Type 1 diabetes (T1D) is a T cell-mediated, tissue-specific autoimmune disease, in which the class II MHC genes play a major role controlling the disease susceptibility. This suggests that islet autoantigens and their short peptides presented on the MHC molecules are the key elements leading to the destruction of the insulin-producing beta cells in the pancreatic islets. Since self-tolerance mechanism in the thymus normally is effective in removing strong autoreactive T cells, peripheral circulating T cells are purged to avoid self- reactivity;however, autoimmune disease does occur despite of rare incidence. We hypothesized that certain inflammatory triggers may initiate the autoimmune responses in the islets by enhancing the immunogenic activity of the islet autoantigens. We have studied one candidate islet antigen, glutamic acid decarboxylase 65 KDa (GAD65), for several years and learned that unique antigen delivery and processing pathways are required to induce disease-causing or diabetogenic effector T cells, and demonstrated that a diabetes- associated candidate gene, Slc11a1, could alter the pathways of processing islet antigens in dendritic cells (DC). We recently isolated one type of microparticles/vesicles, namely exosomes (EXO), from the culture supernatants of mouse insulinomas and primary islet glial cells, and found that the EXO contains strong proinflammatory materials that could stimulate various antigen presenting cells including DC to produce inflammatory cytokines and upregulate MHC and costimulatory molecules;more importantly, the EXO collected from the primary islet glial cells also expresses several known islet autoantigens including GAD65. We thus propose a novel hypothesis that EXO may act as a unique type of endogenous adjuvant and antigen carrier that can condition APC to alter the processing/presenting of the autoantigens and thus, to activate the autoreactive T cells. In this proposal, we will first perform basic biochemistry analysis for the EXO released by the primary islet cells, and study the requirements of different TLRs in the EXO-induced innate responses to characterize the nature of the proinflammatory materials enclosed in the EXO. We will compare the islet glial cells and their EXO between diabetes-susceptible NOD strain and resistant strains to address whether abnormal or excess EXO production could be one diabetes-causative event. Then, we will use EXO as an antigen carrier to study how autoreactive effector T cells specific for islet antigens, particularly GAD65, are induced following processing the EXO in DC. We predict that increased leakage of islet antigens via EXO secretion under stress or inflammatory situation is the key for activating highly diabetogenic T cells. Finally, we will continue studying the Slc11a1 gene for its roles in DC activation and antigen processing. We will use EXO as a vehicle for activating DC and delivering antigens. We anticipate that EXO can upregulate Slc11a1 function in DC and thus promote induction of the disease-causing Th1 cells.

Public Health Relevance

Autoreactive T cells that cause destruction of the insulin-producing beta-cells in Type 1 Diabetes (T1D) recognize small pieces of islet antigens, namely peptides, in the context of major histocompatibility complex (MHC) expressed by antigen presenting cells (APC);however, the choice of peptides and the levels of their presentation are highly regulated in the APC, and could become abnormal in an inflammatory environment such as the pancreas of prediabetic patients. Evidence suggests that exosomes (EXO) secreted by some islet cells contains unique antigenic materials with a strong adjuvant effect, which may cause abnormal activity to the APC and result in activation of the autoreactive T cells in the pancreas. Therefore, studying basic biochemistry of the EXO, their interactions with the APC and consequences on antigen presentation and T cell activation will provide necessary information for designing tools or strategies to prevent the autoreactive T cells from destroying the insulin-producing cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091663-03
Application #
8537447
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2011-09-20
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$381,996
Indirect Cost
$172,108
Name
Torrey Pines Institute for Molecular Studies
Department
Type
DUNS #
605758754
City
Port Saint Lucie
State
FL
Country
United States
Zip Code
34987
Rahman, Muhammad Jubayer; Regn, Danielle; Bashratyan, Roman et al. (2014) Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice. Diabetes 63:1008-20
Bashratyan, Roman; Sheng, Huiming; Regn, Danielle et al. (2013) Insulinoma-released exosomes activate autoreactive marginal zone-like B cells that expand endogenously in prediabetic NOD mice. Eur J Immunol 43:2588-97