Th1-like dominance in high-risk first-degree relatives of type I diabetic patients

Diabetologia. 2000 Jun;43(6):742-9. doi: 10.1007/s001250051372.


Aims/hypothesis: The humoral part of the immune system, including autoantibodies, is known to predict manifest Type I (insulin-dependent) diabetes mellitus in first-degree relatives but the cell-mediated immune process preceding the manifest disease still is not known. The aim of this investigation was to estimate the immunological balance of Th-like lymphocytes (Th1/Th2) in high-risk first-degree relatives of Type I diabetic children.

Methods: Peripheral blood mononuclear cells (PBMC) from 21 healthy high-risk first-degree relatives (ICA > or = 20) were examined and compared with the response seen in PBMC from children with newly diagnosed Type I diabetes and healthy control subjects of similar age, sex and HLA-type. Expression of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) mRNA were determined by RT-PCR and as protein by ELISPOT after stimulation with specific epitopes of GAD65 (a.a. 247-279, 509-528, 524-543), bovine serum albumin, the ABBOS peptide (a.a. 152-169) and insulin.

Results: High-risk relatives had a high ratio of IFN-gamma:IL-4 compared with both diabetic children (p = 0.0005) and healthy control subjects (p = 0.004). Production of IFN-gamma seen in high-risk relatives was negatively correlated to production of GADA (r = -0.44, p = 0.05). The high concentration of IFN-gamma from high-risk relatives, decreased after stimulation with peptides of GAD65, the ABBOS peptide, BSA and insulin. Increased secretion of IL-4 was observed after stimulation with two peptides of GAD65 (a.a. 509-528 and 524-543), the ABBOS peptide and insulin.

Conclusion/interpretation: Overwhelming production of IFN-gamma seen in peripheral blood mononuclear cells from high-risk first-degree relatives of children with Type I diabetes suggests a Th1-like immune deviation in the prediabetic phase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Cattle
  • Child
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes / chemistry
  • Family
  • Female
  • Glutamate Decarboxylase / chemistry
  • Glutamate Decarboxylase / immunology*
  • Histocompatibility Testing
  • Humans
  • Immunity, Cellular / genetics
  • Interferon-gamma / genetics
  • Interleukin-4 / genetics
  • Isoenzymes / chemistry
  • Isoenzymes / immunology*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Assessment
  • Serum Albumin, Bovine
  • Th1 Cells / immunology*
  • Th2 Cells / immunology
  • Transcription, Genetic


  • Epitopes
  • Isoenzymes
  • Peptide Fragments
  • Interleukin-4
  • Serum Albumin, Bovine
  • Interferon-gamma
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2