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Biomolecules
Volume 16
Issue 4
10.3390/biom16040500
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Differential Contributions of IgM and IgG Autoantibodies to Serologic IA2 Reactivity in Type 1 Diabetes

by
Xuming Mao
1,
Jake Konigsberg
1,
Nadia Noorchashm
1,
Wenzhao Meng
1,
James J. Knox
1,
Gregory J. Golden
2,3,
Jacob T. Hamilton
3,4,
Tara K. Maxwell
5,
Chengyang Liu
6,
Michael R. Betts
3,4,
Steven M. Willi
5,
Ali Naji
3,6,7,
Patrick Hanley
8 and
Eline T. Luning Prak
1,3,7,*
1
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
2
Breakthrough T1D, New York, NY 10281, USA
3
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
4
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
5
Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
6
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
7
Colton Center for Autoimmunity, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
8
Division of Endocrinology, Nemours Children’s Hospital, Wilmington, DE 19803, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2026, 16(4), 500; https://doi.org/10.3390/biom16040500
Submission received: 5 February 2026 / Revised: 21 March 2026 / Accepted: 22 March 2026 / Published: 26 March 2026
(This article belongs to the Special Issue Immune Responses in Type 1 Diabetes)
Versions Notes

Abstract

Autoantibodies targeting islet antigen 2 (IA2) are critical diagnostic and prognostic markers for type 1 diabetes (T1D). Standard clinical assays do not differentiate between IgG and IgM isotypes, yet these antibodies have distinct roles in the T1D autoimmunity. We therefore adapted electrochemiluminescence (ECL) assays to separately detect IgG and IgM antibodies against the IA2 intracellular domain (AA601-979). Assay specificity was confirmed by indirect immunofluorescence, which showed autoantibody binding to IA2-overexpressing cells. Plasma samples were analyzed from two independent cohorts: organ donors of the Human Pancreas Analysis Program (HPAP, n = 69) and children from a Janssen–Breakthrough T1D-funded study (n = 65). Diabetics had significantly higher levels of IA2 IgG (p < 0.001) but not IgM (p > 0.05) compared with controls. Notably, IgM and IgG IA2 antibody levels were not correlated. However, IgM modulates IgG detection: IgM depletion increased detected IgG levels to IA2 in some donors, and sera from donors with high IA2-specific IgM levels reduced monoclonal IgG anti-IA2 antibody binding to IA2. Purified IgM from healthy individuals also suppressed monoclonal IgG binding. These findings support distinct, non-redundant roles for IA2-specific IgG and IgM in T1D serology. Isotype-specific autoantibody analysis may improve risk stratification and monitoring of T1D individuals receiving immunomodulatory therapies.
Keywords: type 1 diabetes (T1D); autoantibodies; islet antigen 2 (IA2); Immunoglobulin G (IgG); Immunoglobulin M (IgM); electrochemiluminescence (ECL) type 1 diabetes (T1D); autoantibodies; islet antigen 2 (IA2); Immunoglobulin G (IgG); Immunoglobulin M (IgM); electrochemiluminescence (ECL)

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MDPI and ACS Style

Mao, X.; Konigsberg, J.; Noorchashm, N.; Meng, W.; Knox, J.J.; Golden, G.J.; Hamilton, J.T.; Maxwell, T.K.; Liu, C.; Betts, M.R.; et al. Differential Contributions of IgM and IgG Autoantibodies to Serologic IA2 Reactivity in Type 1 Diabetes. Biomolecules 2026, 16, 500. https://doi.org/10.3390/biom16040500

AMA Style

Mao X, Konigsberg J, Noorchashm N, Meng W, Knox JJ, Golden GJ, Hamilton JT, Maxwell TK, Liu C, Betts MR, et al. Differential Contributions of IgM and IgG Autoantibodies to Serologic IA2 Reactivity in Type 1 Diabetes. Biomolecules. 2026; 16(4):500. https://doi.org/10.3390/biom16040500

Chicago/Turabian Style

Mao, Xuming, Jake Konigsberg, Nadia Noorchashm, Wenzhao Meng, James J. Knox, Gregory J. Golden, Jacob T. Hamilton, Tara K. Maxwell, Chengyang Liu, Michael R. Betts, and et al. 2026. "Differential Contributions of IgM and IgG Autoantibodies to Serologic IA2 Reactivity in Type 1 Diabetes" Biomolecules 16, no. 4: 500. https://doi.org/10.3390/biom16040500

APA Style

Mao, X., Konigsberg, J., Noorchashm, N., Meng, W., Knox, J. J., Golden, G. J., Hamilton, J. T., Maxwell, T. K., Liu, C., Betts, M. R., Willi, S. M., Naji, A., Hanley, P., & Luning Prak, E. T. (2026). Differential Contributions of IgM and IgG Autoantibodies to Serologic IA2 Reactivity in Type 1 Diabetes. Biomolecules, 16(4), 500. https://doi.org/10.3390/biom16040500

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