Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes.
OBJECTIVE
The pattern of the humoral immunity to disease-associated autoantigens may reflect the severity of the autoimmune disease process. The purpose of this study was to delineate the maturation of the humoral immunity to one of the main autoantigens in type 1 diabetes (T1D), glutamic acid decarboxylase (GAD65).


METHODS
Serum samples were obtained for the detection of epitope- and isotype-specific antibodies sequentially with short intervals from 36 young children with HLA-conferred genetic susceptibility to T1D starting from the first appearance of GAD65Ab. During prospective observation, ten children developed T1D. Antibodies were analyzed using biotinylated anti-human immunoglobulin (Ig) antibodies and chimeric GAD molecules in radio-binding assays.


RESULTS
The immune response to GAD65 started as reactivity to the middle region and spread rapidly to the C-terminal region. IgG1 antibodies dominated among the isotypes from the first appearance of GAD65Ab, while other IgG subclasses were observed to a lesser extent. IgG4 antibodies emerged clearly as the last IgG subclass. A broad initial response comprising three to four IgG subclasses and the lack of an emerging IgG4 response during follow-up was associated with increased risk for progression to clinical diabetes (P<0.05).


CONCLUSIONS
The humoral response to GAD65 epitope clusters is relatively uniform in young children, whereas there is conspicuous individual variation in IgG subclass responses except for IgG1. A narrow initial IgG subclass response to GAD65 and the emergence of IgG4 antibodies were characteristic of those who remained non-diabetic over the first few years of GAD65 autoimmunity.
Ronkainen
Matti S
MS
Department of Pediatrics, University of Oulu, Oulu, Finland.
Hoppu
Sanna
S
Korhonen
Sari
S
Simell
Satu
S
Veijola
Riitta
R
Ilonen
Jorma
J
Simell
Olli
O
Knip
Mikael
M
D000917:Antibody Formation; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D018450:Disease Progression; D018572:Disease-Free Survival; D000939:Epitopes / Q000097:blood*; D005260:Female; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000097:blood*; D007223:Infant; D007328:Insulin / Q000627:therapeutic use; D007527:Isoenzymes / Q000276:immunology*; D008297:Male; D010919:Placebos; D011236:Prediabetic State / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D011315:Preventive Medicine
D001323:Autoantibodies; D000939:Epitopes; D007132:Immunoglobulin Isotypes; D007328:Insulin; D007527:Isoenzymes; D010919:Placebos; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2