B cell signalling as therapeutic target
Authors: R H Carter
Journal: Annals of the Rheumatic Diseases (2004)

Biological therapy holds the promise of specificity of intervention.Recent progress in development of such therapies has proved that rational targeting can lead to clinical benefit.B cells pose an attractive target in autoimmunity.Approaches currently being tested lead to depletion of B cells or at least circulating B cells. 1-3Such therapies appear remarkably benign, but the effects of repeated depletion, which might be required to fight autoimmune disease, have yet to be defined.Fundamental studies have uncovered pathways of B cell activation.This work opens the possibility of targeting activated B cells.This review asks how we might approach therapeutic manipulation of activated B cells.The underlying assumption is that it is the activated B cells that are important in pathophysiology of autoimmune disease.The activation pathways lead to the differentiation of self-reactive B cells to plasmablasts that produce the autoantibodies, which may be directly pathogenic. 4In addition, activation of B cells leads to the expression of ligands on B cells that bind costimulatory receptors on T cells. 5Along with presentation of self-derived peptides on surface major histocompatibility complex class II molecules, this drives activation of autoimmune T cells. 6Targeting activated B cells would eliminate both contributions of B cells to disease without depletion of resting memory B cells acquired from previous infection or immunisation.The white pulp in the spleen is organised around the terminal branches of the arterioles.The periarteriolar lymphoid sheath (PALS), which surrounds the arteriole, is rich in T cells.Budding eccentrically off the PALS are collections of B cells, which form the follicular mantle.This is bounded by the marginal sinuses, around which are abundant macrophages.The marginal zone is a band of B cells and macrophages lying between the marginal sinuses and the red pulp.These structures are maintained by signals from chemokine receptors and expression of specific adhesion molecules. 7 8 There are multiple pathways of B cell activation in the spleen. 9-11The first response is the rapid mobilisation of marginal zone B cells to produce a predominantly immunoglobulin (Ig)M response.The germinal centre reaction requires days to develop but leads to a higher affinity IgG response.The germinal centre also leads to the development of memory B cells, which have switched from IgM to other classes of Ig.When pathogens reach the blood, they pass through the marginal sinuses, where they are captured by pathogen recognition receptors on macrophages. 12 13The marginal zone B cells, in close proximity to the macrophages, both recognise specific antigen by their surface Ig and danger signals through recognition of pathogen associated molecular patterns by toll-like receptors (TLRs).These signals lead to the rapid migration of activated cells out of the marginal zone, through the follicular mantle, and into the T cell zone, based on changes in chemokine signals and altered expression of adhesion molecules. 14 15The B cells upregulate expression of ligands for T cell costimulatory receptors and are very efficient antigen presenting cells, even though activation of