B cell activating factor of the tumor necrosis factor (TNF) family (BAFF) and a proliferation-inducing ligand (APRIL) are closely related ligands within the TNF superfamily that play important roles in B lymphocyte biology. Both ligands share two receptors—transmembrane activator and calcium signal–modulating cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA)—that are predominantly expressed on B cells. In addition, BAFF specifically binds BAFF receptor, whereas the nature of a postulated APRIL-specific receptor remains elusive. We show that the TNF homology domain of APRIL binds BCMA and TACI, whereas a basic amino acid sequence (QKQKKQ) close to the NH2 terminus of the mature protein is required for binding to the APRIL-specific “receptor.” This interactor was identified as negatively charged sulfated glycosaminoglycan side chains of proteoglycans. Although T cell lines bound little APRIL, the ectopic expression of glycosaminoglycan-rich syndecans or glypicans conferred on these cells a high binding capacity that was completely dependent on APRIL's basic sequence. Moreover, syndecan-1–positive plasma cells and proteoglycan-rich nonhematopoietic cells displayed high specific, heparin-sensitive binding to APRIL. Inhibition of BAFF and APRIL, but not BAFF alone, prevented the survival and/or the migration of newly formed plasma cells to the bone marrow. In addition, costimulation of B cell proliferation by APRIL was only effective upon APRIL oligomerization. Therefore, we propose a model whereby APRIL binding to the extracellular matrix or to proteoglycan-positive cells induces APRIL oligomerization, which is the prerequisite for the triggering of TACI- and/or BCMA-mediated activation, migration, or survival signals.
The TNF family ligand B cell-activating factor (BAFF, BLyS, TALL-1) is an essential factor for B cell development. BAFF binds to three receptors, BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA), but only BAFF-R is required for successful survival and maturation of splenic B cells. To test whether the effect of BAFF is due to the up-regulation of anti-apoptotic factors, TACI-Ig-transgenic mice, in which BAFF function is inhibited, were crossed with transgenic mice expressing FLICE-inhibitory protein (FLIP) or Bcl-2 in the B cell compartment. FLIP expression did not rescue B cells, while enforced Bcl-2 expression restored peripheral B cells and the ability to mount T-dependent antibody responses. However, many B cells retained immaturity markers and failed to express normal amounts of CD21. Marginal zone B cells were not restored and the Tindependent IgG3, but not IgM, response was impaired in the TACI-Ig×Bcl-2 mice. These results suggest that BAFF is required not only to inhibit apoptosis of maturating B cells, but also to promote differentiation events, in particular those leading to the generation of marginal zone B cells.
IntroductionDendritic cells (DCs) are the antigen-presenting cells (APCs) capable of inducing adaptive immune responses and tolerance. 1 DCs act as sentinels in peripheral tissues and as APCs in secondary lymphoid organs, filtering their environment and detecting environmental changes that modulate the balance between tolerance and immune response. Following infection and inflammation, DCs induce costimulatory molecules, secrete cytokines, and can change their migration properties. 2,3 Several DC subtypes with unique and overlapping functions have been described. Plasmacytoid DCs (pDCs) are the main interferon (IFN) type I-producing cells, whereas several subtypes of conventional DCs (cDCs) are widely distributed. 4,5 In skin, 2 DC populations, namely Langerhans cells (LCs) and dermal DCs, localize to the epidermis and dermis, respectively. Upon pathogen encounter, they migrate to the draining LN. 6 In skin and spleen, DCs are derived either from blood or from immediate local precursors. [7][8][9][10][11][12][13] DCs are dividing cells rather than terminally differentiated cells. [12][13][14][15] The importance of DC cycling on their homeostasis is currently debated, and DC proliferation has been recently proposed to extend the duration of antigen presentation. 15 The human histiocytic diseases are characterized by abnormal accumulation or proliferation of macrophages or DCs. 16 They are divided into LC or non-LC histiocytosis. In the former category, LC histiocytosis (LCH) is best described. LCH can range from a spontaneously regressing single organ disease to a life-threatening or disabling relapsing multisystem disease. 16 In the latter category, a genetic deficiency in cytotoxic activity, familial hemophagocytic lymphohistiocytosis (FHL), is the principal type implicating macrophages and lymphocytes. In contrast to LCH and FHL, lesions with proliferative DCs with or without cytologic atypia are less well classified and their prevalence remains controversial. 16 Unfortunately, a confusing terminology describing these cases of proliferating DCs persists in the literature as malignant histiocytosis, histiocytic sarcoma, and DC sarcoma.The diagnosis of histiocytic diseases relies on the morphologic, ultrastructural, and immunohistochemical histiocyte properties. The macrophage, DC, or LC lineage markers allow LC to be distinguished from non-LC histiocytosis. For example, diagnostic criteria for LCH include expression of Langerin or detection of Birbeck granules that are pathognomonic, as well as CD1a and S100, which are less specific. According to the International Lymphoma Study Group, histiocytic sarcoma, LC tumor, and LC sarcoma (LCS) are the terms used to separate cases based on the degree of cytologic atypia and on lineage markers. 17 For example, diagnosis of LCS requires the same markers as LCH and the additional presence of cellular and mitotic atypia.While LCS, LC, and DC tumors are clearly neoplastic, it is vigorously debated whether LCH is a reactive or a neoplastic The online version of this article ...
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