Dynamic pattern of disease-associated autoantibodies in siblings of children with type 1 diabetes - A population-based study

To study the dynamics of disease-associated humoral immune responses, we an alyzed autoantibodies to the IA-2 protein (IA-2A), glutamic acid decarboxyl ase (GADA), and insulin (IAA) and also islet cell antibodies (ICA) in a pop ulation-based, prospective, representative series of 710 siblings (< 20 yea rs of age) of children with type 1 diabetes. Positivity for single autoanti bodies was observed in 8-13% of these siblings during an average follow-up of 4 years. The overall incidence rates per 1,000 years (number of cases/pe rson-years in parentheses) for positive seroconversion of IA-2A were nine ( 19/2,123), followed by six (12/2,049) for GADA, 19 (40/2,111) for IAA, and 16 (31/1965) for ICA. Positive seroconversions seemed to be associated with a young age of the sibling, HLA DR3/DR4 heterozygosity, HLA identity, and a high initial number of detectable autoantibodies. The overall incidence r ates per 1,000 years (number of cases/person-years in parentheses) for inve rse seroconversion of IA-2A were 76 (12/157), followed by 42 (10/237) for G ADA, 460 (32/70) for 1AA, and 27 (9/331) for ICA. No consistent risk factor for inverse seroconversions was present, although seroconversions were mos t frequent in siblings with older age, male sex, HLA phenotypes other than DR3/DR4, a small family size, and no other autoantibodies detectable at ser oconversion. Altogether, these observations indicate that beta -cell autoim munity may be induced at any age in childhood and adolescence. HLA-conferre d genetic disease susceptibility is a strong determinant of persistent beta -cell autoimmunity, but environmental factors may also contribute to such autoimmunity.