Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B-cell maturation protein (BCMA) is a member of the tumor necrosis factor (TNF) receptor family and is expressed in B lymphocytes. BCMA binds two TNF family members, BAFF and APRIL, that stimulate cellular proliferation. BAFF in particular has been shown to influence B-cell survival and activation, and transgenic mice overexpressing BAFF have a lupus-like autoimmune disorder. We have inactivated BCMA in the mouse germ line. BCMA(-/-) mice have normal B-cell development, and the life span of mutant B lymphocytes is comparable to that of wild-type B cells. The humoral immune responses of BCMA(-/-) mice to T-cell-independent antigens as well as high and low doses of T-cell-dependent antigens are also intact. In addition, mutant mice have normal splenic architecture, and germinal centers are formed during an ongoing immune response. These data suggest a functional redundancy of BCMA in B-cell physiology that is probably due to the presence of TACI, another TNF receptor family member that is expressed on B cells and that can also bind BAFF and APRIL.
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PMID:B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses. 1135 13

TACI is a TNFR homolog expressed by mature B lymphocytes that has been implicated in the positive regulation of B cell growth and antibody production, as well as in the development of autoimmune disease. Its biology is complex due to the existence of two ligands, BLyS and APRIL, and a homologous receptor, BCMA, that similarly binds both ligands. To determine its critical biological role, we generated TACI knockout mice. Surprisingly, these mice demonstrated a 2-fold increase in numbers of circulating and splenic B cells, apparently due to increased proliferation rate. Maturation of B cells and T-dependent antibody production was normal, but responses to T-independent type II antigens were almost completely abolished. It appears that TACI provides an essential costimulatory signal for the T-independent humoral response.
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PMID:Regulation of the T-independent humoral response by TACI. 1137 59

B cell activating factor (BAFF), a ligand belonging to the tumor necrosis factor (TNF) family, plays a critical role in regulating survival and activation of peripheral B cell populations and has been associated with autoimmune disease. BAFF is known to interact with three receptors, BCMA, TACI and BAFF-R, that have distant similarities with other receptors of the TNF family. We have determined the crystal structure of the TNF-homologous domain of BAFF at 2.8 A resolution. The structure reveals significant differences when compared to other TNF family members, including an unusually long D-E loop that participates in the formation of a deep, concave and negatively charged region in the putative receptor binding site. The BAFF structure was further used to generate a homology model of APRIL, a closely related TNF family ligand that also binds to BCMA and TACI, but not BAFF-R. Analysis of the putative receptor binding sites of BAFF and APRIL suggests that differences in the D-E loop structure and electrostatic surface potentials may be important for determining binding specificities for BCMA, TACI and BAFF-R.
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PMID:Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes. 1182 82

B cell activating factor belonging to the TNF family (BAFF) and apoptosis-inducing ligand (APRIL) are two related members of the TNF ligand superfamily. Although they share two receptors, TACI and BCMA, transgenic and knockout mice in this system reveal that their functions are not redundant. BAFF is a critical survival/maturation factor for peripheral B cells and this activity is mediated through a BAFF-specific receptor, BAFF-R. Overexpression of BAFF has been linked to autoimmune disease and aspects of B cell neoplasia. APRIL appears to play a role in T-independent type II antigen responses and T cell survival, but can also induce proliferation/survival of non-lymphoid cells. Elevated expression of APRIL has been found in some tumor cell lines and in tumor tissue libraries. Therapies designed to inhibit the BAFF and APRIL pathways holds great promise for the future.
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PMID:The TNF family members BAFF and APRIL: the growing complexity. 1278 68

The TNF superfamily ligands BAFF and APRIL and their three receptors BAFFR, BCMA, and TACI comprise a network that is critically involved in the development and function of humoral immunity. Failure of this complex system is associated with autoimmune disease, B lymphocyte tumours, and antibody deficiency. While BAFF:BAFFR interactions control peripheral B cell survival and homeostasis, BCMA function seems limited to the survival of long-lived bone marrow plasma cells. The functional activity of the third receptor TACI is, however, ambiguous: while TACI-/- mice predominantly develop autoimmunity and lymphoproliferation, TACI deficiency in humans primarily manifests itself as an antibody deficiency syndrome. An article in this issue of the European Journal of Immunology demonstrates a negative regulation via TACI in human B cells by using TACI specific antibodies. B cell proliferation, class switch recombination, and Ig production induced by various stimuli were inhibited via TACI. Within the BAFF/APRIL network, the expression of the receptors and ligands is spatially, as well as temporally, highly regulated at various stages of B cell development and function. Defining the exact contribution of TACI stimulation by specific triggers in vitro enables us to better understand the complex, context-dependent responses initiated by TACI in vivo.
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PMID:To switch or not to switch--the opposing roles of TACI in terminal B cell differentiation. 1715 64

