Systemic Toll-Like Receptor Ligands Modify B-cell Responses in Human Inflammatory Bowel Disease

Background: Bacteria have a central, although poorly understood, role in inflammatory bowel disease (IBD). Host-bacteria interactions primarily take place in the gastrointestinal tract, but cells may also encounter translocated bacteria in the bloodstream. IBD is associated with activated, circulating Toll-like receptor (TLR)2 and TLR4-expressing B cells suggesting that blood-borne microbial TLR ligands modulate B cell responses. Methods: Serum levels of lipopolysaccharide (LPS)/endotoxin and high mobility group box 1 (HMGB1), an endogenous TLR ligand, were quantified in Crohn's disease (CD) and ulcerative colitis (UC). Responses of purified B cells to LPS and HMGB1 were correlated with levels of systemic TLR ligands and clinical parameters of disease. Results: While IBD patients have increased levels of blood LPS, the net effect of endotoxemia has unexpected characteristics illustrating that LPS has both pro- and antiinflammatory roles through TLR4+ B cells. Experimental treatment of B cells demonstrates that the antiinflammatory effect of LPS is due to its hypo-acylation of lipid A suggesting an increased prevalence of systemic, hypo-acylated LPS in CD. In contrast, high levels of LPS are associated with disease activity in UC. HMGB1 activates B cells through TLR2 and CD36. Serum levels of HMGB1 correlate with spontaneous IL-8 production by B cells suggesting that blood-borne TLR2 ligands increase B-cell activation in vivo. Conclusions: Systemic TLR ligands modulate B cells towards either proinflammatory or antiinflammatory activity depending on the predominant ligand(s). Further, the circulating B cell may rep-resent an important proxy for quantifying the LPS lipid A acylation burden in patients with IBD.