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2. Research Independence in Academia—'The holy grail' and beyond.

Author

Nasteska, Daniela and Leete, Pia

Subjects
*PROFESSIONAL autonomy, *TEAMS in the workplace, *PSYCHOLOGICAL resilience, *LEADERSHIP, *AUTHORSHIP, *MENTORING, *MEDICAL research, *ENDOWMENT of research, *ABILITY, *PUBLISHING, *TRUST, *SOCIAL networks, *DIABETES, *VOCATIONAL guidance, *TRAINING
Abstract

The article focuses on the career trajectories of early career researchers appointed as editors at Diabetic Medicine, emphasizing their research on islet protein dynamics in Type 2 diabetes and pancreatic β-cell loss in Type 1 diabetes. Topics include the challenges and privileges of transitioning to independent research roles, the complexities of building a research identity, and the cultural differences in approaches to research independence between Western and Eastern societies.

Published
2024
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5. Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans

Author

Hanna, Stephanie J., primary, Thayer, Terri C., additional, Robinson, Emma J. S., additional, Vinh, Ngoc-Nga, additional, Williams, Nigel, additional, Landry, Laurie G., additional, Andrews, Robert, additional, Siah, Qi Zhuang, additional, Leete, Pia, additional, Wyatt, Rebecca, additional, McAteer, Martina A., additional, Nakayama, Maki, additional, Wong, F. Susan, additional, Yang, Jennie H. M., additional, Tree, Timothy I. M., additional, Ludvigsson, Johnny, additional, Dayan, Colin M., additional, and Tatovic, Danijela, additional

Published
2023
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7. Differential expression of genes controlling lymphocyte differentiation and migration in two distinct endotypes of type 1 diabetes

Author

Torabi, Forough, primary, Vadakekolathu, Jayakumar, additional, Wyatt, Rebecca, additional, Leete, Pia, additional, Tombs, Melissa A., additional, Richardson, Carolyn C., additional, Boocock, David J., additional, Turner, Mark D., additional, Morgan, Noel G., additional, Richardson, Sarah J., additional, and Christie, Michael R., additional

Published
2023
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8. Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans

Author

Hanna, Stephanie J., Thayer, Terri C., Robinson, Emma J. S., Vinh, Ngoc-Nga, Williams, Nigel, Landry, Laurie G., Andrews, Robert, Siah, Qi Zhuang, Leete, Pia, Wyatt, Rebecca, Mcateer, Martina A., Nakayama, Maki, Wong, F. Susan, Yang, Jennie H. M., Tree, Timothy I. M., Ludvigsson, Johnny, Dayan, Colin M., Tatovic, Danijela, Hanna, Stephanie J., Thayer, Terri C., Robinson, Emma J. S., Vinh, Ngoc-Nga, Williams, Nigel, Landry, Laurie G., Andrews, Robert, Siah, Qi Zhuang, Leete, Pia, Wyatt, Rebecca, Mcateer, Martina A., Nakayama, Maki, Wong, F. Susan, Yang, Jennie H. M., Tree, Timothy I. M., Ludvigsson, Johnny, Dayan, Colin M., and Tatovic, Danijela

Abstract

Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans., Funding Agencies|European Commission under the Health Cooperation Work Programme of the 7th Framework Programme [305305]

Published
2023
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12. Detection of Antiviral Tissue Responses and Increased Cell Stress in the Pancreatic Islets of Newly Diagnosed Type 1 Diabetes Patients: Results From the DiViD Study

Author

Krogvold, Lars, primary, Leete, Pia, additional, Mynarek, Ida M., additional, Russell, Mark A., additional, Gerling, Ivan C., additional, Lenchik, Nataliya I., additional, Mathews, Clayton, additional, Richardson, Sarah J., additional, Morgan, Noel G., additional, and Dahl-Jørgensen, Knut, additional

