Diabetes Pathogenesis - Role of Natural Killer Cells, T Cells and a Novel Neuropeptide

Diabetes is a major health problem affecting nearly 5% of the population world wide. It is a heterogeneous group of diseases with the autoimmune type 1 diabetes (T1D) and the metabolic type 2 diabetes (T2D) being the major types. Here we have investigated immune mechanisms of the pathogenesis of T1D and properties of a novel anorexogenic peptide in the pancreatic islets and in T2D. One drawback with an efficient immune system is the risk of developing autoimmune diseases, where immune reactions are mounted against self. T1D is an example of an autoimmune disease where the insulin producing beta cells in the pancreas are destroyed by the body’s own immune system. As for most autoimmune diseases, the pathophysiology of T1D is complex, involving several susceptibility genes and environmental triggering factors. Autoreactive T cells are key players in the pathogenesis of T1D, but many other immune cells are likely also involved. Studies on T1D are complicated by the difficulty to access the target-organ of the autoimmune attack: the pancreas. The non-obese diabetic (NOD) mouse spontaneously develops an autoimmune disease that well resembles the human T1D. Much of our knowledge on T1D is therefore derived from studies in the NOD mouse. We have investigated the involvement of natural killer (NK) cells in T1D in the NOD mouse, with a particular focus on the pancreas infiltrating NK cells (paper I). The NK cells were found to infiltrate the pancreas of NOD mice early during disease progression. They have distinct phenotype and function consistent with activation but also display signs of exhaustion, suggesting that NK cells may play a role in the pancreas during T1D pathogenesis. To test this hypothesis we depleted NK cells from the NOD mouse with an antibody to the IL-2/15Rβ and found that the mice were protected from T1D (paper II). This supports, but does not fully prove, the notion that NK cells are pathogenic in T1D, since a minor subset of T cells also was affected by the treatment. We further investigated the effect on T1D by the signalling molecule DAP12, which associates to activating receptors on NK cells, myeloid cells and some T and B cells (paper III). DAP12 deficiency led to accelerated T1D in the simplified BDC2.5/B6 animal model for T1D, possibly as a result of impaired suppression by regulatory T cells (Treg) of the T cell priming in the pancreatic lymph node (PLN). The other major type of diabetes is T2D. It is a metabolic disease where impaired beta cell secretion of insulin is the main pathogenic event together with a decreased sensitivity to insulin in liver and non-hepatic cells. Many mediators are shared between the central nervous system (CNS) and the endocrine pancreas. Nucleobindin-2 is a protein with wide distribution in the CNS, which was recently shown to have anorexogenic properties. In paper IV we for the first time demonstrate nucleobindin-2 expression in human pancreatic islets, opening up for a possible involvement of this protein in glucose homeostasis. In conclusion, we have identified new immunologic mechanisms of importance in the pathogenesis of T1D, particularly a novel subset of pancreatic NK cells and DAP12 associated Treg control of autoreactive T cell priming in the PLN. We have also demonstrated nucleobindin-2 in human pancreatic islets. LIST OF PUBLICATIONS I. Brauner H, Elemans M, Lemos S, Broberger C, Holmberg D, FlodstromTullberg M, Karre K, Hoglund P. Distinct phenotype and function of NK cells in the pancreas of nonobese diabetic mice. J Immunol. 2010 Mar 1;184(5):2272-80. II. Brauner H, Johansson S, Hall HT, Flodstrom-Tullberg M, Karre K, Hoglund P. Depletion of IL-2/15Rβ positive cells close to disease onset protects from diabetes in non obese diabetic mice: role of natural killer cells and a subset of T cells. Manuscript III. Hall HT*, Sjolin H*, Brauner H, Tomasello E, Dalod M, Vivier E, Hoglund P. Increased diabetes development and decreased function of CD4+CD25+ Treg in the absence of a functional DAP12 adaptor protein. Eur J Immunol. 2008 Nov;38(11):3191-9.