IntroductionBruton tyrosine kinase (Btk) is a nonreceptor tyrosine kinase belonging to the Tec family of protein tyrosine kinases (PTKs). This family consists of 5 mammalian members: Btk, Itk, Tec, Bmx, and Txk. These kinases are also present in other species. 1,2 Btk is expressed in almost all the hematopoietic cells, except T lymphocytes and plasma cells, and in the B-cell lineage, from the very early up to the mature cell stages. [3][4][5] Btk is required for Blymphocyte survival, proliferation, and differentiation in response to BCR activation. Accordingly, mutations in the gene coding for Btk lead to X-linked agammaglobulinemia (XLA) in humans 6-9 and X-linked immunodeficiency (xid) in mice. 10,11 Btk and its direct substrate, phospholipase C␥2 (PLC-␥2), are essential for the activation of the transcription factor nuclear factor-B (NF-B) in response to BCR engagement. [12][13][14] Moreover, Shinners et al recently found that Btk mediates B-cell-activating factor receptor (BAFF-R)-dependent activation of NF-B, thereby promoting B-cell survival. 15 NF-B is known to be essential for both innate and adaptive immunity. Moreover, it is crucial for the initial responses of sentinel cells to pathogens, as well as for the subsequent events that lead to T cell-and B cell-mediated antigen-specific defense. The role of NF-B in the acute, innate immune response is evolutionarily conserved. 16 NF-B has also been shown to be crucial for the development of several mammalian hematopoietic cell lineages and for the formation of secondary lymphoid-organ structures.The NF-B/Rel family of proteins include NF-B1 (p50), NF-B2 (p52), RelA (p65), c-Rel, and RelB, which can form functional homodimer or heterodimer complexes. 16,17 In resting cells, NF-B is sequestered in the cytoplasm by the inhibitory proteins of the I-B family. Following stimulation of cells by inflammatory cytokines, and bacterial (eg, LPS) and viral products, the inhibitor of B (I-B) is phosphorylated by the I-B kinases (IKKs), leading to its degradation through the ubiquitin-proteasome pathway. Thus, in the absence of I-B, NF-B dimers (p50-p65 and p52-RelB) are released, translocated to the nucleus, and subsequently bound to their cognate elements on target genes. 18 Mice deficient in individual NF-B/Rel family members have demonstrated the essential role of these transcription factors in CD40, TLR4, and IgM receptor pathways leading to B-cell proliferation. In particular, B cells from mice deficient in the NF-B members c-Rel or p65 have decreased responses to antigen cross-linking. 19,20 c-Rel Ϫ/Ϫ B cells also failed to respond to CD40 ligation. An examination of B cells in mice expressing a transdominant form of I-B␣ revealed xid-like defects, including lack of proliferation in response to anti-IgM. 21 The transcriptional regulation of the Btk gene has been studied quite extensively. Accordingly, a number of transcription factors including Sp1, Sp3, Spi-B, PU.1, [22][23][24] and OCT1/OBF1 25 have been shown to bind and activate the Btk promoter. However, most...

The ability to trigger an innate immune response against opportunistic pathogens associated with HIV-1 infection is an important aspect of AIDS pathogenesis. Toll-like receptors (TLRs) play a critical role in innate immunity against pathogens, but in HIV-1 patients coinfected with opportunistic infections, the regulation of TLR expression has not been studied. In this context, we have evaluated the expression of TLR2 and TLR4 in monocytes, plasmacytoid dendritic cells, and myeloid dendritic cells of HIV-1 patients with or without opportunistic infections. Forty-nine HIV-1-infected individuals were classified according to viral load, highly active antiretroviral therapy (HAART), and the presence or absence of opportunistic infections, and 21 healthy subjects served as controls. Increased expression of TLR2 and TLR4 was observed in myeloid dendritic cells of HIV-1 patients coinfected with opportunistic infections (without HAART), while TLR4 increased in plasmacytoid dendritic cells, compared to both HIV-1 without opportunistic infections and healthy subjects. Moreover, TLR2 expression was higher in patients with opportunistic infections without HAART and up-regulation of TLR expression in HIV-1 patients coinfected with opportunistic infections was more pronounced in dendritic cells derived from individuals coinfected with Mycobacterium tuberculosis. The results indicate that TLR expression in innate immune cells is up-regulated in patients with a high HIV-1 load and coinfected with opportunistic pathogens. We suggest that modulation of TLRs expression represents a mechanism that promotes HIV-1 replication and AIDS pathogenesis in patients coinfected with opportunistic pathogens.

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