BAFF and APRIL are two members of the TNF superfamily that have co-stimulatory activity on B cells and contribute to autoimmunity. While BAFF is processed at the cell surface, APRIL is processed inside the cell by a furin-convertase and is able to perform its function only as a soluble factor. However, APRIL can be expressed as a cell surface fusion protein with TWEAK called TWE-PRIL. BAFF can also exist as a soluble molecule and can be detected in human serum. Whether the biological functions controlled by membrane-bound BAFF differ from those triggered by soluble BAFF is unclear. In addition to this complexity, DeltaBAFF, an alternative splice isoform of BAFF shows different properties. BAFF can also, in autoimmune disease form heterotrimers with APRIL but the control and function of these heterotrimers remain unclear. In order to understand the function of these molecules we need to elucidate the complexity of the various forms of these members of the TNF family.
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PMID:BAFF, APRIL, TWE-PRIL: who's who? 1829 28

Proteins of the tumour necrosis factor (TNF) family are implicated in the regulation of essential cell processes such as proliferation, differentiation, survival and cell death. Altered expression of TNF family members is often associated with pathological conditions such as autoimmune disease and cancer. The TNF-like ligand APRIL (A PRoliferation Inducing Ligand), first described in 1998, was named for its capacity to stimulate tumour cell proliferation in vitro. APRIL expression was initially reported in haematopoietic cells in physiological conditions, and it is overexpressed in certain tumour tissues. APRIL is now known to be involved in activation and immune responses of B cells, as well as in B cell malignancies. This review focuses on recent advances in understanding APRIL and its receptors in physiology and tumour pathology, including the accumulating evidence that specific Toll-like receptor ligands can trigger APRIL-mediated responses, and the identification of new sources of APRIL such as epithelial cells and tumour-infiltrating neutrophils.
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PMID:The expanding role of APRIL in cancer and immunity. 1907 79

BAFF (B lymphocyte activating factor of the tumour necrosis factor family) is a vital homeostatic cytokine for B cells that helps regulate both innate and adaptive immune responses. Increased serum levels of BAFF are found in a number of different autoimmune diseases, and BAFF is found in inflammatory sites in which there is lymphoid neogenesis. BAFF antagonism has been used in several autoimmune disease models, resulting in B cell depletion, decreased activation of T cells and dendritic cells (DC) and a reduction in the overall inflammatory burden. BAFF, through its interaction with BAFF-R, is required for survival of late transitional, marginal zone and mature naive B cells, all of which are depleted by BAFF blockade. Through their interactions with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), BAFF and its homologue APRIL (a proliferation-inducing ligand), support the survival of at least some subsets of plasma cells; blockade of both cytokines results in a decrease in serum levels of immunoglobulin (Ig)G. In contrast, neither BAFF nor APRIL is required for the survival or reactivation of memory B cells or B1 cells. BAFF also helps DC maturation and interleukin (IL)-6 release and is required for proper formation of a follicular dendritic cell (FDC) network within germinal centres, although not for B cell affinity maturation. The clinical efficacy of BAFF blockade in animal models of autoimmunity may be caused both by the decline in the number of inflammatory cells and by the inhibition of DC maturation within target organs. Blockade of BAFF and its homologue APRIL are being explored for human use; several Phase I and II clinical trials of BAFF inhibitors for autoimmunity have been completed and Phase III trials are in progress.
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PMID:BAFF: a local and systemic target in autoimmune diseases. 1973 41

IgA deficiency (IgAD) is the most common form of immunodeficiency and frequently associates with autoimmunity, especially with celiac disease (CD). The mechanisms underlying IgAD and the development of autoimmunity are still relatively unknown. Elevated B-lymphocyte stimulator (BLyS) and APRIL (a proliferation-inducing ligand) serum levels characterize several autoimmune diseases. We herein investigated BLyS and APRIL serum levels in IgAD patients with and without CD and compared these patients to CD patients with normal IgA and control patients (HBDs). Compared to HBDs, IgAD patients demonstrated a significant increase of BLyS (P < 0.0001) and APRIL (P = 0.003) levels, and no differences were seen between patients with or without CD. While BLyS appeared similarly overexpressed in IgAD and CD patients, APRIL was significantly increased only in IgAD patients. Because APRIL promotes IgA production, its overexpression may represent a physiological mechanism of compensation. BLyS upregulation may be involved in the increased risk of autoimmune disease development characterizing people carrying IgAD.
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PMID:B-lymphocyte stimulator and a proliferation-inducing ligand serum levels in IgA-deficient patients with and without celiac disease. 1975 61

Multiple sclerosis (MS) has traditionally been considered to be a T cell-mediated disease. However, there is an increasing body of evidence for the involvement of B cells and autoantibodies in the pathology of this disease, providing a rationale for treatment strategies directed against B cells. This paper summarizes the evidence for a key role of B cells in the immunopathology of MS and reviews data supporting the use of a novel B cell-targeted therapy, atacicept, for this condition. Atacicept is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B cell maturation, function and survival. Atacicept has shown selective effects on cells of the B cell lineage, acting on mature B cells and blocking plasma cells and late stages of B cell development while sparing B cell progenitors and memory cells. The efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated. Ongoing clinical studies are investigating the safety, tolerability and efficacy of atacicept in patients with MS, SLE and RA.
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PMID:[Atacicept: a new B lymphocyte-targeted therapy for multiple sclerosis]. 1977 89


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