Mutations in the gene encoding Bruton's tyrosine kinase (btk) cause the B cell deficiency diseases X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. In vivo and in vitro studies indicate that the BTK protein is essential for B cell survival, cell cycle progression, and proliferation in response to B cell antigen receptor (BCR) stimulation. BCR stimulation leads to the activation of transcription factor nuclear factor (NF)-κB, which in turn regulates genes controlling B cell growth. We now demonstrate that a null mutation in btk known to cause the xid phenotype prevents BCR-induced activation of NF-κB. This defect can be rescued by reconstitution with wild-type BTK. This mutation also interferes with BCR-directed activation of IκB kinase (IKK), which normally targets the NF-κB inhibitor IκBα for degradation. Taken together, these findings indicate that BTK couples IKK and NF-κB to the BCR. Interference with this coupling mechanism may contribute to the B cell deficiencies observed in XLA and xid.

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PGG-Glucan (Betafectin®) is a novel soluble β-glucan immunomodulator that enhances leukocyte microbicidal activities without inducing inflammatory cytokines. Although several different receptors for soluble and particulate β-glucans have been described, the signal transduction pathway(s) used by soluble β-glucans have not been elucidated. We report that in a murine monocytic cell line (BMC2.3) PGG-Glucan activates nuclear factor-κB (NF-κB)-like and NF-interleukin-6 (IL-6)-like transcription factors. Electrophoretic mobility shift assays showed that PGG-Glucan activation of the factors is time- and concentration-dependent. The NF-κB-like complex includes subunit p65 (rel-A) as one of its components, but apparently not p50 (κB1), p52 (κB2), p68 (rel-B), or p75 (C-rel) family members. The NF-IL-6-like complex contains subunit C/EBP-β (NF-IL-6α) as one of its components, but apparently not C/EBP-α or C/EBP-δ (NF-IL-6β). As expected, lipopolysaccharide (LPS) activated p65/p50 NF-κB and C/EBP-β NF-IL-6 complexes, increased the nuclear titer of p65 and p50 antigens, and increased cytokine (IL-1β, tumor necrosis factor α) mRNA production. In contrast, PGG-Glucan increased the nuclear titer of p65, but apparently not p50, and did not induce cytokine mRNA production, These data demonstrate that PGG-Glucan utilizes signal transduction pathways different from those used by LPS. The data suggest that activation of the PGG-Glucan-stimulated factors is not sufficient to stimulate cytokine mRNA transcription.

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