Lay Summary

Proposal No. IBD-0235
Principal Investigator: Lisa Ganley-Leal, Ph.D.
Applicant Organization: Boston Medical Center (Massachusetts, U.S.A.)
Project Title: Human B cells as potential mediators of inflammation in chronic inflammatory disease
Period of Award: November 1, 2008 – June 30, 2011

Chronic inflammatory diseases, such as inflammatory bowel disease and diabetes, result when the immune system fails to properly distinguish the body’s own cells from those of pathogens thereby maintaining a continual abnormal immune response. Thus, patients with chronic inflammatory disease may feel ill because the immune system acts as though the body is constantly fighting an infection. Remarkably, although diabetes and inflammatory bowel disease are very different diseases, the reason people feel ill may result from similar mechanisms. For example, there are specific cells in the body that are engineered to respond to molecules produced by infectious pathogens to induce inflammation. This inflammation helps to kill pathogenic microbes. Cells called macrophages and neutrophils are particularly well-suited to perform these tasks upon infection. These cells use a receptor called Toll-like receptor 4, or TLR4, to help detect the infection and induce inflammation. Recently scientists have discovered that some molecules from our bodies, such as certain fats, also bind to TLR4 and may induce inflammation under conditions which are still poorly understood. In chronic inflammatory disease this process may contribute to the abnormal inflammation that makes people feel ill.

We have recently found that patients with diabetes and inflammatory bowel disease have elevated TLR4 on a cell type in their blood which typically does not express this receptor. These cells are called B cells, the cells that normally produce antibody. In chronic inflammatory disease, these atypical B cells may play a role in increasing inflammation through TLR4. However, B cells are unique in that they have multiple functions in addition to antibody production. Therefore we must determine how B cells use this receptor and whether they contribute to inflammation.

In this study, we propose to define why B cells express TLR4 in patients with inflammatory bowel disease and type 2 diabetes. Furthermore, we will detail how molecules naturally found in the body and those produced by microbes activate B cells through TLR4. Our findings may lead to a better understanding of chronic inflammation and perhaps more tailored mechanisms to treat patients.