Pauline Faucher1,2, Frédéric Beuvon3, Daniela Fignani4,5, Guido Sebastiani4,5, Georgia Afonso1, Zhicheng Zhou1, Bertrand Dousset6, Christian Boitard1,2, Francesco Dotta4,5, Roberto Mallone1,2, Etienne Larger7,8. 1. Institut Cochin, CNRS, Inserm, Université de Paris, Paris, France. 2. Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Paris, France. 3. Service d'Anatomie Pathologique Publique, Cochin Hospital, Assistance Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Paris, France. 4. Department of Medicine, Surgery and Neurosciences, Diabetes Unit, University of Siena, Siena, Italy. 5. Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy. 6. Service de Chirurgie Digestive Publique, Cochin Hospital, Assistance Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Paris, France. 7. Institut Cochin, CNRS, Inserm, Université de Paris, Paris, France. etienne.larger@aphp.fr. 8. Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Paris, France. etienne.larger@aphp.fr.
Abstract
AIMS/HYPOTHESIS: We report the case of a woman who underwent a partial pancreatectomy for a serous cystadenoma when aged 56 years. She had been diagnosed with diabetes 6 years before and had Hashimoto's thyroiditis. Despite positive anti-GAD autoantibodies (GADA) and previous surgery, she was transiently weaned off long-acting insulin. Blood glucose levels remained well controlled with low-dose long-acting insulin. Insulin needs eventually increased 8 years after surgery, in conjunction with anti-zinc transporter 8 (ZnT8) seroconversion and decreasing residual C-peptide. We hypothesised that the surgical pancreas specimens and blood autoimmune T cell responses may provide correlates of this indolent clinical course. METHODS: Beta and alpha cell area and insulitis were quantified on pancreas head tissue sections obtained at surgery. Blood T cell responses against beta cell antigens were analysed by enzyme-linked immunospot. RESULTS: Pancreas sections displayed reduced beta cell and normal alpha cell area (0.27% and 0.85% of section area, respectively). High-grade insulitis was observed, mostly in insulin-containing islets, with a peri-insulitis pattern enriched in T cells positive for regulatory forkhead box protein 3 (FOXP3). In vitro challenge with beta cell antigens of circulating T cells collected 4 and 9 years after surgery revealed dominant and persistent IL-10 responses; IFN-γ responses increasing at 9 years, after anti-ZnT8 seroconversion, was observed. CONCLUSIONS/ INTERPRETATION: Despite persistent GADA and the histopathological finding of insulitis and decreased beta cell area 6 years after diabetes diagnosis, glycaemic control was maintained with low-dose insulin up to 8 years after surgery. Regulated T cell responses towards beta cell antigens and FOXP3-positive peri-insulitis suggest spontaneous long-term regulation of islet autoimmunity after substantial beta cell loss, and eventual autoimmune progression upon anti-ZnT8 seroconversion.
AIMS/HYPOTHESIS: We report the case of a woman who underwent a partial pancreatectomy for a serous cystadenoma when aged 56 years. She had been diagnosed with diabetes 6 years before and had Hashimoto's thyroiditis. Despite positive anti-GAD autoantibodies (GADA) and previous surgery, she was transiently weaned off long-acting insulin. Blood glucose levels remained well controlled with low-dose long-acting insulin. Insulin needs eventually increased 8 years after surgery, in conjunction with anti-zinc transporter 8 (ZnT8) seroconversion and decreasing residual C-peptide. We hypothesised that the surgical pancreas specimens and blood autoimmune T cell responses may provide correlates of this indolent clinical course. METHODS: Beta and alpha cell area and insulitis were quantified on pancreas head tissue sections obtained at surgery. Blood T cell responses against beta cell antigens were analysed by enzyme-linked immunospot. RESULTS: Pancreas sections displayed reduced beta cell and normal alpha cell area (0.27% and 0.85% of section area, respectively). High-grade insulitis was observed, mostly in insulin-containing islets, with a peri-insulitis pattern enriched in T cells positive for regulatory forkhead box protein 3 (FOXP3). In vitro challenge with beta cell antigens of circulating T cells collected 4 and 9 years after surgery revealed dominant and persistent IL-10 responses; IFN-γ responses increasing at 9 years, after anti-ZnT8 seroconversion, was observed. CONCLUSIONS/ INTERPRETATION: Despite persistent GADA and the histopathological finding of insulitis and decreased beta cell area 6 years after diabetes diagnosis, glycaemic control was maintained with low-dose insulin up to 8 years after surgery. Regulated T cell responses towards beta cell antigens and FOXP3-positive peri-insulitis suggest spontaneous long-term regulation of islet autoimmunity after substantial beta cell loss, and eventual autoimmune progression upon anti-ZnT8 seroconversion.
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