. 2023 Sep;14(9):1092-1100.

doi: 10.1111/jdi.14031. Epub 2023 Jun 13.

A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes

Leonard C Harrison^{1

2}, Esther Bandala-Sanchez^{1

2}, Helena Oakey³, Peter G Colman⁴, Kelly Watson⁴, Ki Wook Kim^{5

6}, Roy Wu^{5

6}, Emma E Hamilton-Williams⁷, Natalie L Stone^{1

2}, Aveni Haynes⁸, Rebecca L Thomson³, Peter J Vuillermin^{9

10}, Georgia Soldatos^{11

12}, William D Rawlinson^{5

6}, Kelly J McGorm³, Grant Morahan¹³, Simon C Barry³, Richard O Sinnott¹⁴, John M Wentworth^{1

2

4}, Jennifer J Couper^{3

15}, Megan As Penno³; ENDIA Study Group

Collaborators, Affiliations

Collaborators

ENDIA Study Group:
Simon C Barry, Maria E Craig, Peter G Colman, Jennifer J Couper, Elizabeth A Davis, Emma Hamilton-Williams, Mark Harris, Leonard C Harrison, Aveni Haynes, Ki Wook Kim, Grant Morahan, Helena Oakey, Megan A S Penno, William D Rawlinson, Richard O Sinnott, Georgia Soldatos, Rebecca L Thomson, Peter J Vuillermin, Amanda J Anderson, Pat Ashwood, James D Brown, William Hu, Dao Huynh, Kelly J McGorm, Kelly Watson, Jason Tye-Din, Tony Huynh, Claire Morbey, Prudence Lopez, Sarah Beresford, Samantha Bertram, Debra Bezuidenhout, Susan Brandrick, Carlie Butterworth, Jacki Catteau, Nakita Clements, Kyana Gartrell, Abbey Gilbert, Helen Griffiths, Alison Gwiazdzinski, Candice Hall, Gail Harper, Amanda Hulley, Mikayla Hoffman, Renee Kludas, Belinda Moore, Benjamin Ramoso, Alison Roberts, Alexandra Tully, Isabelle Vicary, Rosemary Wood, Rachel Battersby, Chris Hope, Tim Sadlon, Alexandra Roth-Schulze, Ying-Ying Wong, Enrique Zozaya-Valdes, Sabrina Binkowski, Bek Brittain, Minh Bui, Asma Minhaj, Gaetano Naselli, Katrina Ngui, Trung Nguyen, Natalie Stone, Emily Ward, Yan Xu, Cynthia Yau

Affiliations

¹ Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
² Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
³ Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
⁴ Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁵ Virology Research Laboratory, Serology and Virology Division, NSW Health, Prince of Wales Hospital, Sydney, New South Wales, Australia.
⁶ Schools of Biomedical Sciences and Biotechnology and Biomolecular Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
⁷ Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia.
⁸ Telethon Kids Institute for Child Health Research, Centre for Child Health Research, the University of Western Australia, Perth, Western Australia, Australia.
⁹ Faculty of School of Medicine, Deakin University, Geelong, Victoria, Australia.
¹⁰ Child Health Research Unit, Barwon Health, Geelong, Victoria, Australia.
¹¹ Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
¹² Diabetes and Vascular Medicine Unit, Monash Health, Melbourne, Victoria, Australia.
¹³ Centre for Diabetes Research, Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, Western Australia, Australia.
¹⁴ Melbourne eResearch Group, School of Computing and Information Services, University of Melbourne, Melbourne, Victoria, Australia.
¹⁵ Women's and Children's Hospital, North Adelaide, South Australia, Australia.

PMID: 37312283
PMCID: PMC10445231
DOI: 10.1111/jdi.14031

A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes

Leonard C Harrison et al. J Diabetes Investig. 2023 Sep.

. 2023 Sep;14(9):1092-1100.

doi: 10.1111/jdi.14031. Epub 2023 Jun 13.

Authors

Collaborators

ENDIA Study Group:
Simon C Barry, Maria E Craig, Peter G Colman, Jennifer J Couper, Elizabeth A Davis, Emma Hamilton-Williams, Mark Harris, Leonard C Harrison, Aveni Haynes, Ki Wook Kim, Grant Morahan, Helena Oakey, Megan A S Penno, William D Rawlinson, Richard O Sinnott, Georgia Soldatos, Rebecca L Thomson, Peter J Vuillermin, Amanda J Anderson, Pat Ashwood, James D Brown, William Hu, Dao Huynh, Kelly J McGorm, Kelly Watson, Jason Tye-Din, Tony Huynh, Claire Morbey, Prudence Lopez, Sarah Beresford, Samantha Bertram, Debra Bezuidenhout, Susan Brandrick, Carlie Butterworth, Jacki Catteau, Nakita Clements, Kyana Gartrell, Abbey Gilbert, Helen Griffiths, Alison Gwiazdzinski, Candice Hall, Gail Harper, Amanda Hulley, Mikayla Hoffman, Renee Kludas, Belinda Moore, Benjamin Ramoso, Alison Roberts, Alexandra Tully, Isabelle Vicary, Rosemary Wood, Rachel Battersby, Chris Hope, Tim Sadlon, Alexandra Roth-Schulze, Ying-Ying Wong, Enrique Zozaya-Valdes, Sabrina Binkowski, Bek Brittain, Minh Bui, Asma Minhaj, Gaetano Naselli, Katrina Ngui, Trung Nguyen, Natalie Stone, Emily Ward, Yan Xu, Cynthia Yau

