Switch from a dominant Th1-associated immune profile during the pre-diabetic phase in favour of a temporary increase of a Th3-associated and inflammatory immune profile at the onset of type 1 diabetes.
BACKGROUND
Type 1 diabetes (T1D) is an autoimmune disease dominated by loss of self-tolerance resulting in depletion of the beta-cells. This study aims to confirm previous observations of a dominant T-helper (Th)1-like profile during the period close to onset of disease. Further, to follow the immune response from onset to 2 years duration, the study focused on spontaneous as well as autoantigen-induced immune profile.


METHODS
Peripheral blood mononuclear cells were collected 4 days and 1 and 2 years after diagnosis of T1D children, from healthy children carrying the human leukocyte antigen-risk genes and from high-risk children (ICA > or = 20 IJDF units). Peripheral blood mononuclear cells were stimulated with glutamic acid decarboxylase (GAD(65)) and phytohaemagglutinin (PHA). Cytokines and chemokines were detected in cell-culture supernatants by protein microarray (naive T-cells; interleukin (IL)-7, Th1; interferon-gamma, tumour necrosis factor-beta, Th2; IL-5, Th3; transforming growth factor-beta, T-regulatory cell type 1; IL-10 and inflammatory cytokines; tumour necrosis factor-alpha, IL-6 and chemokines; monocyte chemoattractant protein-1, monokine upregulated by IFN-gamma) in relation to clinical outcome (C-peptide).


RESULTS
High-risk children showed a dominant Th1-associated profile with high spontaneous and GAD(65)-induced secretion. The mitogen PHA instead induced a Th2-associated response exclusively in high-risk children. In contrast, newly diagnosed T1D children showed a pronounced Th3-associated cytokine profile as well as a burst of inflammatory cytokines and chemokines secreted both spontaneously and by GAD(65) and PHA stimulation. The immune response to GAD(65) and PHA, however, diminished with duration of disease.


CONCLUSIONS
A dominant Th1-associated immune profile was observed during the pre-diabetic phase. This Th1 dominance, however, diminished in favour of a temporary increase in a Th3-associated and inflammatory immune profile at the onset of disease.
Ryden
Anna
A
Division of Paediatrics & Diabetes Research Centre, Department of Clinical & Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Stechova
Katerina
K
Durilova
Marianna
M
Faresjö
Maria
M
D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018925:Chemokines / Q000097:blood / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D018450:Disease Progression; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D012307:Risk Factors; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
D018925:Chemokines; D016207:Cytokines; D005968:Glutamate Decarboxylase