62 +/- 0.91 ng/ml, P < 0.001). 4. Fulminant hepatic failure plasma had a much lower capacity to inhibit tumour necrosis factor bioactivity in vitro, with a statistically significant difference between the inhibitory capacity of the Fulminant hepatic failure and normal plasma seen at plasma dilutions of 1:5 and 1:20 (P < 0.05). 5. The reduced tumour necrosis factor neutralization capacity observed in Fulminant hepatic failure, despite the increased levels of soluble tumour necrosis factor receptors, suggests enhanced susceptibility to the potential deleterious effects of tumour necrosis factor in Fulminant hepatic failure.
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Failure of simple biochemical indexes to reliably differentiate Fulminant Wilson's disease from other causes of Fulminant liver failure.
Hepatology (Baltimore Md.), 1992Co-Authors: Richard Sallie, Leah Katsiyiannakis, Dianne Baldwin, Susan E. Davies, John O'grady, Alex P. Mowat, Giorgina Mieli-vergani, Roger WilliamsAbstract:Serum, urine and tissue biochemical findings were studied in 21 cases of Fulminant Wilson's disease with respect to the value of a recently described biochemical index based on serum alkaline phosphatase and total serum bilirubin levels, and these cases were compared with 193 other cases of Fulminant liver failure. Serum bilirubin, alkaline phosphatase and AST levels found in Fulminant Wilson's disease were significantly different from those found in other cases of Fulminant liver failure, but differentiation from other causes of Fulminant liver failure on the basis of these biochemical parameters was not possible. The alkaline phosphatase/bilirubin and aspartate AST/bilirubin ratios derived from the above parameters were also significantly lower in Fulminant Wilson's disease than in other categories of Fulminant liver failure, but distinction between diagnostic categories on this basis was not possible. When ratios that correctly identified all cases of Fulminant Wilson's disease were selected, 59/190 (31%) and 84/190 (44%) cases of non-Wilsonian Fulminant liver failure would erroneously be assigned a diagnosis of Fulminant Wilson's disease, by alkaline phosphatase/bilirubin and AST/bilirubin ratios, respectively. A low alkaline phosphatase–to–bilirubin ratio (
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Inhibitors of hepatic DNA synthesis in Fulminant hepatic failure
Digestive Diseases and Sciences, 1991Co-Authors: Robin D Hughes, C. D. Gove, Haruki Yamada, Roger WilliamsAbstract:In certain etiological groups of patients with Fulminant hepatic failure, poor survival may be due to lack of liver regeneration.In vitro experiments have shown that Fulminant hepatic failure serum is cytotoxic to rabbit hepatocytes and inhibits DNA synthesis on short-term incubation with isolated regenerating rat hepatocytes. When Fulminant hepatic failure serum is injected into partially hepatectomized rats at the time of maximal DNA synthesis, [3H]thymidine incorporation into hepatic DNA is reduced significantly. The effect is greater with sera obtained from patients with Fulminant hepatic failure due to non-A, non-B hepatitis or an adverse drug reaction and is associated with a 10,000-dalton serum fraction into normal rats. In preliminary experiments, no increase in epidermal growth factor production has been found in liver failure. Overall, the substances present in Fulminant hepatic failure serum appear to be inhibitory rather than stimulatory for liver cell regeneration.
Akihisa Imagawa - One of the best experts on this subject based on the ideXlab platform.
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Pathogenesis of Fulminant type 1 diabetes: Genes, viruses and the immune mechanism, and usefulness of patient-derived induced pluripotent stem cells for future research.
Journal of Diabetes Investigation, 2019Co-Authors: Yoshiya Hosokawa, Toshiaki Hanafusa, Akihisa ImagawaAbstract:: We reviewed Fulminant type 1 diabetes, a recently established subtype of type 1 diabetes, from the aspects of genes, viruses, immune mechanism and usefulness of patient-derived induced pluripotent stem cells (iPSCs). In an analysis of the pancreas of patients with Fulminant type 1 diabetes, viral antigens and viral receptors were expressed in β-cells, as well as macrophages and T lymphocytes surrounding the β-cells. These findings suggest that the β-cells of patients with Fulminant type 1 diabetes are destroyed during an immune response against viral infection of the pancreas. Recently, Fulminant type 1 diabetes was induced by treatment with anti-programmed cell death 1 antibodies, suggesting that immune regulatory mechanisms are also involved in the onset of this disease. We generated iPSCs from patients with Fulminant type 1 diabetes for the first time. We also successfully differentiated patient-derived iPSCs into insulin-producing cells in vitro, and produced a disease model. The proportion of cytokine-induced apoptotic cells among insulin-positive cells was higher in the iPSCs from patients with Fulminant type 1 diabetes than in iPSCs from healthy control participants. We carried out ribonucleic acid sequencing in insulin-producing cells differentiated from patient-derived iPSCs, and are now attempting to identify new biomarkers for the disease.
