Showing papers by "Amy Chadburn published in 2006"

HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors.

Abstract: Switching from IgM to IgG and IgA is essential for antiviral immunity and requires engagement of CD40 on B cells by CD40L on CD4 + T cells. HIV-1 is thought to impair CD40-dependent production of protective IgG and IgA by inducing progressive loss of CD4 + T cells. Paradoxically, this humoral immunodeficiency is associated with B cell hyperactivation and increased production of nonprotective IgG and IgA that are either nonspecific or specific for HIV-1 envelope glycoproteins, including gp120. Nonspecific and gp120-specific IgG and IgA are sensitive to antiretroviral therapy and remain sustained in infected individuals with very few CD4 + T cells. One interpretation is that some HIV-1 Ags elicit IgG and IgA class switch DNA recombination (CSR) in a CD40-independent fashion. We show that a subset of B cells binds gp120 through mannose C-type lectin receptors (MCLRs). In the presence of gp120, MCLR-expressing B cells up-regulate the CSR-inducing enzyme, activation-induced cytidine deaminase, and undergo CSR from IgM to IgG and IgA. CSR is further enhanced by IL-4 or IL-10, whereas Ab secretion requires a B cell-activating factor of the TNF family. This CD40L-related molecule is produced by monocytes upon CD4, CCR5, and CXCR4 engagement by gp120 and cooperates with IL-4 and IL-10 to up-regulate MCLRs on B cells. Thus, gp120 may elicit polyclonal IgG and IgA responses by linking the innate and adaptive immune systems through the B cell-activating factor of the TNF family. Chronic activation of B cells through this CD40-independent pathway could impair protective T cell-dependent Ab responses by inducing immune exhaustion.

Magnitude of stromal hemangiogenesis correlates with histologic subtype of non-Hodgkin's lymphoma.

Abstract: Purpose: Tumor stromal microenvironment promotes neoplastic growth and angiogenesis. We have previously shown that recruitment of marrow-derived vascular endothelial growth factor receptor-1 + (VEGFR-1 + ) proangiogenic hematopoietic progenitors contributes instructively and structurally to neoangiogenesis in mouse models. Here, we investigated whether stromal incorporation of CD68 + hemangiogenic cells and α-smooth muscle actin + (α-SMA + ) stromal cells correlates with neoangiogenesis and progression in human non–Hodgkin9s lymphoma subtypes. Experimental Design: Spatial localizations of vascular and stromal cells expressing CD34, VEGFR-1, α-SMA, and CD68 were examined by immunohistochemistry in 42 cases of non–Hodgkin9s lymphoma, including diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and compared with benign follicular hyperplasia. Results: Compared with indolent lymphomas, there was a profound increase in recruitment of CD68 + cells and VEGFR-1 + neovessels in aggressive subtypes (including those transformed from indolent subtypes), where CD68 + cells were localized to the perivascular region of neovessels as well as the stromal compartment. The perivascular CD68 + cells expressed VEGFR-1 and VEGF-A. In contrast, there was a diffuse increase in α-SMA incorporation throughout the stromal compartment of indolent subtype of CLL/SLL compared with the scant perivascular pattern in aggressive subtypes. Overall, there was no correlation between CD34 + microvessel density and lymphoma histologic subtype. Conclusions: Heightened stromal hemangiogenesis as marked by infiltration of proangiogenic VEGFR-1 + CD68 + VEGF-A + cells and their paracrine cross-talk with neovasculature appears to be a distinct feature of aggressive lymphoma, providing novel targets for antiangiogenic therapy, whereas α-SMA + stromal vascular network may be differentially targeted in CLL/SLL.