Autoimmunity to CD38 and GAD in Type I and Type II diabetes: CD38 and HLA genotypes and clinical phenotypes.
OBJECTIVE
Autoantibodies against CD 38 have been found in some patients with Type II (non-insulin-dependent) diabetes mellitus and have been shown to stimulate insulin secretion by cultured human islets. We tested whether this new form of autoimmunity, (i). overlaps with anti-GAD autoimmunity, (ii). identifies an insulin-deficient phenotype, (iii). is under the influence of genetic factors.


METHODS
We screened 496 adults by immuno-blot analysis in the Botnia Study (298 with Type II and 98 with Type I (insulin-dependent) diabetes mellitus, 100 non-diabetic control subjects).


RESULTS
CD 38-autoantibodies were found in 8.4% of Type II diabetic patients ( p<0.003 vs 0% of control subjects), particularly in anti-GAD positive (14% vs 6% of anti-GAD negative, p=0.0004). CD 38 ab were also found in 4% of Type I diabetic patients; in the whole study group, 59% of anti- CD 38 positive had DQB1*02 compared with 38% of anti-CD 38 negative ( p=0.04). On the OGTT, beta-cell function (as the ratio of insulin-to-glucose areas) was impaired ( p=0.02) only in association with anti-GAD positivity (3.2+/-3.1 U/mol, mean +/- SD) but not in anti- CD 38 positive patients (5.6+/-2.9) as compared with patients free of autoimmunity (4.5+/-4.6, p=NS). In 44 Type II diabetic patients (22 negative and 22 positive for anti- CD 38), no mutations were detected in any of the 8 exons, 5' end of intron 1 or the 5' and 3' untranslated regions of the CD 38 gene. The previously described missense mutation (Arg140Trp) in exon 3 was not found in this cohort. There was no association between the PvUII polymorphism and clinical phenotype.


CONCLUSIONS
Anti-CD 38 autoimmunity identifies a clinical phenotype similar to non-autoimmune Type II diabetes, with relative preserved beta-cell function and weak genetic influence.
Antonelli
A
A
Department of Internal Medicine and Metabolism Unit of the CNR Institute of Clinical Physiology, University of Pisa, Italy.
Tuomi
T
T
Nannipieri
M
M
Fallahi
P
P
Nesti
C
C
Okamoto
H
H
Groop
L
L
Ferrannini
E
E
D036541:ADP-ribosyl Cyclase / Q000235:genetics* / Q000276:immunology; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D016208:Databases, Factual; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D010641:Phenotype
D015703:Antigens, CD; D001323:Autoantibodies; D006680:HLA Antigens; D008562:Membrane Glycoproteins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D005968:Glutamate Decarboxylase