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class ii hla genotype in Fulminant type 1 diabetes a nationwide survey with reference to glutamic acid decarboxylase antibodies
Journal of Diabetes Investigation, 2012Co-Authors: Chiharu Tsutsumi, Akihisa Imagawa, Hiroshi Ikegami, Hideichi Makino, Tetsuro Kobayashi, Toshiaki HanafusaAbstract:Aims/Introduction: Fulminant type 1 diabetes is a subtype of type 1 diabetes characterized by a remarkably abrupt onset of insulin‐deficient hyperglycemia within a few days. The aim of the present study was to clarify characteristic class II HLA genotypes in a large number of patients with Fulminant type 1 diabetes to date. Materials and Methods: We analyzed the HLA‐DRB1 and DQB1 genotypes, and their haplotypes in 207 patients with Fulminant type 1 diabetes and 325 control subjects in the Japanese population. Results: The frequencies of the DRB1*04:05‐DQB1*04:01 and DRB1*09:01‐DQB1*03:03 haplotypes were significantly higher, and those of the DRB1*01:01‐DQB1*05:01, DRB1*15:02‐DQB1*06:01 and DRB1*08:03‐DQB1*06:01 haplotypes were significantly lower in patients with Fulminant type 1 diabetes than in the control subjects. Combination analysis showed that the frequencies of homozygotes with DRB1*04:05‐DQB1*04:01 [odds ratio (OR) 7.0] and DRB1*09:01‐DQB1*03:03 (OR 9.5) were significantly higher in patients with Fulminant type 1 diabetes. Within a limited portion of patients with Fulminant type 1 diabetes with antibodies to glutamic acid decarboxylase (GADab; n = 25), the frequency of DRB1*09:01‐DQB1*03:03, but not DRB1*04:05‐DQB1*04:01, was significantly higher than in control subjects (44.0% vs 13.7%; Pc < 0.05, OR 5.0). [Correction to last line of Results, added after online publication 29 July 2011: “OR 5.1” is changed to “OR 5.0”.] Conclusions: Our large‐scale study showed the characteristic class II HLA genotypes in Fulminant type 1 diabetes, and implicated that genetic contribution to disease susceptibility is distinct between GADab‐positive and GADab‐negative Fulminant type 1 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00139.x, 2012)
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High titres of IgA antibodies to enterovirus in Fulminant type-1 diabetes
Diabetologia, 2005Co-Authors: Akihisa Imagawa, Tadashi Hanafusa, J.-i. Miyagawa, H Makino, P. JutoAbstract:Aims/hypothesis We have recently proposed that Fulminant type-1 diabetes is a novel subtype of type-1 diabetes with abrupt onset of insulin-deficient hyperglycaemia without islet-related autoantibodies. The pathogenesis is still unknown, but flu-like symptoms are frequently observed before the onset of disease of this subtype. Enterovirus infection is a candidate environmental factor causing type-1 diabetes. The aim of this study was to determine whether enterovirus infection contributes to the development of Fulminant type-1 diabetes. Methods We investigated 19 patients with recent-onset Fulminant type-1 diabetes, 18 patients with recent-onset typical type-1A diabetes, and 19 healthy controls. IgM, IgG, and IgA subclasses of antibodies to enterovirus were determined by ELISA. Results IgA antibody titres to enterovirus were significantly higher in Fulminant type-1 diabetes than in typical type-1A diabetes ( p =0.033) and controls ( p =0.0003). IgM antibodies to enterovirus were not detected in any subject. IgG titres were lower in autoimmune diabetes than Fulminant type and controls ( p =0.014 and 0.019, respectively). Conclusions/interpretation High titres of enterovirus IgA antibodies in serum suggest recurrent enterovirus infection in Fulminant type-1 diabetic patients, indicating higher susceptibility to enteroviral infections among them. Such infections might have pathogenetic importance in the triggering of Fulminant type-1 diabetes.
