T-cell mediated autoimmunity to the insulinoma-associated protein 2 islet tyrosine phosphatase in type 1 diabetes mellitus

Francesco Dotta, Sabrina Dionisi, Vissia Viglietta, Claudio Tiberti, Maria Cristina Matteoli, Marco Cervoni, Carla Bizzarri, Giovanni Marietti, Manuela Testi, Giuseppe Multari, Lucio Lucentini, Umberto Di Mario

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Abstract

The target molecules of the T-cell response in type 1 diabetes, despite their pathogenic importance, remain largely uncharacterized, especially in humans. Interestingly, molecules such as insulin and glutamic acid decarboxylase (GAD) have been shown to be a target not only of autoantibodies, but also of autoreactive T-lymphocytes both in man and in the non-obese diabetic (NOD) mouse. In the present study we aimed to determine the existence of a specific T-cell response towards the insulinoma-associated protein 2 (IA-2) islet tyrosine phosphatase, a recently identified autoantigen which is the target of autoantibodies strongly associated with diabetes development. Human recombinant IA-2 produced in Escherichia coli, was tested for its reactivity with peripheral blood lymphocytes obtained from 16 newly diagnosed type i diabetic patients and from 25 normal controls, 15 of whom were HLA-DR-matched. A T-cell proliferation assay was performed in triplicate employing freshly isolated cells in the absence or in the presence of the antigen to be tested (at two different concentrations: 2 μg/ml and 10 μg/ml). A specific T-cell proliferation (defined as a stimulation index (S.I.) ≥3) was observed against IA-2 used at a concentration of 10 μg/ml (but not of 2 μg/ml) in 8/16 diabetic patients, in 1/15 HLA-DR-matched control subjects (P <0.01 by Fisher exact test) and in 0/10 of the remaining normal individuals. A statistically significant difference (P <0.003 by Mann-Whitney U test) was also observed in S.I. values between patients (3.1 ± 1.4) and HLA-DR-matched controls (1.7 ± 0.54) employing IA-2 at a concentration of 10 μg/ml. However, when IA-2 was used at a concentration of 2 μg/ml, the difference in S.I. between patients (1.65 ± 0.8) and controls (1.0 ± 0.3) did not reach statistical significance. In conclusion, these data show the presence of a specific, dose-dependent T-lymphocyte response against the IA-2 islet tyrosine phosphatase at the onset of type 1 diabetes. Consequently, this molecule appears to be a target not only at the B- lymphocyte but also at the T-lymphocyte level, reinforcing the potential pathogenic role of this autoantigen in the islet destructive process.

Original languageEnglish
Pages (from-to)272-278
Number of pages7
JournalEuropean Journal of Endocrinology
Volume141
Issue number3
DOIs
Publication statusPublished - Sep 1999

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ASJC Scopus subject areas

  • Endocrinology

Cite this

Dotta, F., Dionisi, S., Viglietta, V., Tiberti, C., Matteoli, M. C., Cervoni, M., Bizzarri, C., Marietti, G., Testi, M., Multari, G., Lucentini, L., & Di Mario, U. (1999). T-cell mediated autoimmunity to the insulinoma-associated protein 2 islet tyrosine phosphatase in type 1 diabetes mellitus. European Journal of Endocrinology, 141(3), 272-278. https://doi.org/10.1530/eje.0.1410272