Differential insulitic profiles determine the extent of beta cell destruction and the age at onset of type 1 diabetes

Abstract

Type 1 diabetes (T1D) results from a T-cell mediated destruction of pancreatic beta cells following the infiltration of leukocytes (including CD8+, CD4+ and CD20+ cells) into and around pancreatic islets ("insulitis"). Recently, we reported that two distinct patterns of insulitis occur in patients with recent-onset T1D from the UK and that these differ principally in the proportion of infiltrating CD20+ B-cells (designated "CD20Hi" and "CD20Lo" respectively). We have now extended this analysis to include patients from the nPOD (USA) and DiViD (Norway) cohorts and confirm that the two profiles of insulitis occur more widely. Moreover, we show that patients can be directly stratified according to their insulitic profile and that those receiving a diagnosis before the age of 7 years always display the CD20Hi profile. By contrast, individuals diagnosed beyond the age of 13 years are uniformly defined as CD20Lo. This implies that the two forms of insulitis are differentially aggressive and that patients with a CD20Hi profile lose their beta cells at a more rapid rate. In support of this, we also find that the proportion of residual insulin-containing islets (ICIs) increases in parallel with age at onset of T1D. Importantly, those diagnosed in, or beyond, their teenage years retain ∼40% ICIs at diagnosis, implying that a functional deficit rather than absolute beta cell loss may be causal for disease onset in these patients. We conclude that appropriate patient stratification will be critical for correct interpretation of the outcomes of intervention therapies targeted to islet-infiltrating immune cells in T1D.