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Fulminant Type 1 Diabetes: A nationwide survey in Japan
Diabetes care, 2003Co-Authors: Akihisa Imagawa, Toshiaki Hanafusa, Tetsuro Kobayashi, A. Kanatsuka, Yasuko Uchigata, Ikki Shimizu, Eiji Kawasaki, Akira Shimada, Tetsuya Toyoda, Taro MaruyamaAbstract:OBJECTIVE — To describe the clinical and immunologic characteristics of Fulminant type 1 diabetes, a novel subtype of type 1 diabetes, we conducted a nationwide survey. RESEARCH DESIGN AND METHODS —History and laboratory data, including islet-related autoantibodies, were examined in 222 patients with Fulminant and nonFulminant type 1 diabetes in our hospitals in addition to another 118 patients with Fulminant type 1 diabetes located outside our hospitals in Japan. RESULTS —In our hospitals, of the 222 patients studied, 43 (19.4%) were diagnosed with Fulminant type 1 diabetes, 137 (61.7%) were classified as having autoimmune type 1 diabetes, and 42 were type 1 diabetic subjects who were not Fulminant and did not have anti-islet antibodies. An additional 118 Fulminant patients outside our hospitals were enrolled, making a total of 161 Fulminant type 1 diabetic subjects (83 male and 78 female subjects; 14 children/adolescents and 147 adults) identified from all over Japan. (In 2000, the average incidence was three cases per month.) Flu-like symptoms and pregnancy were more frequently observed in the Fulminant than in the autoimmune group ( P CONCLUSIONS —Fulminant type 1 diabetes is a distinct subtype and accounts for ∼20% of the ketosis-onset type 1 diabetes cases in Japan. Flu-like symptoms are characteristic of disease onset. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes.
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Association of Fulminant type 1 diabetes with pregnancy
Diabetes research and clinical practice, 2003Co-Authors: Ikki Shimizu, Akihisa Imagawa, Toshiaki Hanafusa, Hideichi Makino, Haruhiko Osawa, E. Kounoue, Eiji Kawasaki, Yasuhisa FujiiAbstract:Abstract It has been reported that Fulminant type 1 diabetes is a novel subtype of type 1B diabetes. However, whether the etiology of Fulminant type 1 diabetes is associated with an autoimmune or nonautoimmune process remains to be solved. In order to further characterize Fulminant type 1 diabetes, we compared the clinical, immunological and genetic characteristics with those of acute-onset type 1A diabetes. Nine patients with Fulminant diabetes and nine patients with acute-onset type 1A diabetes, who had been newly diagnosed during 1998–2001, were analyzed. In female patients of child-bearing age, the onset of diabetes occurred during pregnancy or after delivery in three cases of six Fulminant cases, but not in any of seven type 1A diabetes. Eight of nine Fulminant patients had fever immediately prior to the onset of hyperglycemic symptoms, whereas only one of nine type 1A patients had this ( P =0.002). In Japanese type 1 susceptible HLA haplotypes, DRB1*0901-DQB1*0303 was more frequent in type 1A diabetes than Fulminant diabetes (7/18 vs. 0/18, P =0.004), whereas the frequency of DRB1*0405-DQB1*0401 was similar (type 1A 4/18 vs. Fulminant 6/18). Therefore, pregnancy, possible viral infection, or HLADRB1*0405-DQB1*0401 may contribute to the onset of Fulminant type 1 diabetes.
Toshiaki Hanafusa - One of the best experts on this subject based on the ideXlab platform.
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Pathogenesis of Fulminant type 1 diabetes: Genes, viruses and the immune mechanism, and usefulness of patient-derived induced pluripotent stem cells for future research.
