Scientific Abstract

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

Although type 2 diabetes (T2DM) and IBD are seemingly distinct diseases, they share a common mediator of morbidity, namely unresolved inflammation. In general, the mechanisms underlying the chronicity of inflammation are poorly defined, though inflammatory cytokines, such as TNF- and IL-1β, are thought to be overrepresented. Toll-like receptor 4 (TLR4) expression by myeloid cells plays an important role in sensing endotoxin and inducing pro-inflammatory cytokine secretion. Thus, it is likely that LPS-stimulated cells contribute to chronic inflammation in IBD, for example, but might not explain how TLR4 contributes to inflammation in a disease such as diabetes. Nevertheless, it is becoming clear that the biology of TLR4 is exceedingly complex. TLR4 is expressed by multiple host cells and has numerous exogenous and endogenous ligands. Host endogenous ligands have been shown to play a role in propagating chronic inflammation through TLR4 in the absence of microbes. Thus, TLR4 may be an important molecule linking the etiology of chronic inflammation in T2DM and IBD. Our group has defined a unique TLR4+ cell population in the blood of patients with chronic inflammatory disease, namely TLR4+ B cells. In general, human B cells have been shown to be refractory to LPS stimulation due to a lack of surface TLR4. However, patients with T2DM and IBD have significantly increased levels of TLR4+ B cells compared to healthy donors. Furthermore, B cells from patients with chronic inflammatory disease demonstrate distinct signatures of activation, such as active IL-1β gene enhancers, suggesting that these B cells may represent an unappreciated source of pro-inflammatory mediators. Interestingly, TLR4 is differentially regulated on B cells than on monocytes. Moreover, TLR4+ B cells may be optimally stimulated by TLR4 antagonists rather than agonists suggesting that the immunobiology of TLR4 differs significantly from that of monocytes. Taken together, these observations suggest that a commonality in the inflammatory milieu generates atypical TLR4+ B cells in T2DM and IBD. TLR4+ B cells, therefore, represent a novel cell population which must be characterized.

Our proposal will first focus on identifying the immunological and clinical predictors of TLR4 expression on B cells to lend a better understanding of chronic inflammation in T2DM and IBD. Secondly, we will define the function of TLR4 on human B cells and potential implications for patients.