Endocrine self and gut non-self intersect in the pancreatic lymph nodes

Abstract

The autoimmune cascade that culminates in diabetes initiates within pancreatic lymph nodes (PLNs). Here, we show that developmentally controlled lymphogenesis establishes a preferential trafficking route from the gut to the PLN, where T cells can be activated by antigens drained from the peritoneum and the gastrointestinal tract. Furthermore, intestinal stress modifies the presentation of pancreatic self-antigens in PLNs. The convergence of endocrine and intestinal contents within PLNs has significant implications for type 1 diabetes and may help to explain the link between autoimmune pathogenesis and environmental provocation.autoimmunity ͉ diabetes ͉ peritoneal lymphatics ͉ enteropathy T ype 1 diabetes (T1D) is an autoimmune disorder characterized by destruction of the insulin-producing ␤ cells of the endocrine pancreas. The first stage of disease, known as insulitis, entails leukocyte invasion of the pancreatic islets; the second stage, overt diabetes, is marked by massive death of islet ␤ cells and the subsequent loss of glucose homeostasis (1). The immune assault on ␤ cells that preludes diabetes is orchestrated by T cells. Naïve, ␤ cell-reactive T cells initially encounter their cognate antigen in pancreatic lymph nodes (PLNs) (2). Islet antigens are shuttled to these nodes by CD11b ϩ dendritic cells and subsequently presented to T lymphocytes (3). Thus, PLNs are key to diabetes pathogenesis (4, 5), the location where tolerance to pancreatic self-antigens is first broken.Environmental factors impinge on an individual's genetic susceptibility to type 1 diabetes (6). Alimentary agents such as enteroviruses (e.g., coxsackie virus) and dietary antigens (e.g., gluten) are associated with T1D (7-13), and there is a frequent association between T1D and celiac disease (14). However, the precise mechanisms by which these factors might influence the autoimmune response to pancreatic ␤ cells remain elusive. The common entry route of such environmental components certainly raises the question of how the gastrointestinal tract relates to the pancreatic axis. Materials and MethodsMice. All mice were bred and maintained under barrier conditions in the Joslin Diabetes Center animal facility in accordance with National Institutes of Health guidelines. BDC2.5͞NOD, OT-I͞Rag-1 0 , and OT-II TCR transgenic (tg) mice are described in refs. 15-17. NOD, NOD͞SCID, and B6.H2 g7/g7 mice were bred at the Joslin Diabetes Center animal facility, and B6 mice were obtained from The Jackson Laboratory.Antigens. Mice were injected i.p., intragastrically, or i.v. with chicken ovalbumin (OVA) (Sigma), BSA (Sigma), or saline (as controls), and OVA-coated beads, OVA-loaded apoptotic cells, or purified pancreatic islets. Soluble OVA was adsorbed onto 0.5-m polystyrene microparticles (beads) (Polysciences) according to the manufacturer's protocol. Purified pancreatic islets were purified from 4-to 6-week-old NOD mice at the Islet Core of the Juvenile Diabetes Research Foundation Center at Harvard Medical School and were resuspended in PBS for in...

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

“…This hypothesis is supported by the observation that chemical disruption of the intestine with 2% (wt/vol.) dextran sodium sulphate in the drinking water also leads to the proliferation of diabetogenic T cells and accelerates development of insulitis [18].…”

“…The primary activation of diabetogenic CTLs occurs within the pancreatic and gut-associated lymph nodes (LNs) [16,17]. Lymphocytes within the pancreatic LNs thus communicate with the intestinal immune system, and the gut and its luminal contents may contribute to the initiation of type 1 diabetes [18]. Luminal antigens from the gut are preferentially transported to the pancreatic LNs, resulting in the local proliferation of antigen-specific CTLs [18].…”

“…Lymphocytes within the pancreatic LNs thus communicate with the intestinal immune system, and the gut and its luminal contents may contribute to the initiation of type 1 diabetes [18]. Luminal antigens from the gut are preferentially transported to the pancreatic LNs, resulting in the local proliferation of antigen-specific CTLs [18]. Additionally, diabetogenic CTLs express the gut-homing receptor α4β7 integrin [19][20][21] and CTLs activated in the gastrointestinal (GI) tract of NOD mice home to islets that express the mucosal-homing receptor mucosal addressin cell adhesion molecule-1 [19][20][21].…”

Enhanced trafficking to the pancreatic lymph nodes and auto-antigen presentation capacity distinguishes peritoneal B lymphocytes in non-obese diabetic mice

“…Peritoneal B cells in mice respond to microbial and inflammatory signals derived from the gastrointestinal tract [12]. Moreover, Turley and collegues have suggested the existence of an inherent trafficking route between the peritoneum and the pancreatic lymph nodes (PaLN) [14].…”

Visualization of Mouse Pancreas Architecture Using MR Microscopy

“…Although lymph nodes have a similar shape, they were ruled out as candidates based on the number and size of these spheres, their microstructural details, and pancreatic structures located nearby. Lymph nodes are fewer in number in the pancreas (three per pancreas) than are islets (Ն500 per pancreas), 6,7 and they tend to be much larger than islets and are generally located along the periphery of the gland (ie, not within the parenchyma) 8,9 (based also on personal communication from Shannon J. Turley and Catharina Alam, authors of Refs. 8 and 9).…”