NIH Backs Project Examining Failure of Immune Tolerance Leading to Autoimmune Disease

A new research project will seek to understand the development of immune cells that drive autoimmune diseases such as multiple sclerosis (MS).

The project will be led by Leszek Ignatowicz, PhD, a professor in the Institute for Biomedical Sciences at Georgia State University, and will be funded by a five-year, $1.95 million grant from the National Institutes of Health.

Autoimmune diseases are conditions in which the body’s immune system attacks the body’s own tissues. More than 100 autoimmune diseases have been described, including MS, lupus, inflammatory bowel disease, and myasthenia gravis.

Many of these conditions involve immune T-cells that attack the body’s own tissues. T-cells have specialized receptors that allow them to detect a particular molecular pattern, called an antigen. Individual T-cells have receptors that are specifically tailored to recognize a particular antigen. Upon recognizing their antigen, most T-cells will become activated, triggering an inflammatory immune response.

The process of T-cell development has evolved to produce T-cells with receptors that do not recognize antigens that are normally found in the body (e.g., proteins that are part of human cells), a phenomenon called tolerance. There are two types of tolerance: central and peripheral.

Central tolerance involves having immature T-cells undergo “training” in the thymus. Within this organ, immature T-cells are presented with an abundance of antigens found in the body. Most T-cells that react with these antigens — called autoreactive T-cells — are killed off, while those that do not react mature and exit the thymus into the body.

“However, an unknown number of autoreactive cells escape deletion or commit to immunosuppressive, regulatory linage (Tregs),” the researchers state in their research project.

Some autoreactive T-cells can mature into regulatory T-cells (Tregs), a specialized kind of T-cell that, when activated in response to one of the body’s own antigens, releases signaling molecules that limit inflammation. This is peripheral tolerance, an additional tolerance mechanism that exists to prevent autoreactive reactions in the body.

Autoimmune diseases are caused by a failure in tolerance, in which T-cells that are autoreactive leave the thymus and mature into inflammatory T-cells, rather than Tregs.

The new project will investigate tolerance mechanisms further in order to better understand how they can go awry in the context of autoimmune disease development.

“This research will help us to understand the basis of self-reactivity, revisit the relative significance of thymic and peripheral tolerance, and can lead to the development of new therapeutic protocols to treat autoimmune diseases,” the team wrote.

Researchers will specifically assess how autoreactive T-cells escape tolerance mechanisms, and determine the antigens they respond to.

“The goal of this work is to better understand how the natural limitations of thymic selection predispose us to autoimmunity,” Ignatowicz said in a press release.

“This research will provide a better understanding of cellular and molecular mechanisms driving autoimmunity and help to develop therapeutic strategies targeting autoreactive T cells that escaped central tolerance. From a clinical perspective, identification of dormant, autoreactive T cells is critically important,” Ignatowicz added.