Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes

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

doi:10.2337/db14-0365

Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

195 Citations (Scopus)

Abstract

Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of beta-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-gamma-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/ adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD2OLo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.

Original language	English
Pages (from-to)	3835-3845
Number of pages	11
Journal	Diabetes
Volume	63
Issue number	11
Early online date	1 Nov 2014
DOIs	https://doi.org/10.2337/db14-0365
Publication status	Published - 1 Nov 2014

Keywords

T-CELL RESPONSES
PLACEBO-CONTROLLED TRIAL
ZINC TRANSPORTER 8
KILL BETA-CELLS
C-PEPTIDE
ONSET
AGE
CLASSIFICATION
MODULATION
AUTOIMMUNE

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/db14-0365

195 Citations
1 Article

Erratum. Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes. Diabetes 2014; 63:3835-3845
Arif, S., Leete, P., Nguyen, V., Marks, K., Nor, N. M., Estorninho, M., Kronenberg-Versteeg, D., Bingley, P. J., Todd, J. A., Guy, C., Dunger, D. B., Powrie, J., Willcox, A., Foulis, A. K., Richardson, S. J., de Rinaldis, E., Morgan, N. G., Lorenc, A. & Peakman, M., Sept 2015, In: Diabetes. 64, 9, 1 p., 3334.
Research output: Contribution to journal › Article › peer-review

Cite this

Arif, S., Leete, P., Nguyen, V., Marks, K., Nor, N. M., Estorninho, M., Kronenberg-Versteeg, D., Bingley, P. J., Todd, J. A., Guy, C., Dunger, D. B., Powrie, J., Willcox, A., Foulis, A. K., Richardson, S. J., de Rinaldis, E., Morgan, N. G., Lorenc, A., & Peakman, M. (2014). Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes. Diabetes, 63(11), 3835-3845. https://doi.org/10.2337/db14-0365

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title = "Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes",

abstract = "Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of beta-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-gamma-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/ adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed {"}hyper-immune CD20Hi{"} and {"}pauci-immune CD2OLo.{"} Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.",

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

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Arif, S, Leete, P, Nguyen, V , Marks, K, Nor, NM, Estorninho, M , Kronenberg-Versteeg, D, Bingley, PJ, Todd, JA, Guy, C, Dunger, DB, Powrie, J, Willcox, A, Foulis, AK, Richardson, SJ, de Rinaldis, E, Morgan, NG, Lorenc, A & Peakman, M 2014, 'Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes', Diabetes, vol. 63, no. 11, pp. 3835-3845. https://doi.org/10.2337/db14-0365

TY - JOUR

T1 - Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes

AU - Arif, Sefina

AU - Leete, Pia

AU - Nguyen, Vy

AU - Marks, Katherine

AU - Nor, Nurhanani Mohamed

AU - Estorninho, Megan

AU - Kronenberg-Versteeg, Deborah

AU - Bingley, Polly J.

AU - Todd, John A.

AU - Guy, Catherine

AU - Dunger, David B.

AU - Powrie, Jake

AU - Willcox, Abby

AU - Foulis, Alan K.

AU - Richardson, Sarah J.

AU - de Rinaldis, Emanuele

AU - Morgan, Noel G.

AU - Lorenc, Anna

AU - Peakman, Mark

PY - 2014/11/1

Y1 - 2014/11/1

N2 - Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of beta-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-gamma-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/ adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD2OLo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.

AB - Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of beta-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-gamma-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/ adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD2OLo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.

KW - T-CELL RESPONSES

KW - PLACEBO-CONTROLLED TRIAL

KW - ZINC TRANSPORTER 8

KW - KILL BETA-CELLS

KW - C-PEPTIDE

KW - ONSET

KW - AGE

KW - CLASSIFICATION

KW - MODULATION

KW - AUTOIMMUNE

U2 - 10.2337/db14-0365

DO - 10.2337/db14-0365

M3 - Article

SN - 0012-1797

VL - 63

SP - 3835

EP - 3845

JO - Diabetes

JF - Diabetes

IS - 11

ER -

Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes

Abstract

Keywords

UN SDGs

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Research output

Erratum. Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes. Diabetes 2014; 63:3835-3845

Cite this