Insulitis and Exocrinitis in Autoantibody-positive Non-diabetic Individuals: Role of HLA Genotypes

Context: Type 1 diabetes (T1D) is characterized by the presence of autoantibodies on a genetic background largely determined by HLA class II haplotypes. Stage 1 T1D is characterized by the presence of multiple autoantibodies and normoglycemia.

Objective: To investigate the prevalence of high-risk HLA-DQB1 haplotypes and the extent of islet autoimmunity in pancreatic tissues from non-diabetic organ donors with autoantibodies.

Design: We analyzed 117 virtual pancreatic slides from 30 antibody-positive non-diabetic donors, from the Network for Pancreatic Organ Donors with Diabetes (nPOD).

Patients: 30 non-diabetic individuals positive for ≥1 autoantibody. HLA haplotypes were classified as at risk (DQ2, namely DQB1*02:01 and/or DQ8, namely DQB1*03:02), protective (DQ6, namely DQB1*06:02) or neutral (other HLA-DQ alleles).

Main Outcome Measure: CD3+ lymphocyte infiltration of both endocrine and exocrine pancreas, according to HLA.

Results: Among these 30 individuals with a median age of 25 years (interquartile range 21-39); median BMI 24 kg/m² (21-30), 23 were single autoantibody-positive and 7 were positive for 2 autoantibodies. β-cell mass was normal in all. HLA-DQ allele distribution was similar to that of autoantibody-negative non-diabetic nPOD donors, and differed from that of nPOD donors with stage 3 T1D. Insulitis was identified only in one case. CD3+ lymphocyte densities did no correlate with HLA status or autoantibody number or titers, neither in islets nor in the exocrine pancreas.

Conclusions: Contrary to stage 3 T1D, autoantibody-positive donors had normal β-cell mass and no significant insulitis, suggesting heterogeneity in the progression of autoimmunity, even in the presence of genetic risk, rather than a uniform slow-progressing process.