Heterogeneity and Lobularity of Pancreatic Pathology in Type 1 Diabetes during the Prediabetic Phase

Abstract

SummaryType 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells are destroyed in the islets of Langerhans. One of its main pathological manifestations is the hyper-expression of Major Histocompatibility Complex I (MHC-I) by beta cells, which was first described over 3 decades ago yet its cause remains unknown. It might not only be a sign of beta cell dysfunction but could also render the cells susceptible to autoimmune destruction; for example, by islet-infiltrating CD8 T cells. In this report, we studied pancreas tissue from a 22-year-old non-diabetic male cadaveric organ donor who had been at high risk of developing T1D, in which autoantibodies against GAD and IA-2 were detected. Pancreas sections were analyzed for signs of inflammation. Multiple insulin-containing islets were identified, which hyper-expressed MHC-I. However, islet density and MHC-I expression exhibited a highly lobular and heterogeneous pattern even within the same section. In addition, many islets with high expression of MHC-I presented higher levels of CD8 T cell infiltration than normal islets. These results demonstrate the heterogeneity of human pathology that occurs early during the pre-diabetic, autoantibody positive phase, and should contribute to the understanding of human T1D. (J Histochem Cytochem 63:626-636, 2015)

Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes

“…To our surprise, none of the 94 CDR3β sequences matched that of the GAD4.13 clone (Supplemental Table 9), despite the 1 in 4 frequency of abundance predicted from prior sampling (Figure 9). Absence of the clone from this second pLN sample was also observed using a HLA-DR*04-01 GAD-peptide-loaded tetramer (555-567; 557I) that was originally used to isolate the GAD4.13 clone (data not shown) (45). These findings highlight the potential for heterogeneity among nPOD pLN; however, to evaluate the degree of heterogeneity will require direct testing of multiple pLN.…”

“…Alternatively, it is possible that within the pLN, detection of pathogenic clones may depend upon the proximity of the sampled LN to an active insulitis lesion. In contrast to NOD mice, human insulitis and HLA class I overexpression can be found in only a small percentage of the pancreatic islets (50) and occurs in a lobular fashion (45,(51)(52)(53). This may imply that future studies investigating the T cell repertoire in the pLN should document the anatomical position of the LN in relation to nearby histological findings within the pancreas.…”

Differential Insulitic Profiles Determine the Extent of β-Cell Destruction and the Age at Onset of Type 1 Diabetes

“…This then raises an important question about the extent to which an individual set of data derived from one section can be considered representative of the entire pancreas. This is especially true given that the processes of insulitis and b-cell loss occur in a lobular manner across the gland (20)(21)(22)(23). Such considerations inevitably mean that it would be dangerous to draw firm conclusions from a single pancreatic section taken from one individual patient studied in isolation.…”

Histochemical Insights into Pancreatic Islet Biology

“…They observed an enormous increase in islet cell mass with 586442J HCXXX10.1369/0022155415586442Hull and BaskinEditorial editorial2015 altered architectural organization of α-and δ-cells, suggesting that EpCAM may potentially regulate islet expansion. Rodriguez-Calvo et al (2015) investigated the pancreas of a double autoantibody-positive human donor at high risk of developing T1D, showing that elevated MHC-I expression and CD8 T cell infiltration are heterogeneously distributed in the islets and differentially affect islets situated in different regions of the pancreas. Brissova et al (2015) addressed the question of whether vascularization of islets in humans resembles the high degree of vascularization found in mouse islets and whether this arrangement is altered in diabetes.…”