Affiliations

¹ Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
² Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
³ Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
⁴ Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁵ Virology Research Laboratory, Serology and Virology Division, NSW Health, Prince of Wales Hospital, Sydney, New South Wales, Australia.
⁶ Schools of Biomedical Sciences and Biotechnology and Biomolecular Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
⁷ Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia.
⁸ Telethon Kids Institute for Child Health Research, Centre for Child Health Research, the University of Western Australia, Perth, Western Australia, Australia.
⁹ Faculty of School of Medicine, Deakin University, Geelong, Victoria, Australia.
¹⁰ Child Health Research Unit, Barwon Health, Geelong, Victoria, Australia.
¹¹ Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
¹² Diabetes and Vascular Medicine Unit, Monash Health, Melbourne, Victoria, Australia.
¹³ Centre for Diabetes Research, Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, Western Australia, Australia.
¹⁴ Melbourne eResearch Group, School of Computing and Information Services, University of Melbourne, Melbourne, Victoria, Australia.
¹⁵ Women's and Children's Hospital, North Adelaide, South Australia, Australia.

PMID: 37312283
PMCID: PMC10445231
DOI: 10.1111/jdi.14031

Abstract

Aims/introduction: Autoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at-risk for type 1 diabetes followed from birth who had developed islet autoantibodies ("seroconverted"), by measuring mucosa-associated cytokines in their sera.

Materials and methods: Sera were collected 3 monthly from birth from children with a first-degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines.

Results: Of eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa-associated cytokines IL-21, IL-22, IL-25, and IL-10, the Th17-related cytokines IL-17F and IL-23, as well as IL-33, IFN-γ, and IL-4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex- and age-matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children.

Conclusions: In a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa-associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.

Keywords: Islet autoantibody; Seroconversion; Serum cytokine.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Approval of the research protocol: The ENDIA study was reviewed and approved by human research ethics committees at each clinical site, with the Women's and Children's Hospital Network Human Research Ethics Committee in Adelaide acting as the lead under the Australian National Mutual Acceptance Scheme (reference number HREC/16/WCHN/066). Conduct in Western Australia was approved by the Women and Newborn Health Service Ethics Committee (reference number RGS0000002639) and Child and Adolescent Health Service HREC (RGS0000002402). The research conforms to the provisions of the Declaration of Helsinki (as revised in Fortaleza, Brazil, October 2013).

Informed consent: Written informed consent was obtained by parents on behalf of themselves and the child.

Registry and the registration no. of the study/trial: The ENDIA study was registered with the Australia New Zealand Clinical Trials Registry July 16, 2013, under registration number ACTRN12613000794707.

Animal studies: N/A.

Figures

**Figure 1**
Serum cytokine concentrations in children with islet autoimmunity and in age‐ and sex‐matched controls. Below the x‐axis is shown the absence (−) or presence (+) of islet autoantibodies to insulin (IAA), glutamic acid decarboxylase 65 (GADA), islet‐associated antigen‐2 (IA‐2A), and zinc transporter 8 (ZnT8A) against age in months. Type 1 diabetes after the last time point indicates the diagnosis of clinical type 1 diabetes. Each figure set represents data from a matched case and control pair.

See this image and copyright information in PMC

References

1. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 2013; 309: 2473–2479. - PMC - PubMed
1. Bonifacio E, Achenbach P. Birth and coming of age of islet autoantibodies. Clin Exp Immunol 2019; 198: 294–305. - PMC - PubMed
1. Hyöty H. Viruses in type 1 diabetes. Pediatr Diabetes 2016; 17: 56–64. - PubMed
1. Harrison LC, Perrett KP, Jachno K, et al. Does rotavirus turn on type 1 diabetes? PLoS Pathol 2019; 15: e1007965. - PMC - PubMed
1. Faulkner CL, Luo YX, Isaacs S, et al. The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: A systematic review and meta‐analysis of observational studies. Rev Med Virol 2020; 31: 1–14. - PMC - PubMed

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A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes

Collaborators

Affiliations

A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

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References

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