News & Research

    Children's Hospital of Pittsburgh UPMC, Pittsburgh, Pennsylvania

Environmental triggers, ER-stress and type 1 diabetes

General Research Subject: Type 1 Diabetes

Focus: Immunology

Type of Grant: Career Development

Project Start Date: July 1, 2007

Project End Date: June 30, 2012

Research Description

At present we do not know what triggers Type 1 Diabetes (T1D), despite tremendous efforts made toward understanding the events that lead to triggering the immune system toward normal tissue. It is believed that certain environmental triggers, such virus infections can lead to the normal activation of the immune system to clear the infection. The islet beta cell also induces a response that helps to block the virus from replicating, unfortunately in individuals with autoimmunity, the immune system becomes fooled into believing that the normal islet beta cell response to infection is foreign and it destroys the islet beta cells. It has now become evident in the mouse models of T1D that these normal islet beta cell responses occur naturally during early development.

We have begun to study this physiologically normal event by using a T-lymphocyte that recognizes some islet-beta cell antigen that may become present during normal islet development events, to further test the hypothesis that these normal events of islet-beta cells turns on anti-stress signals, and that these signals are not tolerated by individuals that suffer from autoimmunity. This work will allow us to better understand the series of events that leads to the immune system accidentally attacking normal tissue during normal development, as wells as to better understand how environmental triggers that cause the same type of induced anti-stress protection lead to immune system activation and islet-beta cell destruction.

Reseacher Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

The area of research this project focuses on is the recognition of islet beta cell antigens by the host immune system under conditions of ER-stress, leading to T cell mediated beta cell destruction and ultimately diabetes. Our hypothesis is that in autoimmune prone individuals the normal physiological generation of ER-stress leads to the production of neo-antigens that elicit auto-reactive T cells. To test this hypothesis we will focus on the correlation between ER-stress induced apoptosis and the time window of activation for two model systems used to study T cell mediated beta cell destruction, BDC2.5 TCR-Tg as well as the original BDC2.5 T cell clone. We hypothesize that during the developmental wave of beta cell apoptosis in mouse pancreata, the ER-Stress/UPR pathway becomes activated leading to the overexpression of ER-Stress associated proteins. Further, the up-regulation of these ER-stress associated proteins in autoimmune prone mice, like NOD, may no be tolerated by immune system with a propensity to react to self-antigen, and therefore these proteins are looked upon as foreign. The ER-stress associated proteins are available to be picked up by dendritic cells and presented to T cells in the draining lymph node to initiate a self-reactive immune response. Interestingly, many of the proposed environmental triggers that lead to the initiation of T1D such as viral infections and chemical toxins lead to ER-stress induced stress.

What role will this particular project play in preventing, treating and/or curing diabetes?

This work will help to link the role of environmental triggers that initiate diabetes and why the autoimmune prone immune system mistakenly attacks normal tissue. Furthermore we hope that this work will allow us to better understand how these environmental triggers activate the immune system, and whether what we gain from understanding these new target antigens can new initiate prophylactic therapy to quell this non-tolerated response.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

We are hopeful that the work will lead us to a better understanding of why ER-stress induced by environmental triggers leads to the aberrant recognition of self-antigen and why these normal proteins produced during stressful events are recognized by the immune system as foreign. Furthermore, if we have a better understanding as to why the immune system becomes activated against particular antigens we can begin to design therapies in conjunction with other strategies that we are developing to derive protocols that will incorporate the elimination of the rogue T cells without globally making individuals immunodeficient. These strategies are a long way off, however understanding the processes that lead to self-antigen recognition can be looked upon as a major milestone toward realizing this approach as a viable option for early intervention.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

Diabetes is a devastating disease that affects all of us. Those individuals that do not have the disease know someone who struggles with it and those with it know their struggle and fear the long-term affects of the complications. The complications associated with the disease took their toll on my mother, by ravaging her body until in the end she finally succumbed. Studying Type 1 diabetes, which affects primarily children, leaves me with an even stronger sense of urgency to understand the disease. I truly believe and began my career in the field because I think I can help to find a cure for this disease. When you decide to study a chronic disease like T1D, you have to dedicate your life to it, and all you can hope for is that through your work and the ability to teach and train others it will all come together to find a cure for this disease. This award obviously helps me to continue my work toward understanding the disease process and also to train the next group of young scientists to continue the efforts.

I always joke with the people in my lab, telling them we are in unique job situation. We work to put ourselves out of work. I hope that I have to change jobs sooner than later. In what direction do you see the future of diabetes research going? I see the direction for T1D moving toward understanding and controlling aberrant immune function. In conjunction with our ability to now predict with reasonable confidence those individuals who will progress to disease we can utilize our knowledge gained from regulation of immune function to designed strategies that will lead to prophylactic treatment individuals predisposed to diabetes onset. Also detailed analysis of environmental factors would be critical for understanding triggers that lead to the initiation of T1D. Although these types of studies do not appear to be in the applied channel of research the knowledge gained from them is critical for the implementation of therapeutic design.