Abstract
Autoantibodies against islet cell antigens are routinely used to identify subjects at increased risk of symptomatic type 1 diabetes, but their relation to the intra-islet pathogenetic process that leads to positivity for these markers is poorly understood. We screened 556 non-diabetic organ donors (3 months to 24 years) for five different autoantibodies and found positivity in 27 subjects, 25 single- and two double autoantibody-positive donors. Histopathological screening of pancreatic tissue samples showed lesion characteristic for recent-onset type 1 diabetes in the two organ donors with a high-risk profile, due to their positivity for multiple autoantibodies and HLA-inferred risk. Inflammatory infiltrates (insulitis) were found in a small fraction of islets (<5%) and consisted predominantly of CD3+CD8+ T-cells. Islets with insulitis were found in close proximity to islets devoid of insulin-positivity; such pseudo-atrophic islets were present in multiple small foci scattered throughout the pancreatic tissue or were found to be distributed with a lobular pattern. Relative beta cell area in both single and multiple autoantibody-positive donors was comparable to that in autoantibody-negative controls. In conclusion, in organ donors under age 25 years, insulitis and pseudo-atrophic islets were restricted to multiple autoantibody-positive individuals allegedly at high risk of developing symptomatic type 1 diabetes, in line with reports in older age groups. These observations may give further insight into the early pathogenetic events that may culminate in clinically overt disease.
Highlights
Insulitis is an inflammatory lesion of the islets of Langerhans characteristic for patients with recent-onset type 1 diabetes
Four autoantibody-positive individuals in total were identified with insulitis according to international consensus criteria [4, 18], half of them in subjects >45 years of age, an age group that is substantially older than the group of 10–14 years in which the incidence of type 1 diabetes is at its highest level [1]
Beta cell area and replication The relative beta cell area was measured in all 27 autoantibody-positive donors and an equal number of autoantibody-negative controls matched for age, sex, and BMI (Table 1)
Summary
Insulitis is an inflammatory lesion of the islets of Langerhans characteristic for patients with recent-onset type 1 diabetes. In a classical model for the development of type 1 diabetes, autoantibodies are considered to be indicators for ongoing autoimmune beta cell destruction in genetically susceptible individuals, triggered, and promoted by as yet unidentified environmental factors [15, 16]. Donor pancreata from autoantibody-positive non-diabetic organ donors—used as a model for at risk individuals [3, 4, 18,19,20,21,22]—showed no evidence of decreased relative beta cell area [4, 18, 20, 21]. Insight into early histopathological changes in islet tissue in autoantibody-positive individuals under the age of 25 years is limited and formed the rationale for studying a large cohort of non-diabetic organ donors below the age of 25 years. We compared histopathological changes in islet tissue from autoantibody-positive organ donors to a matched control group of autoantibodynegative organ donors from the same cohort
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