Journal of Diabetes Investigation, 2019Co-Authors: Yoshiya Hosokawa, Toshiaki Hanafusa, Akihisa ImagawaAbstract:: We reviewed Fulminant type 1 diabetes, a recently established subtype of type 1 diabetes, from the aspects of genes, viruses, immune mechanism and usefulness of patient-derived induced pluripotent stem cells (iPSCs). In an analysis of the pancreas of patients with Fulminant type 1 diabetes, viral antigens and viral receptors were expressed in β-cells, as well as macrophages and T lymphocytes surrounding the β-cells. These findings suggest that the β-cells of patients with Fulminant type 1 diabetes are destroyed during an immune response against viral infection of the pancreas. Recently, Fulminant type 1 diabetes was induced by treatment with anti-programmed cell death 1 antibodies, suggesting that immune regulatory mechanisms are also involved in the onset of this disease. We generated iPSCs from patients with Fulminant type 1 diabetes for the first time. We also successfully differentiated patient-derived iPSCs into insulin-producing cells in vitro, and produced a disease model. The proportion of cytokine-induced apoptotic cells among insulin-positive cells was higher in the iPSCs from patients with Fulminant type 1 diabetes than in iPSCs from healthy control participants. We carried out ribonucleic acid sequencing in insulin-producing cells differentiated from patient-derived iPSCs, and are now attempting to identify new biomarkers for the disease.
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class ii hla genotype in Fulminant type 1 diabetes a nationwide survey with reference to glutamic acid decarboxylase antibodies
Journal of Diabetes Investigation, 2012Co-Authors: Chiharu Tsutsumi, Akihisa Imagawa, Hiroshi Ikegami, Hideichi Makino, Tetsuro Kobayashi, Toshiaki HanafusaAbstract:Aims/Introduction: Fulminant type 1 diabetes is a subtype of type 1 diabetes characterized by a remarkably abrupt onset of insulin‐deficient hyperglycemia within a few days. The aim of the present study was to clarify characteristic class II HLA genotypes in a large number of patients with Fulminant type 1 diabetes to date. Materials and Methods: We analyzed the HLA‐DRB1 and DQB1 genotypes, and their haplotypes in 207 patients with Fulminant type 1 diabetes and 325 control subjects in the Japanese population. Results: The frequencies of the DRB1*04:05‐DQB1*04:01 and DRB1*09:01‐DQB1*03:03 haplotypes were significantly higher, and those of the DRB1*01:01‐DQB1*05:01, DRB1*15:02‐DQB1*06:01 and DRB1*08:03‐DQB1*06:01 haplotypes were significantly lower in patients with Fulminant type 1 diabetes than in the control subjects. Combination analysis showed that the frequencies of homozygotes with DRB1*04:05‐DQB1*04:01 [odds ratio (OR) 7.0] and DRB1*09:01‐DQB1*03:03 (OR 9.5) were significantly higher in patients with Fulminant type 1 diabetes. Within a limited portion of patients with Fulminant type 1 diabetes with antibodies to glutamic acid decarboxylase (GADab; n = 25), the frequency of DRB1*09:01‐DQB1*03:03, but not DRB1*04:05‐DQB1*04:01, was significantly higher than in control subjects (44.0% vs 13.7%; Pc < 0.05, OR 5.0). [Correction to last line of Results, added after online publication 29 July 2011: “OR 5.1” is changed to “OR 5.0”.] Conclusions: Our large‐scale study showed the characteristic class II HLA genotypes in Fulminant type 1 diabetes, and implicated that genetic contribution to disease susceptibility is distinct between GADab‐positive and GADab‐negative Fulminant type 1 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00139.x, 2012)
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Fulminant Type 1 Diabetes: A nationwide survey in Japan
Diabetes care, 2003Co-Authors: Akihisa Imagawa, Toshiaki Hanafusa, Tetsuro Kobayashi, A. Kanatsuka, Yasuko Uchigata, Ikki Shimizu, Eiji Kawasaki, Akira Shimada, Tetsuya Toyoda, Taro MaruyamaAbstract:OBJECTIVE — To describe the clinical and immunologic characteristics of Fulminant type 1 diabetes, a novel subtype of type 1 diabetes, we conducted a nationwide survey. RESEARCH DESIGN AND METHODS —History and laboratory data, including islet-related autoantibodies, were examined in 222 patients with Fulminant and nonFulminant type 1 diabetes in our hospitals in addition to another 118 patients with Fulminant type 1 diabetes located outside our hospitals in Japan. RESULTS —In our hospitals, of the 222 patients studied, 43 (19.4%) were diagnosed with Fulminant type 1 diabetes, 137 (61.7%) were classified as having autoimmune type 1 diabetes, and 42 were type 1 diabetic subjects who were not Fulminant and did not have anti-islet antibodies. An additional 118 Fulminant patients outside our hospitals were enrolled, making a total of 161 Fulminant type 1 diabetic subjects (83 male and 78 female subjects; 14 children/adolescents and 147 adults) identified from all over Japan. (In 2000, the average incidence was three cases per month.) Flu-like symptoms and pregnancy were more frequently observed in the Fulminant than in the autoimmune group ( P CONCLUSIONS —Fulminant type 1 diabetes is a distinct subtype and accounts for ∼20% of the ketosis-onset type 1 diabetes cases in Japan. Flu-like symptoms are characteristic of disease onset. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes.