Published
2022
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14. Circulating C-Peptide Levels in Living Children and Young People and Pancreatic β-Cell Loss in Pancreas Donors Across Type 1 Diabetes Disease Duration

Author

Carr, Alice L.J., primary, Inshaw, Jamie R.J., additional, Flaxman, Christine S., additional, Leete, Pia, additional, Wyatt, Rebecca C., additional, Russell, Lydia A., additional, Palmer, Matthew, additional, Prasolov, Dmytro, additional, Worthington, Thomas, additional, Hull, Bethany, additional, Wicker, Linda S., additional, Dunger, David B., additional, Oram, Richard A., additional, Morgan, Noel G., additional, Todd, John A., additional, Richardson, Sarah J., additional, and Besser, Rachel E.J., additional

Published
2022
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15. Circulating C-Peptide Levels in Living Children and Young People and Pancreatic Beta Cell Loss in Pancreas Donors Across Type 1 Diabetes Disease Duration

Author

Carr, Alice L.J., primary, Inshaw, Jamie R.J., primary, Flaxman, Christine S., primary, Leete, Pia, primary, Wyatt, Rebecca C., primary, Russell, Lydia A., primary, Palmer, Matthew, primary, Prasolov, Dmytro, primary, Worthington, Thomas, primary, Hull, Bethany, primary, Wicker, Linda S., primary, Dunger, David B., primary, Oram, Richard A., primary, Morgan, Noel G., primary, Todd, John A., primary, Richardson, Sarah J., primary, and Besser, Rachel E.J., primary

Published
2022
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16. Evaluation of the fidelity of immunolabelling obtained with clone 5D8/1, a monoclonal antibody directed against the enteroviral capsid protein, VP1, in human pancreas

Author

Richardson, Sarah J., Leete, Pia, Dhayal, Shalinee, Russell, Mark A., Oikarinen, Maarit, Laiho, Jutta E., Svedin, Emma, Lind, Katharina, Rosenling, Therese, Chapman, Nora, Bone, Adrian J., Foulis, Alan K., Frisk, Gun, Flodstrom-Tullberg, Malin, Hober, Didier, Hyoty, Heikki, Morgan, Noel G., and The nPOD-V Consortium

Published
2014
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17. Detection of a Low-Grade Enteroviral Infection in the Islets of Langerhans of Living Patients Newly Diagnosed With Type 1 Diabetes

Author

Krogvold, Lars, Edwin, Bjørn, Buanes, Trond, Frisk, Gun, Skog, Oskar, Anagandula, Mahesh, Korsgren, Olle, Undlien, Dag, Eike, Morten C., Richardson, Sarah J., Leete, Pia, Morgan, Noel G., Oikarinen, Sami, Oikarinen, Maarit, Laiho, Jutta E., Hyöty, Heikki, Ludvigsson, Johnny, Hanssen, Kristian F., and Dahl-Jørgensen, Knut

Published
2015
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18. Detection of enterovirus in the islet cells of patients with type 1 diabetes: what do we learn from immunohistochemistry? Reply to Hansson SF, Korsgren S, Pontén F et al [letter]

Author

Richardson, Sarah J., Leete, Pia, Dhayal, Shalinee, Russell, Mark A., Oikarinen, Maarit, Laiho, Jutta E., Svedin, Emma, Lind, Katharina, Rosenling, Therese, Chapman, Nora, Bone, Adrian J., Foulis, Alan K., Frisk, Gun, Flodström-Tullberg, Malin, Hober, Didier, Hyoty, Heikki, Pugliese, Alberto, and Morgan, Noel G.

