Modulation of B cell responses by Campylobacter jejuni: focus on BAFF

Campylobacter infections (C. jejuni) represent a major public health concern. Clinical manifestations range from enteritis to post-infectious sub-acute inflammatory polyneuropathy (Guillain-Barré syndrome, GBS), and possibly the development of B cell malignancies. Occurrence of symptomatic C. jejuni infection is inversely related to development of humoral immunity, whereas GBS is thought to be caused by derailment of the specific B cell response. Therefore, regulation of B cell responses is not only critical for the containment of C. jejuni infection, but also prevents development of unwanted B cell activation. Dendritic cells (DC) are the first immune cells that encounter C. jejuni in the intestinal mucosa. These professional antigen-presenting cells (APC) regulate humoral immune responses, either through polarization of T cell responses, or through direct interaction with B cells. An emerging player in the field of B cell development and function is the B cell activating factor of the TNF family (BAFF), which is produced both as soluble and membrane-bound molecule by different immune cells, including DC, monocytes, and macrophages. BAFF is likely to be important during normal immune responses to microbial challenge, by priming or enhancing T and B cell activity to facilitate bacterial clearance. However, regulation of BAFF expression is critical, since overexpression of BAFF is associated with the development of autoimmune disease and B cell lymphomas in both humans and transgenic mice. We studied C. jejuni-induced DC activation, and found considerable qualitative and quantitative differences, depending on donor and particular bacterial strain used. All tested C. jejuni strains matured DC efficiently, and induced production of IL-6, IL-10, TNFa. Additionally, C. jejuni-stimulated DC also specifically increased expression of BAFF mRNA and protein, which was not observed using two other gram-negative bacteria, E. coli and N. meningitidis. BAFF production appears to be a direct effect of DC-C. jejuni interaction, mediated by a heat-stable component of C. jejuni. The current proposal would allow me to 1) quantify membrane-bound BAFF protein expression, and BAFF secretion by human C. jejuni-stimulated DC; 2) learn techniques to isolate, culture, and study responses of human B cell subsets, i.e. survival, proliferation, differentiation, and Ig class switching. Assays for all these procedures have been set-up and tested in the lab of the host institution; 3) study B cell responses in the context of C. jejuni-stimulated DC by development of co-culture systems, and 4) dissect the specific role of BAFF on B cell responses in the cocktail of produced cytokines by addition of specific decoy receptors or blocking antibodies. The proposed experiments aim at dissecting B cell responses during C. jejuni infection. These data could therefore contribute to a better understanding of C. jejuni pathogenesis, and its post-infectious sequelae.