B cells and beyond: therapeutic opportunities targeting inflammation.

Classically, B-lymphocytes (B cells) are considered to be the mediators of humoral immunity and their role in inflammatory disease largely confined to the down-stream function of antigen-antibody complexes, e.g., in fixing complement and mediating antibody dependent cellular cytotoxicity. More recently, and with the growing acceptance of the view that the immune system operates as an interconnected web of cells and cytokines, a larger role for B cells has been proposed. In this review, with a focus on how B cells and their cytokine products may present novel therapeutic targets, we will briefly discuss B cell ontogeny and discuss the evidence supporting a larger role for B cells in a variety of inflammatory diseases. Special emphasis will be placed on autoimmune diseases. These discussions are intended to provide the reader with the basis for viewing B cells as players of a broader role in inflammatory disease and thus suggest avenues for exploiting B cell directed therapy in novel ways.

Toll-like receptor 9 can be expressed at the cell surface of distinct populations of tonsils and human peripheral blood mononuclear cells.

Unmethlylated CpG dinucleotides induce a strong T-helper-1-like inflammatory response, presumably mediated by Toll-like receptor 9 (TLR9). However, the nature and cellular localization of TLR9 in primary human cells remain controversial. Here we demonstrate, using flow cytometry and immunofluorescence microscopy techniques, that TLR9 can be expressed at the cell surface. The primary human cell subsets that were positive for TLR9 expression were distinct depending on the tissues analyzed. Specifically, in human peripheral blood mononuclear cells (PBMC) the majority of cell surface TLR9(+) cells were confined to the major histocompatibility complex (MHC) class II(+) CD19(-) populations that express CD11c and/or CD14, whereas in tonsils the same gated population contained primarily MHC class II(+) CD19(+) cells. Cells positive for surface expression represented a minor fraction of the total cell populations examined, varying between 2 and 10%. In addition, we found that TLR9 expression at the surface of PBMC was up-regulated approximately fourfold following stimulation with the gram-negative bacterial cell wall component lipopolysaccharide, suggesting a potential modulatory role of TLR4 agonists on TLR9 expression. Taken together, these data validate human TLR9 expression at the surface of primary cells, in addition to the previously described intracellular localization. Further, our results suggest that human antigen-presenting cells comprise the major cell populations expressing cell surface TLR9.