Insulitis Revisited.

Restricted access to the inflammatory lesions in patients with type 1 diabetes (T1D) has slowed insight into human insulitis. The conception of a network collecting pancreases of donors with diabetes (Network for Pancreatic Organ Donors with Diabetes [nPOD]; www.jdrfnpod.org) has focused the international diabetes research community on islet inflammation in new tissue for the first time in decades, leading to an overhaul in insight in human insulitis. In this issue of Diabetes, Campbell-Thompson et al. (1) present the latest status of insulitis in relation to b-cell mass, serving the diabetes research community some unexpected findings. The investigators studied the frequency and composition of insulitis in relation to b-cell mass throughout the natural history of T1D, i.e., from seropositive donors without diabetes to donors with newly diagnosed and long-standing disease. Insulitis in donors with islet autoantibodies was rare (none of the 13 donors with a single antibody, 2 out of 5 with multiple antibodies, with the proportion of inflamed islets ranging from 1.4 to 6.4%), whereas a large proportion of patients with longlasting disease lacked islet autoantibodies, even if insulitis persisted. The few donors with recent-onset T1D all showed insulitis; in those individuals with established disease, the frequency of insulitis in both individual islets and within patients was less, irrespective of the age of disease onset. The rate of insulitis remains greatest in islets producing insulin compared with insulin-negative islets (33% vs. 2%), suggesting this inflammatory process is driven by the presence of b-cells. Residual b-cells persisted in all T1D donors with insulitis, and b-cell area and mass were significantly higher in T1D donors with insulitis compared with those without insulitis. The degree of heterogeneity in the numbers of inflamed islets, the rate and composition of insulitis, and the remaining b-cell mass within a tissue and between T1D patients was overwhelming. In its relatively short existence, nPOD has changed the landscape and paradigms of T1D. Recent lessons from nPOD’s tissue platform include the demonstration of islet-specific autoreactive CD8+ T cells in destructive insulitic lesions, which supports the concept of an autoimmune nature of T1D. Other seminal lessons include the persistence of b-cells, insulin production, and insulitic lesions that endure many years following the clinical manifestation of hyperglycemia. We have learned that there is an apparent disconnect between b-cell mass and function (b-cell quiescence or hibernation), that there is a profound difference in the immunopathology between men and mice, and that there exists an overwhelming heterogeneity in the pathologic lesions (varying from no infiltrate to “pauci”-autoimmune to “fulminant”) of this patient population. nPOD has also led to the demonstration of focal disease activity, similar to vitiligo or alopecia, and the persistence of b-cell mass and function long after manifestation of hyperglycemia (2–4). The latter was recently appreciated again by the findings in Exeter of C-peptide in the urine of the vast majority of T1D patients, in spite of disease duration for decades (3). Although some of the findings presented by CampbellThompson et al. (1) have been reported anecdotally before, the mere large sample size in the study alone deserves credit and adds value (2,5–7). Given this is work in progress, corroboration with new pancreas tissue is essential. The term “confirmation” does not do sufficient justice to the studies presented here, and many more studies and reports on many more tissues are warranted for common themes to emerge and be validated. At the same time, several issues need reconciliation. The study by Campbell-Thompson et al. (1) is descriptive and cross-sectional, precluding firm conclusions on changes in time throughout disease progression. It should also be appreciated that the tissues investigated were derived from autopsy, not biopsy. Indeed, subtle differences in the patterns of infiltration between living and dying donors may emerge, e.g., leukocyte infiltration of the exocrine pancreas increases with the time a donor spent in an intensive care unit (2,8). Although the number of donors and pancreas sections investigated is impressive,