Published
2014
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20. Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes

Author

Rodriguez-Calvo, Teresa, primary, Chen, Yi-Chun, additional, Verchere, C. Bruce, additional, Haataja, Leena, additional, Arvan, Peter, additional, Leete, Pia, additional, Richardson, Sarah J., additional, Morgan, Noel G., additional, Qian, Wei-Jun, additional, Pugliese, Alberto, additional, Atkinson, Mark, additional, Evans-Molina, Carmella, additional, and Sims, Emily K., additional

Published
2021
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23. HLA Class II Antigen Processing and Presentation Pathway Components Demonstrated by Transcriptome and Protein Analyses of Islet β-Cells From Donors With Type 1 Diabetes

Author

Russell, Mark A., primary, Redick, Sambra D., additional, Blodgett, David M., additional, Richardson, Sarah J., additional, Leete, Pia, additional, Krogvold, Lars, additional, Dahl-Jørgensen, Knut, additional, Bottino, Rita, additional, Brissova, Marcela, additional, Spaeth, Jason M., additional, Babon, Jenny Aurielle B., additional, Haliyur, Rachana, additional, Powers, Alvin C., additional, Yang, Chaoxing, additional, Kent, Sally C., additional, Derr, Alan G., additional, Kucukural, Alper, additional, Garber, Manuel G., additional, Morgan, Noel G., additional, and Harlan, David M., additional

Published
2019
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24. Coxsackie-adenovirus receptor expression is enhanced in pancreas from patients with type 1 diabetes

Author

Hodik, M., Anagandula, M., Fuxe, J., Krogvold, L., Dahl Jørgensen, K., Hyã¶ty, H., Sarmiento, L., Frisk, G, Atkinson, Mark, Pugliese, Alberto, Campbell Thompson, Martha, Kaddis, John, Kusmartseva, Irina, Yang, Mingder, Clare Salzler, Michael, Chapman, Nora, Tracy, Steven, Smithee, Shane, Alhazmi, Abdulaziz, Frisk, Gun, Anagandula, Mahesh, Sarimiento, Luis, Giepmans, Ben, Kalicharan, Ruby, Kuipers, Jeroen, Wolters, Anouk, Jelmer, Willems, Morgan, Noel, Richardson, Sarah, Dyahal, Shalinee, Russell, Mark, Leete, Pia, Nadler, Jerry, Morris, Margaret, Nyalwidhe, Julius, Burch, Tayna, von Herrath, Matthias, Rodriguez Calvo, Teresa, Sabouri, Somayeh, Anquetil Besnard, Florence, Plagnol, Vincent, Breuer, Judith, Depledge, Daniel, Dotta, Francesco, Sebastiani, Guido, Patti, Aurora, Nigi, Laura, Ventriglia, Giuliana, Mancarella, Francesca, Gerling, Ivan, Kakoola, Dorothy, Lenchik, Nataliya, Hyã¶ty, Heikki, Laiho, Jutta, Oikarnen, Maarit, Eizirik, Decio, Opdebeeck, Anne, Lloyd, Richard, Petrosino, Joseph, Homann, Dirk, Kent, Sally, Sarkar, Suparna, Toniolo, Antonio, Gianani, Roberto, Horwitz, Marc, Marjomaki, Varpu, Flodström Tullberg, Malin, Domsgen, Erna, Larsson, Pã¤r, PIEMONTI, LORENZO, Hodik, M., Anagandula, M., Fuxe, J., Krogvold, L., Dahl Jørgensen, K., Hyã¶ty, H., Sarmiento, L., Frisk, G, Atkinson, Mark, Pugliese, Alberto, Campbell Thompson, Martha, Kaddis, John, Kusmartseva, Irina, Yang, Mingder, Clare Salzler, Michael, Chapman, Nora, Tracy, Steven, Smithee, Shane, Alhazmi, Abdulaziz, Frisk, Gun, Anagandula, Mahesh, Sarimiento, Lui, Giepmans, Ben, Kalicharan, Ruby, Kuipers, Jeroen, Wolters, Anouk, Jelmer, Willem, Morgan, Noel, Richardson, Sarah, Dyahal, Shalinee, Russell, Mark, Leete, Pia, Nadler, Jerry, Morris, Margaret, Nyalwidhe, Juliu, Burch, Tayna, von Herrath, Matthia, Rodriguez Calvo, Teresa, Sabouri, Somayeh, Anquetil Besnard, Florence, Plagnol, Vincent, Breuer, Judith, Depledge, Daniel, Dotta, Francesco, Sebastiani, Guido, Patti, Aurora, Nigi, Laura, Ventriglia, Giuliana, Mancarella, Francesca, Gerling, Ivan, Kakoola, Dorothy, Lenchik, Nataliya, Hyã¶ty, Heikki, Laiho, Jutta, Oikarnen, Maarit, Eizirik, Decio, Opdebeeck, Anne, Lloyd, Richard, Petrosino, Joseph, Homann, Dirk, Kent, Sally, Sarkar, Suparna, Toniolo, Antonio, Gianani, Roberto, Piemonti, Lorenzo, Horwitz, Marc, Marjomaki, Varpu, Flodström Tullberg, Malin, Domsgen, Erna, and Larsson, Pã¤r

