Microparticles (MPs) are small membrane-bound vesicles with potent biological activities that can promote the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus (SLE). These particles contain diverse cellular components and are shed from cells during apoptosis or activation. MPs can drive inflammation and autoimmunity by multiple mechanisms reflecting their content of bioactive molecules and ability to engage multiple receptor systems simultaneously. In the rheumatoid joint, particles can stimulate synovitis via their display of cytokines, chemokines, complement and angiogenesis factors. In SLE, particles can serve as an important source of extracellular nuclear molecules to signal 'danger' and form pathogenic immune complexes. Future studies will define the pathways by which particles promote pathogenesis, strategies to block their activity and their utility as biomarkers to assess disease activity and the response to therapy.

BCR signaling in naive B cells depends on the function of signalosome mediators; however, prior engagement of CD40 or of IL-4R produces an alternate signaling pathway in which Bruton’s tyrosine kinase, PI3K, phospholipase Cγ2, and protein kinase Cβ are no longer required for BCR-induced downstream events. To explore the range of mediators capable of producing such an alternate pathway for BCR signaling, we examined the TLR4 agonist, LPS. B cell treatment with LPS at relatively low doses altered subsequent BCR signaling such that ERK phosphorylation and NF-κB activation occurred in a PI3K-independent manner. This effect of LPS extended to MEK phosphorylation and IκBα degradation, and it developed slowly over a period of 16–24 h. The involvement of TLRs is suggested by similar effects observed with a structurally distinct TLR agonist, PAM3CSK4 and by the need for MyD88 for induction of alternate BCR signaling by LPS. Thus, LPS-mediated TLR engagement produces an alternate pathway for BCR-triggered signal propagation that differs from the classical, signalosome-dependent pathway.

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The classical pathway for BCR signaling requires signalosome elements including PI-3K, Btk, PLCγ2 and PKCβ. Inhibition or ablation of any of these signaling mediators results in a block in BCR-triggered downstream events such as ERK phosphorylation and NF-κB activation. However, recent work in this lab has demonstrated that exposure to certain molecules such as CD40L and IL-4 produces an alternate pathway such that BCR-induced signaling bypasses the need for signalosome elements. This led us to investigate whether bacterial products that signal “danger” can create an alternate pathway for MAPK activation. We found that BCR-triggered ERK phosphorylation became resistant to the PI-3K inhibitor LY294002 after B cell treatment with LPS, CpG or PAM3CSK. LPS and PAM3CSK were also tested further and found to induce PI-3K independent NF-κB activation recapitulating the alternate pathway induced by CD40L and distinct from that produced by IL-4. Induction of the alternate pathway for BCR signaling by LPS required MyD88. These data demonstrate that TLR agonists induce an alternate pathway for BCR signaling that bypasses essential signalosome elements. This is of special interest considering that high LPS/CpG levels occur during severe gram-negative bacterial infections. This suggests that consideration of the alternate pathway may be prudent when designing treatments for bacterial infections.