Altered chemokine levels in individuals at risk of Type 1 diabetes mellitus.
OBJECTIVE
The hypothesis was tested in an exploratory study that individuals at high risk of developing Type 1 diabetes mellitus have altered systemic levels of cytokines and chemokines.


METHODS
Forty-two non-diabetic first-degree relatives of patients with Type 1 diabetes mellitus were recruited. Of these, 18 had multiple islet autoantibodies (islet cell antibody, glutamic acid decarboxylase antibody, IA-2 antibody). Follow-up for 9-11 years confirmed high vs. moderate diabetes risk in islet autoantibody-positive vs. -negative relatives. Cytokines and chemokines were determined by enzyme-linked immunosorbent assay (ELISA).


RESULTS
Serum concentrations of classic Th1-associated cytokines (IFN-gamma, IL-12, IL-18) or Th2/Treg-associated cytokines (IL-5, IL-10, IL-13) did not significantly differ in high vs. moderate diabetes risk group. However, of six chemokines analysed, levels of CCL3 and CCL4 were increased (P = 0.0442 and P = 0.0334) while CCL2 was decreased (P = 0.0318) in the multiple islet autoantibody-positive group. No significant differences were seen for CCL5, CCL11, CXCL10. There was a significant correlation between the two closely related chemokines CCL3 and CCL4 in individuals at risk (r = 0.84, P = 0.00005), but not in the autoantibody-negative group.


CONCLUSIONS
Relatives at high risk of developing Type 1 diabetes mellitus have abnormal cellular immune regulation at the level of systemic chemokines. The up-regulation of CCL3 and CCL4 vs. down-regulation of CCL2 suggests opposed functions of these chemokines in the disease process. These findings need to be confirmed by independent studies.
Hanifi-Moghaddam
P
P
German Diabetes Clinic, German Diabetes Center, Leibniz Institute at the Heinrich-Heine-University, Düsseldorf, Germany.
Kappler
S
S
Seissler
J
J
Müller-Scholze
S
S
Martin
S
S
Roep
B O
BO
Strassburger
K
K
Kolb
H
H
Schloot
N C
NC
D001323:Autoantibodies / Q000032:analysis; D018932:Chemokine CCL2 / Q000097:blood; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000097:blood*; D019742:Chemokines, CC / Q000097:blood; D015331:Cohort Studies; D016207:Cytokines / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D018793:Interleukin-13 / Q000097:blood; D020382:Interleukin-18 / Q000097:blood; D015848:Interleukin-5 / Q000097:blood; D007515:Islets of Langerhans / Q000737:chemistry; D019402:Macrophage Inflammatory Proteins / Q000097:blood; D012307:Risk Factors
D001323:Autoantibodies; C111835:CCL2 protein, human; C066507:CCL4 protein, human; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D019742:Chemokines, CC; D016207:Cytokines; D018793:Interleukin-13; D020382:Interleukin-18; D015848:Interleukin-5; D019402:Macrophage Inflammatory Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma