M. Fuchtenbusch et al., Exposure to exogenous insulin promotes IgG1 and the T-Helper 2-associated IgG4 responses to insulin but not to other islet autoantigens, DIABETES, 49(6), 2000, pp. 918-925
Insulin immunization in animal models induces T-helper (Th) 2-like antibody
subclass responses to insulin and other beta-cell antigens. The aim of thi
s study was to determine whether exposure to insulin in humans resulted in
a similar subclass bias of the humoral immune response. Levels of IgG subcl
ass antibodies to insulin (IAs), GAD, and IA-2 were measured before and aft
er treatment with insulin in the following groups of patients: 29 patients
with newly diagnosed type 1 diabetes treated with intravenous and/or subcut
aneous insulin; 10 newly diagnosed patients randomized to cyclosporin A (Cs
A) or placebo plus subcutaneous insulin for 12 months; and 14 islet cell an
tibody-positive relatives receiving either intravenous and subcutaneous ins
ulin prophylaxis or no treatment. At the onset of diabetes, the major subcl
ass distributions of insulin autoantibodies (IAAs) were IgG1 and, to a less
er extent, IgG4. After insulin treatment in the 29 new-onset patients, IAs
were initially of the IgG1 subclass. IgG4-IAs appeared later, but. at 12 mo
nths, they were at higher levels than IgG1-IAs in 11 patients. Responses we
re higher in children compared with adults and were higher in subjects with
IAAS (P < 0.001). Insulin prophylaxis in relatives showed a similar profil
e, with a decline in levels of IgG1-IAs after cessation of daily subcutaneo
us insulin. Patients treated with CsA took longer to develop IAs and showed
suppressed levels of IgG4-IAs; however, their levels of high-titer IgG1-IA
s persistently rebounded after completion of CsA therapy Despite the presen
ce of IgG4-IAs in most insulin-treated patients and relatives, a shift to I
gG4-anti-GAD or IgG4-IA-2 was not found for up to 3 years after the initiat
ion of insulin therapy. While our findings need to be correlated with T-cel
l cytokine responses, we suggest that. the strong IgG4-IA response in insul
in-treated patients is consistent with an enhancement of Th2 immunity, but
there is no evidence of subsequent spreading of potentially Th2-associated
IgG4 responses to other autoantigens.