Subjects
0301 basic medicine, medicine.medical_specialty, Chemokine, endocrine system, Receptor(s), endocrine system diseases, Endocrinology, Diabetes and Metabolism, Endocrinology and Diabetes, Proinflammatory cytokine, 03 medical and health sciences, Internal medicine, medicine, Receptor, Islet of Langerhans, geography, geography.geographical_feature_category, Islet of Langerhan, Type 1, Virus, biology, business.industry, Viru, Pancreatic islets, Islet, Reverse transcription polymerase chain reaction, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Islet Studies, Endokrinologi och diabetes, biology.protein, Immunohistochemistry, Pancreas, business
Abstract

Objectives: One of the theories connecting enterovirus (EV) infection of human islets with type 1 diabetes (T1D) is the development of a fertile field in the islets. This implies induction of appropriate proteins for the viral replication such as the coxsackie-adenovirus receptor (CAR). The aim of this study was to investigate to what extent CAR is expressed in human islets of Langerhans, and what conditions that would change the expression. Design: Immunohistochemistry for CAR was performed on paraffin-embedded pancreatic tissue from patients with T1D (n=9 recent onset T1D, n=4 long-standing T1D), islet autoantibody-positive individuals (n=14) and non-diabetic controls (n=24) individuals. The expression of CAR was also examined by reverse transcription PCR on microdissected islets (n=5), exocrine tissue (n=5) and on explanted islets infected with EV or exposed to chemokines produced by EV-infected islet cells. Results: An increased frequency of patients with T1D and autoantibody-positive individuals expressed CAR in the pancreas (p

Published
2016

25. PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-alpha and-gamma via IRF1 induction.

Author

Colli, Maikel Luis, Hill, Jessica L E, Marroquí, Laura, Chaffey, Jessica, Dos Santos, Reinaldo Sousa, Leete, Pia, Coomans De Brachene, Alexandra, Paula, Flavia M M, Op De Beeck, Anne, Castela, Angela, Marselli, Lorella, Krogvold, Lars, Dahl-Jorgensen, Knut, Marchetti, Piero, Morgan, Noel G, Richardson, Sarah J, Eizirik, Decio L., Colli, Maikel Luis, Hill, Jessica L E, Marroquí, Laura, Chaffey, Jessica, Dos Santos, Reinaldo Sousa, Leete, Pia, Coomans De Brachene, Alexandra, Paula, Flavia M M, Op De Beeck, Anne, Castela, Angela, Marselli, Lorella, Krogvold, Lars, Dahl-Jorgensen, Knut, Marchetti, Piero, Morgan, Noel G, Richardson, Sarah J, and Eizirik, Decio L.

Abstract

Antibodies targeting PD-1 and its ligand PDL1 are used in cancer immunotherapy but may lead to autoimmune diseases, including type 1 diabetes (T1D). It remains unclear whether PDL1 is expressed in pancreatic islets of people with T1D and how is it regulated., “Innovative Medicines Initiative 2”;“European Union(EU)”“Horizon2020”; and EFPIA”,“JDRF International” and The Leona M.and Harry B.Helmsley Charitable Trust”, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

26. Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis.

Author

Leete, Pia, Oram, Richard A., McDonald, Timothy J., Shields, Beverley M., Ziller, Clemens, TIGI study team, Roep, Bart O., Tree, Timothy I., Patel, Kashyap, Hammersley, Suzy, Bolt, Robert, Hill, Anita V., Hattersley, Andrew T., Richardson, Sarah J., and Morgan, Noel G.

Abstract

Aims/hypothesis: It is unclear whether type 1 diabetes is a single disease or if endotypes exist. Our aim was to use a unique collection of pancreas samples recovered soon after disease onset to resolve this issue. Methods: Immunohistological analysis was used to determine the distribution of proinsulin and insulin in the islets of pancreas samples recovered soon after type 1 diabetes onset (<2 years) from young people diagnosed at age <7 years, 7–12 years and ≥13 years. The patterns were correlated with the insulitis profiles in the inflamed islets of the same groups of individuals. C-peptide levels and the proinsulin:C-peptide ratio were measured in the circulation of a cohort of living patients with longer duration of disease but who were diagnosed in these same age ranges. Results: Distinct patterns of proinsulin localisation were seen in the islets of people with recent-onset type 1 diabetes, which differed markedly between children diagnosed at <7 years and those diagnosed at ≥13 years. Proinsulin processing was aberrant in most residual insulin-containing islets of the younger group but this was much less evident in the group ≥13 years (p < 0.0001). Among all individuals (including children in the middle [7–12 years] range) aberrant proinsulin processing correlated with the assigned immune cell profiles defined by analysis of the lymphocyte composition of islet infiltrates. C-peptide levels were much lower in individuals diagnosed at <7 years than in those diagnosed at ≥13 years (median <3 pmol/l, IQR <3 to <3 vs 34.5 pmol/l, IQR <3–151; p < 0.0001), while the median proinsulin:C-peptide ratio was increased in those with age of onset <7 years compared with people diagnosed aged ≥13 years (0.18, IQR 0.10–0.31) vs 0.01, IQR 0.009–0.10 pmol/l; p < 0.0001). Conclusions/interpretation: Among those with type 1 diabetes diagnosed under the age of 30 years, there are histologically distinct endotypes that correlate with age at diagnosis. Recognition of such differences should inform the design of future immunotherapeutic interventions designed to arrest disease progression. [ABSTRACT FROM AUTHOR]

Published
2020
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27. PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and-γ via IRF1 induction

Author

Colli, Maikel L., primary, Hill, Jessica L.E., additional, Marroquí, Laura, additional, Chaffey, Jessica, additional, Dos Santos, Reinaldo S., additional, Leete, Pia, additional, Coomans de Brachène, Alexandra, additional, Paula, Flavia M.M., additional, Op de Beeck, Anne, additional, Castela, Angela, additional, Marselli, Lorella, additional, Krogvold, Lars, additional, Dahl-Jorgensen, Knut, additional, Marchetti, Piero, additional, Morgan, Noel G., additional, Richardson, Sarah J., additional, and Eizirik, Décio L., additional

Published
2018
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28. Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes

Author

Vecchio, Federica, primary, Lo Buono, Nicola, additional, Stabilini, Angela, additional, Nigi, Laura, additional, Dufort, Matthew J., additional, Geyer, Susan, additional, Rancoita, Paola Maria, additional, Cugnata, Federica, additional, Mandelli, Alessandra, additional, Valle, Andrea, additional, Leete, Pia, additional, Mancarella, Francesca, additional, Linsley, Peter S., additional, Krogvold, Lars, additional, Herold, Kevan C., additional, Larsson, Helena Elding, additional, Richardson, Sarah J., additional, Morgan, Noel G., additional, Dahl-Jørgensen, Knut, additional, Sebastiani, Guido, additional, Dotta, Francesco, additional, Bosi, Emanuele, additional, and Battaglia, Manuela, additional

Published
2018
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30. C-Peptide Decline in Type 1 Diabetes Has Two Phases: An Initial Exponential Fall and a Subsequent Stable Phase.