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Association of Fulminant type 1 diabetes with pregnancy
Diabetes research and clinical practice, 2003Co-Authors: Ikki Shimizu, Akihisa Imagawa, Toshiaki Hanafusa, Hideichi Makino, Haruhiko Osawa, E. Kounoue, Eiji Kawasaki, Yasuhisa FujiiAbstract:Abstract It has been reported that Fulminant type 1 diabetes is a novel subtype of type 1B diabetes. However, whether the etiology of Fulminant type 1 diabetes is associated with an autoimmune or nonautoimmune process remains to be solved. In order to further characterize Fulminant type 1 diabetes, we compared the clinical, immunological and genetic characteristics with those of acute-onset type 1A diabetes. Nine patients with Fulminant diabetes and nine patients with acute-onset type 1A diabetes, who had been newly diagnosed during 1998–2001, were analyzed. In female patients of child-bearing age, the onset of diabetes occurred during pregnancy or after delivery in three cases of six Fulminant cases, but not in any of seven type 1A diabetes. Eight of nine Fulminant patients had fever immediately prior to the onset of hyperglycemic symptoms, whereas only one of nine type 1A patients had this ( P =0.002). In Japanese type 1 susceptible HLA haplotypes, DRB1*0901-DQB1*0303 was more frequent in type 1A diabetes than Fulminant diabetes (7/18 vs. 0/18, P =0.004), whereas the frequency of DRB1*0405-DQB1*0401 was similar (type 1A 4/18 vs. Fulminant 6/18). Therefore, pregnancy, possible viral infection, or HLADRB1*0405-DQB1*0401 may contribute to the onset of Fulminant type 1 diabetes.
Robin D Hughes - One of the best experts on this subject based on the ideXlab platform.
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Plasma Inhibitory Activity against Tumour Necrosis Factor in Fulminant Hepatic Failure
Clinical Science, 1996Co-Authors: Helen M. Keane, Nick Sheron, J. Goka, Robin D Hughes, Roger WilliamsAbstract:1. Soluble tumour necrosis factor receptors released into the circulation inhibit the effects of excess tumour necrosis factor-alpha and represent an important protective response. 2. In this study we have measured the levels of tumour necrosis factor and soluble tumour necrosis factor receptors p55 and p75 in the plasma of 10 patients with Fulminant hepatic failure and 10 healthy control subjects. The capacity of the plasmas at varying dilutions to inhibit the biological activity of 1000 pg/ml of recombinant tumour necrosis factor in a tumour necrosis factor cytotoxicity assay in vitro was also determined. 3. The mean plasma levels of tumour necrosis factor in patients with Fulminant hepatic failure (48.4 +/- 10.9 pg/ml) were significantly increased compared with normal control subjects (6.1 +/- 1.04 pg/ml, P < 0.01). Plasma soluble tumour necrosis factor receptors p55 and p75 were also significantly elevated in patients with Fulminant hepatic failure (18.16 +/- 9.94 ng/ml and 16.06 +/- 9.93 ng/ml respectively) when compared with normal control subjects (1.28 +/- 0.24 ng/ml and 1.62 +/- 0.91 ng/ml, P < 0.001). 4. Fulminant hepatic failure plasma had a much lower capacity to inhibit tumour necrosis factor bioactivity in vitro, with a statistically significant difference between the inhibitory capacity of the Fulminant hepatic failure and normal plasma seen at plasma dilutions of 1:5 and 1:20 (P < 0.05). 5. The reduced tumour necrosis factor neutralization capacity observed in Fulminant hepatic failure, despite the increased levels of soluble tumour necrosis factor receptors, suggests enhanced susceptibility to the potential deleterious effects of tumour necrosis factor in Fulminant hepatic failure.
