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


CONCLUSIONS
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.
Karlsson
M G
MG
Department of Health and Environment, Faculty of Health Sciences, Linköping University, Sweden.
Lawesson
S S
SS
Ludvigsson
J
J
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry; D005190:Family; D005260:Female; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D007527:Isoenzymes / Q000737:chemistry / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012710:Serum Albumin, Bovine; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014158:Transcription, Genetic
D000939:Epitopes; D007527:Isoenzymes; D010446:Peptide Fragments; D015847:Interleukin-4; D012710:Serum Albumin, Bovine; D007371:Interferon-gamma; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2