Author

Shields, Beverley M., McDonald, Timothy J., Oram, Richard, Hill, Anita, Hudson, Michelle, Leete, Pia, Pearson, Ewan R., Richardson, Sarah J., Morgan, Noel G., Hattersley, Andrew T., and TIGI Consortium

Subjects
TYPE 1 diabetes, C-peptide, TREATMENT of diabetes, CHRONIC diseases, AUTOIMMUNITY, DIAGNOSIS, THERAPEUTICS, BIOCHEMISTRY, BLOOD testing, COMPARATIVE studies, LONGITUDINAL method, PHENOMENOLOGY, RESEARCH methodology, MEDICAL cooperation, RESEARCH, RESEARCH funding, TIME, EVALUATION research, CROSS-sectional method, DISEASE progression
Abstract

Objective: The decline in C-peptide in the 5 years after diagnosis of type 1 diabetes has been well studied, but little is known about the longer-term trajectory. We aimed to examine the association between log-transformed C-peptide levels and the duration of diabetes up to 40 years after diagnosis.Research Design and Methods: We assessed the pattern of association between urinary C-peptide/creatinine ratio (UCPCR) and duration of diabetes in cross-sectional data from 1,549 individuals with type 1 diabetes using nonlinear regression approaches. Findings were replicated in longitudinal follow-up data for both UCPCR (n = 161 individuals, 326 observations) and plasma C-peptide (n = 93 individuals, 473 observations).Results: We identified two clear phases of C-peptide decline: an initial exponential fall over 7 years (47% decrease/year [95% CI -51, -43]) followed by a stable period thereafter (+0.07%/year [-1.3, +1.5]). The two phases had similar durations and slopes in patients above and below the median age at diagnosis (10.8 years), although levels were lower in the younger patients irrespective of duration. Patterns were consistent in both longitudinal UCPCR (n = 162; ≤7 years duration: -48%/year [-55, -38]; >7 years duration -0.1% [-4.1, +3.9]) and plasma C-peptide (n = 93; >7 years duration only: -2.6% [-6.7, +1.5]).Conclusions: These data support two clear phases of C-peptide decline: an initial exponential fall over a 7-year period, followed by a prolonged stabilization where C-peptide levels no longer decline. Understanding the pathophysiological and immunological differences between these two phases will give crucial insights into understanding β-cell survival. [ABSTRACT FROM AUTHOR]

Published
2018
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31. Erratum. Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes. Diabetes 2014;63:3835–3845

Author

Arif, Sefina, primary, Leete, Pia, additional, Nguyen, Vy, additional, Marks, Katherine, additional, Nor, Nurhanani Mohamed, additional, Estorninho, Megan, additional, Kronenberg-Versteeg, Deborah, additional, Bingley, Polly J., additional, Todd, John A., additional, Guy, Catherine, additional, Dunger, David B., additional, Powrie, Jake, additional, Willcox, Abby, additional, Foulis, Alan K., additional, Richardson, Sarah J., additional, de Rinaldis, Emanuele, additional, Morgan, Noel G., additional, Lorenc, Anna, additional, and Peakman, Mark, additional

Published
2015
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32. Detection of a Low-Grade Enteroviral Infection in the Islets of Langerhans of Living Patients Newly Diagnosed With Type 1 Diabetes

