Receptor crosstalk: reprogramming B cell receptor signalling to an alternate pathway results in expression and secretion of the autoimmunity‐associated cytokine,osteopontin

Intracellular signalling emanating from the B‐cell antigen receptor is considered to follow a discrete course that requires participation by a set of mediators, grouped together as the signalosome, in order for downstream events to occur. Recent work indicates that this paradigm is true only for naïve B cells. Following engagement of the IL‐4 receptor, a new, alternate pathway for B‐cell receptor (BCR)‐triggered intracellular signalling is established that bypasses the need for signalosome elements and operates in parallel with the classical, signalosome‐dependent pathway. Reliance on Lyn and sensitivity to rottlerin by the former, but not the latter, distinguishes these two pathways. The advent of alternate pathway signalling leads to production and secretion by B cells of osteopontin (Opn). As Opn is a polyclonal B‐cell activator that is strongly associated with a number of autoimmune diseases including lupus and rheumatoid arthritis, this novel finding is likely to be clinically relevant. Our results highlight the potential role of B‐cell‐derived Opn in immunity and autoimmunity and suggest that stress‐related IL‐4 expression might act to strengthen immunoglobulin secretion at the risk of autoantibody formation. Further, these results illustrate receptor crosstalk in the form of reprogramming, whereby engagement of one receptor (IL‐4R) produces an effect that persists after the original ligand (IL‐4) is removed and results in alteration of the pathway, and outcome, of signalling via a second receptor (BCR) following its activation.