Immunosupression of Type 1 Diabetes

Physiological changes in T1D vs a healthy person
(inability to control glucose levels due to lack of insulin being produced)

Type 1 diabetes (T1D) is a serious, yet often overlooked, autoimmune disease that affects approximately 3 million Americans.  It is often lumped into the general category of “diabetes” alongside type 2 diabetes, even though T1D is generally more serious and isn’t preventable.  In people with T1D, islet, or beta (β) cells, in the pancreas are slowly destroyed by the body.  These cells are responsible for producing insulin, which controls blood glucose levels and keeps them at a healthy level.  People with T1D have to constantly monitor their blood sugar and inject themselves with insulin in order to control their glucose levels or risk serious complications such as blindness, foot amputation, or even coma.  As of now, there is no cure for the disease.  Recent research has focused on trying to find a way to prevent the body from attacking itself through manipulation of the immune system and/or to restore β cell function.  However, even an improvement in treatment would greatly increase the quality of life for T1D patients.

            

Creation of Insulin: proinsulin cleaved to
produce active insulin and C-peptide

Autoimmune diseases are more complex to treat since it’s often very difficult to suppress only the part of the immune system that isn’t functioning.   Similar to cancer, it’s hard to kill only the bad cells in the body without affecting the good ones.  Roep et al have taken a step in the direction of successful immunosupression of the bad immune cells involved with T1D.  In order to understand their work, it’s first necessary to understand a little more about insulin and the immune system.  Insulin isn’t synthesized in its functional state.  It is synthesized as pro-insulin and then cleaved into an active portion with the A and B peptides, which is insulin, and an inactive portion, called C-peptide; you can’t have one without the other (as seen in the figure to the left).  When doctors want to measure β-cell function, they look at C-peptide levels.  So the researchers use C-peptide levels to determine if their methods are preventing immune cells from destroying insulin-producing cells.

LAG3 Gene and Early Onset of Type 1 Diabetes

The lymphocyte activation gene-3, LAG3, is a significant regulator of the immune system and recently has been concretely attributed to development in Type 1 Diabetes in diabetes prone mice. Type 1 Diabetes is an autoimmune disease in which cells of the body are mistaken as pathogens and destroyed by the immune system. In Type 1 Diabetes, the cells that are destroyed are the insulin-producing beta cells. This disease is generally characterized by insulitis and beta-cell autoantibodies (Van den Driessche et. al, 2009).

LAG3 may be responsible for the malfunctioning of the immune system and the onset of Type 1 Diabetes. LAG3 plays a large part in regulating T cells, which are critical to fighting infections and diseases. LAG3 both regulates the numbers of T cells in the body and is required for the proper functioning of T cells and Natural Killer cells (Workman et. al, 2009). Moreover, many critical cell types in the immune system express LAG3, including CD4⁺ and CD8⁺ T cells, natural killer cells, and plasmacytoid dendritic cells (Workman et. al, 2009). These cells each play important functions in detecting pathogens throughout the body and carrying out the removal of harmful entities.

Lag3 deletion in normal mice has been documented to have minor noticeable changes, with little to no effect on the prevalence of diabetes development (Miyazaki et. al, 1996). However, it has been recently demonstrated that in autoimmune-prone conditions, LAG3 plays a critical role in an early onset of Type 1 Diabetes (Bettini et. al, 2011).

Bettini et. al used non-obese diabetic mice, or NOD mice, to test the control of LAG3 on three important types of cells in the immune system: T cells, natural killer cells and plasmacytoid dendritic cells (2011). NOD mice were the subjects of choice, for they are often used as a mouse model of Type 1 Diabetes (Crawford et al., 2011). Bettini et. al bred NOD mice with a Lag3 mutation, rendering the gene non-functional. The mice were then tested for diabetes onset at various points of development by analysis of urine samples and blood glucose levels.