Author

Krogvold, Lars, primary, Edwin, Bjørn, additional, Buanes, Trond, additional, Frisk, Gun, additional, Skog, Oskar, additional, Anagandula, Mahesh, additional, Korsgren, Olle, additional, Undlien, Dag, additional, Eike, Morten C., additional, Richardson, Sarah J., additional, Leete, Pia, additional, Morgan, Noel G., additional, Oikarinen, Sami, additional, Oikarinen, Maarit, additional, Laiho, Jutta E., additional, Hyöty, Heikki, additional, Ludvigsson, Johnny, additional, Hanssen, Kristian F., additional, and Dahl-Jørgensen, Knut, additional

Published
2014
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34. Induction of an Antiviral State and Attenuated Coxsackievirus Replication in Type III Interferon-Treated Primary Human Pancreatic Islets

Author

Lind, Katharina, Richardson, Sarah J., Leete, Pia, Morgan, Noel G., Korsgren, Olle, Flodstrom-Tullberg, Malin, Lind, Katharina, Richardson, Sarah J., Leete, Pia, Morgan, Noel G., Korsgren, Olle, and Flodstrom-Tullberg, Malin

Abstract

Type III interferons (IFNs), also called lambda interferons (IFN-lambda), comprise three isoforms, IFN-lambda 1 (interleukin-29 [IL-29]), IFN-lambda 2 (IL-28A), and IFN-lambda 3 (IL-28B). Only limited information is available on their expression and biological functions in humans. Type I and type II IFNs protect human pancreatic islets against coxsackievirus infection, and this is important since such viruses have been proposed to play a role in the development of human type 1 diabetes. Here we investigated whether type III IFN is expressed during infection of human islet cells with coxsackievirus and if type III IFN regulates permissiveness to such infections. We show that human islets respond to a coxsackievirus serotype B3 (CVB3) infection by inducing the expression of type III IFNs. We also demonstrate that islet endocrine cells from nondiabetic individuals express the type III IFN receptor subunits IFN-lambda R1 and IL-10R2. Pancreatic alpha cells express both receptor subunits, while pancreatic beta cells express only IL-10R2. Type III IFN stimulation elicited a biological response in human islets as indicated by the upregulated expression of antiviral genes as well as pattern recognition receptors. We also show that type III IFN significantly reduces CVB3 replication. Our studies reveal that type III IFNs are expressed during CVB3 infection and that the expression of the type III IFN receptor by the human pancreatic islet allows this group of IFNs to regulate the islets' permissiveness to infection. Our novel observations suggest that type III IFNs may regulate viral replication and thereby contribute to reduced tissue damage and promote islet cell survival during coxsackievirus infection.

Published
2013
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36. Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes

