Cellular immune responses against proinsulin: No evidence for enhanced reactivity in individuals with IDDM

Tamir Ellis, Eric Jodoin, Eric Ottendorfer, Patricia Salisbury, Jin Xiong She, Desmond Schatz, Mark A. Atkinson

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Investigations of humans and nonobese diabetic mice suggest that proinsulin and/or a fragment of the region spanning C-peptide and the B- chain of insulin (i.e., proinsulin peptide) may serve as key autoantigens in IDDM. Therefore, we analyzed cellular immune reactivities against these molecules in people with or at varying risks for the disease to clarify their role in the pathogenesis of IDDM. In vitro peripheral blood mononuclear cell (PBMC) responses against these antigens, a control antigen (tetanus toxoid), and phytohemaglutinin were determined in 60 individuals with newly diagnosed IDDM (≤1 day from diagnosis) in 34 islet cell cytoplasmic autoantibody- and/or insulin autoantibody-negative first-degree relatives of the IDDM subjects, and in 28 autoantibody-negative control subjects. Unlike previous reports suggesting diabetes-associated elevations in cellular immunity to other β-cell antigens (e.g., GAD, IA-2, etc.), we observed equivalent levels of phytohemaglutinin stimulation and cellular proliferation in all groups against these antigens (all P values were not significant). The mean stimulation index ± SD and frequency of reactivity to proinsulin for healthy control subjects and IDDM patients, respectively, were as follows: 1 μg/ml (1.5 ± 1.0, 1 out of 17 [6%]; 1.9 ± 1.4, 4 out of 33 [12%]); 10 μg/ml (1.7 ± 1.3, 1 out of 17 [6%]; 1.2 ± 0.6, 0 out of 28 [0%]); and 50 μg/ml (1.2 ± 0.6, 1 out of 16 [6%]; 1.1 ± 0.6, 1 out of 27 [4%]). The response in healthy control subjects, autoantibody-negative relatives, and IDDM patients, respectively, against the proinsulin peptide fragment were as follows: 1 μg/ml (0.9 ± 0.4, 1 out of 12 [8%]; 1.3 ± 1.1, 4 out of 34 [11%]; 1.1 ± 0.3, 2 out of 28 [7%]); 10 μg/ml (0.9 ± 0.6, 1 out of 12 [8%]; 1.2 ± 0.6, 3 out of 34 [9%] 1.4 ± 1.7, 2 out of 28 [7%]); and 50 μg/ml (1.0 ± 0.7, 1 out of 12 [8%]; 1.2 μ 0.5, 2 out of 34 [6%]; 1.3 ± 0.5, 2 out of 28 [7% ]). Taken together with previous studies reporting relatively infrequent occurrences of autoantibodies to proinsulin, the role of immunity to this molecule in the pathogenesis of IDDM in humans remains unclear.

Original languageEnglish (US)
Pages (from-to)299-303
Number of pages5
JournalDiabetes
Volume48
Issue number2
DOIs
StatePublished - Jan 1 1999

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Proinsulin
Type 1 Diabetes Mellitus
Cellular Immunity
Autoantibodies
Antigens
Healthy Volunteers
Inbred NOD Mouse
Tetanus Toxoid
Peptide Fragments
C-Peptide
Autoantigens
Islets of Langerhans
Immunity
Blood Cells
Cell Proliferation
Insulin
Peptides

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ellis, T., Jodoin, E., Ottendorfer, E., Salisbury, P., She, J. X., Schatz, D., & Atkinson, M. A. (1999). Cellular immune responses against proinsulin: No evidence for enhanced reactivity in individuals with IDDM. Diabetes, 48(2), 299-303. https://doi.org/10.2337/diabetes.48.2.299

Cellular immune responses against proinsulin : No evidence for enhanced reactivity in individuals with IDDM. / Ellis, Tamir; Jodoin, Eric; Ottendorfer, Eric; Salisbury, Patricia; She, Jin Xiong; Schatz, Desmond; Atkinson, Mark A.

In: Diabetes, Vol. 48, No. 2, 01.01.1999, p. 299-303.

