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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The United States Department of Defense Blast Injury Research Program Coordinating Office organized the 2015 International State-of-the-Science meeting to explore links between blast-related head injury and the development of chronic traumatic encephalopathy (CTE). Before the meeting, the planning committee examined articles published between 2005 and October 2015 and prepared this literature review, which summarized broadly CTE research and addressed questions about the pathophysiological basis of CTE and its relationship to blast- and nonblast-related head injury. It served to inform participants objectively and help focus meeting discussion on identifying knowledge gaps and priority research areas. CTE is described generally as a progressive neurodegenerative disorder affecting persons exposed to head injury. Affected individuals have been participants primarily in contact sports and military personnel, some of whom were exposed to blast. The symptomatology of CTE overlaps with Alzheimer's disease and includes neurological and cognitive deficits, psychiatric and behavioral problems, and dementia. There are no validated diagnostic criteria, and neuropathological evidence of CTE has come exclusively from autopsy examination of subjects with histories of exposure to head injury. The perivascular accumulation of hyperphosphorylated tau (p-tau) at the depths of cortical sulci is thought to be unique to CTE and has been proposed as a diagnostic requirement, although the contribution of p-tau and other reported pathologies to the development of clinical symptoms of CTE are unknown. The literature on CTE is limited and is focused predominantly on head injuries unrelated to blast exposure (e.g., football players and boxers). In addition, comparative analyses of clinical case reports has been challenging because of small case numbers, selection biases, methodological differences, and lack of matched controls, particularly for blast-exposed individuals. Consequently, the existing literature is not sufficient to determine whether the development of CTE is associated with head injury frequency (e.g., single vs. multiple exposures) or head injury type (e.g., impact, nonimpact, blast-related). Moreover, the incidence and prevalence of CTE in at-risk populations is unknown. Future research priorities should include identifying additional risk factors, pursuing population-based longitudinal studies, and developing the ability to detect and diagnose CTE in living persons using validated criteria.

Engagement of the B-cell antigen receptor (BCR) induces the activation of various transcription factors, including NFAT (nuclear factor of activated T-cells) and NF-kappaB (nuclear factor kappaB), which participate in long-term biological responses such as proliferation, survival and differentiation of B-lymphocytes. We addressed the biochemical basis of this process using the DT40 chicken B-cell lymphoma. We discovered that Bruton's tyrosine kinase (BTK) and phospholipase C-gamma2 (PLC-gamma2) are required to activate NFAT and NF-kappaB, and to produce the lipid second messenger diacylglycerol in response to BCR cross-linking. Therefore the functional integrity of the BTK/PLC-gamma2/diacylglycerol signalling axis is crucial for BCR-directed activation of both transcription factors NFAT and NF-kappaB.

Disruption of Bruton's tyrosine kinase (BTK) function leads to x-linked immunode¢ciency (xid) in mice. BTKde¢cient (btk 3 3/3 3 ) B cells are defective for survival. Prior studies show that BTK is required for the induction of Bcl-x L following B cell antigen receptor (BCR) engagement. However, the mechanism underlying Bcl-x L induction in response to BCR ligation remains unresolved. We now demonstrate that BTK regulates bcl-x expression by transcriptional control in response to BCR engagement. BTK targets nuclear factor-U UB (NF-U UB) to activate the bcl-x promoter via a phospholipase C-Q Q2 (PLC-Q Q2)-dependent mechanism. Perturbation of the BTK/PLC-Q Q2/NF-U UB signaling axis likely contributes to the defective expression of bcl-x and compromised survival of xid B cells. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.