TY - JOUR
T1 - Cellular immune responses against proinsulin
T2 - No evidence for enhanced reactivity in individuals with IDDM
AU - Ellis, Tamir
AU - Jodoin, Eric
AU - Ottendorfer, Eric
AU - Salisbury, Patricia
AU - She, Jin Xiong
AU - Schatz, Desmond
AU - Atkinson, Mark A.
PY - 1999
Y1 - 1999
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.
AB - 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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U2 - 10.2337/diabetes.48.2.299
DO - 10.2337/diabetes.48.2.299
M3 - Article
C2 - 10334305
AN - SCOPUS:0032968699
SN - 0012-1797
VL - 48
SP - 299
EP - 303
JO - Diabetes
JF - Diabetes
IS - 2
ER -