Research output: Contribution to journalArticle

Ellis, T, Jodoin, E, Ottendorfer, E, Salisbury, P, She, JX, Schatz, D & Atkinson, MA 1999, 'Cellular immune responses against proinsulin: No evidence for enhanced reactivity in individuals with IDDM', Diabetes, vol. 48, no. 2, pp. 299-303. https://doi.org/10.2337/diabetes.48.2.299
Ellis, Tamir ; Jodoin, Eric ; Ottendorfer, Eric ; Salisbury, Patricia ; She, Jin Xiong ; Schatz, Desmond ; Atkinson, Mark A. / Cellular immune responses against proinsulin : No evidence for enhanced reactivity in individuals with IDDM. In: Diabetes. 1999 ; Vol. 48, No. 2. pp. 299-303.
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abstract = "Investigations of humans and nonobese diabetic mice suggest that proinsulin and/or a fragment of the region spanning C-peptide and the B- chain of insulin (i.e., proinsulin peptide) may serve as key autoantigens in IDDM. Therefore, we analyzed cellular immune reactivities against these molecules in people with or at varying risks for the disease to clarify their role in the pathogenesis of IDDM. In vitro peripheral blood mononuclear cell (PBMC) responses against these antigens, a control antigen (tetanus toxoid), and phytohemaglutinin were determined in 60 individuals with newly diagnosed IDDM (≤1 day from diagnosis) in 34 islet cell cytoplasmic autoantibody- and/or insulin autoantibody-negative first-degree relatives of the IDDM subjects, and in 28 autoantibody-negative control subjects. Unlike previous reports suggesting diabetes-associated elevations in cellular immunity to other β-cell antigens (e.g., GAD, IA-2, etc.), we observed equivalent levels of phytohemaglutinin stimulation and cellular proliferation in all groups against these antigens (all P values were not significant). The mean stimulation index ± SD and frequency of reactivity to proinsulin for healthy control subjects and IDDM patients, respectively, were as follows: 1 μg/ml (1.5 ± 1.0, 1 out of 17 [6{\%}]; 1.9 ± 1.4, 4 out of 33 [12{\%}]); 10 μg/ml (1.7 ± 1.3, 1 out of 17 [6{\%}]; 1.2 ± 0.6, 0 out of 28 [0{\%}]); and 50 μg/ml (1.2 ± 0.6, 1 out of 16 [6{\%}]; 1.1 ± 0.6, 1 out of 27 [4{\%}]). The response in healthy control subjects, autoantibody-negative relatives, and IDDM patients, respectively, against the proinsulin peptide fragment were as follows: 1 μg/ml (0.9 ± 0.4, 1 out of 12 [8{\%}]; 1.3 ± 1.1, 4 out of 34 [11{\%}]; 1.1 ± 0.3, 2 out of 28 [7{\%}]); 10 μg/ml (0.9 ± 0.6, 1 out of 12 [8{\%}]; 1.2 ± 0.6, 3 out of 34 [9{\%}] 1.4 ± 1.7, 2 out of 28 [7{\%}]); and 50 μg/ml (1.0 ± 0.7, 1 out of 12 [8{\%}]; 1.2 μ 0.5, 2 out of 34 [6{\%}]; 1.3 ± 0.5, 2 out of 28 [7{\%} ]). Taken together with previous studies reporting relatively infrequent occurrences of autoantibodies to proinsulin, the role of immunity to this molecule in the pathogenesis of IDDM in humans remains unclear.",
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N2 - Investigations of humans and nonobese diabetic mice suggest that proinsulin and/or a fragment of the region spanning C-peptide and the B- chain of insulin (i.e., proinsulin peptide) may serve as key autoantigens in IDDM. Therefore, we analyzed cellular immune reactivities against these molecules in people with or at varying risks for the disease to clarify their role in the pathogenesis of IDDM. In vitro peripheral blood mononuclear cell (PBMC) responses against these antigens, a control antigen (tetanus toxoid), and phytohemaglutinin were determined in 60 individuals with newly diagnosed IDDM (≤1 day from diagnosis) in 34 islet cell cytoplasmic autoantibody- and/or insulin autoantibody-negative first-degree relatives of the IDDM subjects, and in 28 autoantibody-negative control subjects. Unlike previous reports suggesting diabetes-associated elevations in cellular immunity to other β-cell antigens (e.g., GAD, IA-2, etc.), we observed equivalent levels of phytohemaglutinin stimulation and cellular proliferation in all groups against these antigens (all P values were not significant). The mean stimulation index ± SD and frequency of reactivity to proinsulin for healthy control subjects and IDDM patients, respectively, were as follows: 1 μg/ml (1.5 ± 1.0, 1 out of 17 [6%]; 1.9 ± 1.4, 4 out of 33 [12%]); 10 μg/ml (1.7 ± 1.3, 1 out of 17 [6%]; 1.2 ± 0.6, 0 out of 28 [0%]); and 50 μg/ml (1.2 ± 0.6, 1 out of 16 [6%]; 1.1 ± 0.6, 1 out of 27 [4%]). The response in healthy control subjects, autoantibody-negative relatives, and IDDM patients, respectively, against the proinsulin peptide fragment were as follows: 1 μg/ml (0.9 ± 0.4, 1 out of 12 [8%]; 1.3 ± 1.1, 4 out of 34 [11%]; 1.1 ± 0.3, 2 out of 28 [7%]); 10 μg/ml (0.9 ± 0.6, 1 out of 12 [8%]; 1.2 ± 0.6, 3 out of 34 [9%] 1.4 ± 1.7, 2 out of 28 [7%]); and 50 μg/ml (1.0 ± 0.7, 1 out of 12 [8%]; 1.2 μ 0.5, 2 out of 34 [6%]; 1.3 ± 0.5, 2 out of 28 [7% ]). Taken together with previous studies reporting relatively infrequent occurrences of autoantibodies to proinsulin, the role of immunity to this molecule in the pathogenesis of IDDM in humans remains unclear.

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