Identification and characterisation of tertiary lymphoid organs in human type 1 diabetes

Abstract

Aims/hypothesis We and others previously reported the presence of tertiary lymphoid organs (TLOs) in the pancreas of NOD mice, where they play a role in the development of type 1 diabetes. Our aims here are to investigate whether TLOs are present in the pancreas of individuals with type 1 diabetes and to characterise their distinctive features, in comparison with TLOs present in NOD mouse pancreases, in order to interpret their functional significance. Methods Using immunofluorescence confocal microscopy, we examined the extracellular matrix (ECM) and cellular constituents of pancreatic TLOs from individuals with ongoing islet autoimmunity in three distinct clinical settings of type 1 diabetes: at risk of diabetes; at/after diagnosis; and in the transplanted pancreas with recurrent diabetes. Comparisons were made with TLOs from 14-week-old NOD mice, which contain islets exhibiting mild to heavy leucocyte infiltration. We determined the frequency of the TLOs in human type 1diabetes with insulitis and investigated the presence of TLOs in relation to age of onset, disease duration and disease severity. Results TLOs were identified in preclinical and clinical settings of human type 1 diabetes. The main characteristics of these TLOs, including the cellular and ECM composition of reticular fibres (RFs), the presence of high endothelial venules and immune cell subtypes detected, were similar to those observed for TLOs from NOD mouse pancreases. Among 21 donors with clinical type 1 diabetes who exhibited insulitis, 12 had TLOs and had developed disease at younger age compared with those lacking TLOs. Compartmentalised TLOs with distinct T cell and B cell zones were detected in donors with short disease duration. Overall, TLOs were mainly associated with insulin-containing islets and their frequency decreased with increasing severity of beta cell loss. Parallel studies in NOD mice further revealed some differences in so far as regulatory T cells were essentially absent from human pancreatic TLOs and CCL21 was not associated with RFs. Conclusions/interpretation We demonstrate a novel feature of pancreas pathology in type 1 diabetes. TLOs represent a potential site of autoreactive effector T cell generation in islet autoimmunity and our data from mouse and human tissues suggest that they disappear once the destructive process has run its course. Thus, TLOs may be important for type 1 diabetes progression. Graphical abstract

A decisive bridge between innate immunity and the pathognomonic morphological characteristics of type 1 diabetes demonstrated by instillation of heat-inactivated bacteria in the pancreatic duct of rats

“…Also, the areas of dense lymphatic tissues seemingly randomly distributed in the exocrine pancreas in the rats (Fig. 3 ) mimic the compartmentalized tertiary lymphoid organs recently reported in human subjects with short T1D disease duration [ 27 , 28 ]. Similarly, the rats showed small multifocal infiltrates of CD3+ cells in acinar regions (Fig.…”

100 YEARS OF INSULIN: Pancreas pathology in type 1 diabetes: an evolving story

“…Among donors with autoantibodies, and donors with T1D with residual beta cells, there was a polarization of the CD8+ T cells toward the islets (Rodriguez-Calvo et al 2014). As noted, TLOs were also observed in the pancreas of donors with multiple autoantibodies and insulitis, but not among donors with a single autoantibody (Korpos et al 2021). This is also consistent with TLOs having a role in promoting islet autoimmunity.…”

“…Recent studies of extracellular matrix components have led to the observation that another feature of pancreas pathology is the formation of tertiary lymphoid organs (TLOs). First described in NOD mice pancreas (Penaranda et al 2010), TLOs were demonstrated in the human pancreas among donors without diabetes expressing multiple autoantibodies, among patients with T1D, and in the transplanted pancreas with demonstrated recurrence of islet autoimmunity (Korpos et al 2021). Several features of the TLOs in the human pancreas were shared with NOD mice, such as the cellular and ECM composition of reticular fibers, the presence of high endothelial venules, and immune cell subtypes detected.…”

CD4+ Cytotoxic T Cells Involved in the Development of EBV-Associated Diseases

“…They have also been observed in the kidneys of patients with lupus nephritis, being associated with increased renal function impairment [ 240 ]. The same occurs in the pancreas of patients with T1D, where these ectopic lymphoid structures generate autoreactive effector T cells against pancreatic islets, and they may be important for disease progression [ 241 , 242 ]. However, in the latter two cases, the presence of EBV in the lymphoid aggregates was not analyzed.…”