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Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes.
J. Clin. Invest. 114, 589-597 (2004)
Children at risk for type 1 diabetes can develop early insulin autoantibodies (IAAs). Many, but not all, of these children subsequently develop multiple islet autoantibodies and diabetes. To determine whether disease progression is reflected by autoantibody maturity, IAA affinity was measured by competitive radiobinding assay in first and subsequent IAA-positive samples from children followed from birth in the BABYDIAB cohort. IAA affinity in first positive samples ranged from less than 10(6) l/mol to more than 10(11) l/mol. High affinity was associated with HLA DRB1*04, young age of IAA appearance, and subsequent progression to multiple islet autoantibodies or type 1 diabetes. IAA affinity in multiple antibody-positive children was on average 100-fold higher than in children who remained single IAA positive or became autoantibody negative. All high-affinity IAAs required conservation of human insulin A chain residues 8-13 and were reactive with proinsulin. In contrast, most lower-affinity IAAs were dependent on COOH-terminal B chain residues and did not bind proinsulin. These data are consistent with the concept that type 1 diabetes is associated with sustained early exposure to (pro)insulin in the context of HLA DR4 and show that high-affinity proinsulin-reactive IAAs identify children with the highest diabetes risk.
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Anmerkungen
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Sprache
englisch
Veröffentlichungsjahr
2004
HGF-Berichtsjahr
0
ISSN (print) / ISBN
0021-9738
e-ISSN
1558-8238
Zeitschrift
Journal of Clinical Investigation
Quellenangaben
Band: 114,
Heft: 4,
Seiten: 589-597
Verlag
American Society of Clinical Investigation
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Diabetes Research (IDF)
Institute of Diabetes and Obesity (IDO)
Institute of Pancreatic Islet Research (IPI)
Institute of Diabetes and Obesity (IDO)
Institute of Pancreatic Islet Research (IPI)
POF Topic(s)
30201 - Metabolic Health
30502 - Diabetes: Pathophysiology, Prevention and Therapy
30502 - Diabetes: Pathophysiology, Prevention and Therapy
Forschungsfeld(er)
Helmholtz Diabetes Center
PSP-Element(e)
G-502100-001
G-502290-001
G-502290-001
PubMed ID
15314696
DOI
10.1172/JCI21307
WOS ID
000223287500019
Erfassungsdatum
2004-08-00