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Inhibitors of hepatic DNA synthesis in Fulminant hepatic failure
Digestive Diseases and Sciences, 1991Co-Authors: Robin D Hughes, C. D. Gove, Haruki Yamada, Roger WilliamsAbstract:In certain etiological groups of patients with Fulminant hepatic failure, poor survival may be due to lack of liver regeneration.In vitro experiments have shown that Fulminant hepatic failure serum is cytotoxic to rabbit hepatocytes and inhibits DNA synthesis on short-term incubation with isolated regenerating rat hepatocytes. When Fulminant hepatic failure serum is injected into partially hepatectomized rats at the time of maximal DNA synthesis, [3H]thymidine incorporation into hepatic DNA is reduced significantly. The effect is greater with sera obtained from patients with Fulminant hepatic failure due to non-A, non-B hepatitis or an adverse drug reaction and is associated with a 10,000-dalton serum fraction into normal rats. In preliminary experiments, no increase in epidermal growth factor production has been found in liver failure. Overall, the substances present in Fulminant hepatic failure serum appear to be inhibitory rather than stimulatory for liver cell regeneration.
H Makino - One of the best experts on this subject based on the ideXlab platform.
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High titres of IgA antibodies to enterovirus in Fulminant type-1 diabetes
Diabetologia, 2005Co-Authors: Akihisa Imagawa, Tadashi Hanafusa, J.-i. Miyagawa, H Makino, P. JutoAbstract:Aims/hypothesis We have recently proposed that Fulminant type-1 diabetes is a novel subtype of type-1 diabetes with abrupt onset of insulin-deficient hyperglycaemia without islet-related autoantibodies. The pathogenesis is still unknown, but flu-like symptoms are frequently observed before the onset of disease of this subtype. Enterovirus infection is a candidate environmental factor causing type-1 diabetes. The aim of this study was to determine whether enterovirus infection contributes to the development of Fulminant type-1 diabetes. Methods We investigated 19 patients with recent-onset Fulminant type-1 diabetes, 18 patients with recent-onset typical type-1A diabetes, and 19 healthy controls. IgM, IgG, and IgA subclasses of antibodies to enterovirus were determined by ELISA. Results IgA antibody titres to enterovirus were significantly higher in Fulminant type-1 diabetes than in typical type-1A diabetes ( p =0.033) and controls ( p =0.0003). IgM antibodies to enterovirus were not detected in any subject. IgG titres were lower in autoimmune diabetes than Fulminant type and controls ( p =0.014 and 0.019, respectively). Conclusions/interpretation High titres of enterovirus IgA antibodies in serum suggest recurrent enterovirus infection in Fulminant type-1 diabetic patients, indicating higher susceptibility to enteroviral infections among them. Such infections might have pathogenetic importance in the triggering of Fulminant type-1 diabetes.
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Different contribution of class II HLA in Fulminant and typical autoimmune type 1 diabetes mellitus
Diabetologia, 2005Co-Authors: A. Imagawa, Tetsuro Kobayashi, T. Hanafusa, Y. Uchigata, A. Kanatsuka, E. Kawasaki, A. Shimada, I. Shimizu, T. Maruyama, H MakinoAbstract:Aims/hypothesis Fulminant type 1 diabetes, which is characterised by a markedly acute onset of diabetes and an absence of islet-related autoantibodies, accounts for 20% of type 1 diabetes in Japan. We aimed to clarify the contribution of the HLA subtype to Fulminant type 1 diabetes in Japanese. Methods We determined the serological subtypes of HLA-A, -DR and -DQ in 115 patients with Fulminant type 1 diabetes, 98 patients with typical type 1A diabetes and 190 normal control subjects. Results The frequency of HLA-DR4, but not DR9, was significantly higher in Fulminant type 1 diabetes, while those of HLA-DR1, DR2, DR5 and DR8 were significantly lower than those in controls. In contrast, DR9 but not DR4 was more frequent and DR2 was extremely rare in typical type 1A diabetes. Haplotype analysis revealed that DR4-DQ4 was significantly more frequent, and both DR2-DQ1 and DR8-DQ1 were less frequent in Fulminant diabetes. In type 1A diabetes, DR2-DQ1 was extremely rare while DR9-DQ3 was significantly more frequent. In the combination analysis, the homozygotes of DR4-DQ4 in Fulminant type 1 diabetes and DR9-DQ3 in typical type 1A diabetes indicated high odds ratios (13.3 and 13.3, respectively). Conclusions/interpretation Our results suggest that class II HLA contributes to the development of Fulminant type 1 diabetes. Susceptibility and resistance of the HLA subtype to type 1 diabetes are distinct between Fulminant and typical autoimmune type 1 diabetes.
