Achenbach Peter, Koczwara Kerstin, Knopff Annette, Naserke Heike, Ziegler Anette-G, Bonifacio Ezio
Institut für Diabetesforschung, Kölner Platz 1, 80804 Munich, Germany.
J Clin Invest. 2004 Aug;114(4):589-97. doi: 10.1172/JCI21307.
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.
1型糖尿病风险儿童可早期出现胰岛素自身抗体（IAA）。这些儿童中许多（但并非全部）随后会出现多种胰岛自身抗体并发展为糖尿病。为了确定自身抗体成熟度是否反映疾病进展，在BABYDIAB队列中对从出生就开始随访的儿童的首次及后续IAA阳性样本，通过竞争性放射结合试验测量IAA亲和力。首次阳性样本中的IAA亲和力范围从小于10⁶ l/mol到大于10¹¹ l/mol。高亲和力与HLA DRB1*04、IAA出现时的年轻年龄以及随后发展为多种胰岛自身抗体或1型糖尿病有关。多种抗体阳性儿童的IAA亲和力平均比仍为单一IAA阳性或自身抗体转为阴性的儿童高100倍。所有高亲和力IAA都需要保留人胰岛素A链8 - 13位残基，并且与胰岛素原反应。相比之下，大多数低亲和力IAA依赖于B链羧基末端残基，且不与胰岛素原结合。这些数据与以下概念一致，即1型糖尿病与在HLA DR4背景下早期持续暴露于（前）胰岛素有关，并且表明高亲和力的胰岛素原反应性IAA可识别出糖尿病风险最高的儿童。