Author

Jay M. Sosenko, D. J. Becker, Kevan C. Herold, E. Leschek, James W. Thomas, Francesco Dotta, Jeffrey L. Mahon, K. Nanto-Salonen, Diane K. Wherrett, Lisa M. Spain, Andrew Muir, Polly J. Bingley, Massimo Trucco, Jeffrey P. Krischer, S. E. Gitelman, Alessandra Mandelli, Mark S. Anderson, Sarah J. Richardson, Peter S. Linsley, Riccardo Bonfanti, Eleonora Bianconi, George S. Eisenbarth, M. Siegelman, J. Peyman, Angela Stabilini, M. Redondo, Bernhard J. Hering, Richard A. Insel, Maurizio De Pellegrin, Franco Meschi, Francesca Ragogna, Mark A. Clements, Lars Krogvold, Mark Peakman, Alberto Pugliese, J. Blum, William E. Russell, P. Chase, Pia Leete, Anette-Gabriele Ziegler, Mark A. Atkinson, Jane H. Buckner, Andrea Rigamonti, Tihamer Orban, Laura Nigi, Philip Raskin, Guido Sebastiani, Louis H. Philipson, Linda A. DiMeglio, Clara Bonura, Manuela Battaglia, Jay S. Skyler, David A. Baidal, Giulio Frontino, Emanuele Bosi, Matthew J. Dufort, Andrea Valle, William E. Winter, Peter A. Gottlieb, C. G. Fathman, Helena Elding Larsson, Robin Goland, Michael J. Clare-Salzler, M. G. Roncarolo, Raphael Clynes, Peter A. Antinozzi, Andrea K. Steck, Mikael Knip, Olli Simell, R. Parkman, Bart O. Roep, Desmond A. Schatz, Henry Rodriguez, Nicola Lo Buono, John M. Wentworth, Andrea Laurenzi, Francesca Mancarella, P. Savage, Jennifer B. Marks, G. Grave, Paola M.V. Rancoita, Federica Vecchio, Åke Lernmark, Darrell M. Wilson, Noel G. Morgan, Thomas W.H. Kay, Francine R. Kaufman, Federica Cugnata, Christophe Benoist, Susan Geyer, Peter G. Colman, Mark D. Pescovitz, Robert S. Sherwin, Gerald T. Nepom, John E. Wagner, Antoinette Moran, Knut Dahl-Jørgensen, Jerry P. Palmer, Kasia Bourcier, Wayne V. Moore, Carla J. Greenbaum, Pauline Grogan, Vecchio, Federica, Lo Buono, Nicola, Stabilini, Angela, Nigi, Laura, Dufort, Matthew J., Geyer, Susan, Rancoita, Paola Maria, Cugnata, Federica, Mandelli, Alessandra, Valle, Andrea, Leete, Pia, Mancarella, Francesca, Linsley, Peter S., Krogvold, Lar, Herold, Kevan C., Elding Larsson, Helena, Richardson, Sarah J., Morgan, Noel G., Dahl-Jørgensen, Knut, Sebastiani, Guido, Dotta, Francesco, Bosi, Emanuele, and Battaglia, Manuela

Subjects
0301 basic medicine, endocrine system diseases, Neutrophils, Immunology, Gene Expression, Autoimmunity, Disease, Immunofluorescence, medicine.disease_cause, Extracellular Traps, Autoimmune Diseases, 03 medical and health sciences, Insulin-Secreting Cells, Diabetes mellitus, Autoimmune disease, medicine, Humans, Pancreas, Autoantibodies, Innate immunity, Type 1 diabetes, Innate immune system, medicine.diagnostic_test, business.industry, Gene Expression Profiling, General Medicine, Neutrophil extracellular traps, medicine.disease, Immunity, Innate, 3. Good health, Diabetes Mellitus, Type 1, 030104 developmental biology, medicine.anatomical_structure, Interferons, Clinical Medicine, Transcriptome, business
Abstract

BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic components in multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a disease that progresses sequentially through identifiable stages prior to the clinical onset, is not well understood. We previously reported that the number of circulating neutrophils is reduced in patients with T1D and in presymptomatic at-risk subjects. The aim of the present work was to identify possible changes in circulating and pancreas-residing neutrophils throughout the disease course to better elucidate neutrophil involvement in human T1D. METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinct studies performed by TrialNet, were analyzed with comprehensive statistical approaches to determine whether the number of circulating neutrophils correlates with pancreas function. To obtain a broad analysis of pancreas-infiltrating neutrophils throughout all disease stages, pancreas sections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) were analyzed by immunohistochemistry and immunofluorescence. Finally, circulating neutrophils were purified from unrelated nondiabetic subjects and donors at various T1D stages and their transcriptomic signature was determined by RNA sequencing. RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowest peripheral neutrophil numbers. Neutrophils infiltrate the pancreas prior to the onset of symptoms and they continue to do so as the disease progresses. Of interest, a fraction of these pancreas-infiltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specific pathogenic role. Whole-transcriptome analysis of purified blood neutrophils revealed a unique molecular signature that is distinguished by an overabundance of IFN-associated genes; despite being healthy, said signature is already present in T1D-autoantibody-negative at-risk subjects. CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both in the circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying that targeting neutrophils might represent a previously unrecognized therapeutic modality. FUNDING. Juvenile Diabetes Research Foundation (JDRF), NIH, Diabetes UK.

Published
2018

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