Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 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

The B lymphocyte stimulator (BLyS), also known as BAFF, THANK, TALL-1 and zTNF4, is the most recent addition to the tumor necrosis factor family (TNF) ligands and has a unique role in B cell immunity. Its requirement for the humoral immune response is evident in mice lacking BlyS, which exhibit profound deficiencies in peripheral B cell development and maturation. It regulates the antibody response, as shown in mice overexpressing BLyS, which develop autoimmune manifestations resulting from peripheral B cell expansion and differentiation. Attenuation of apoptosis appears to underlie BLyS action in B cells. However, elucidation of the mechanism of BLyS has proven to be more challenging, because BLyS binds three different TNF receptors (TACI/BCMA/BAFF-R) and shares overlapping functions with a related TNF ligand, APRIL. The unique role of BLyS in B cell development and differentiation and the pathogenesis of autoimmune diseases, systemic lupus erythematosus (SLE) in particular, makes the study of BLyS and its downstream targets attractive in the development of novel therapies.
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PMID:Mechanism of BLyS action in B cell immunity. 1175 Aug 77

BLyS/BAFF (B-lymphocyte stimulator/B-cell activating factor) is a vital B-cell survival factor. Overexpression of BLyS in mice may lead to systemic-lupus-erythematosus-like (SLE-like) disease, and BLyS overexpression is common in human SLE. Treatment of SLE-prone mice with a BLyS antagonist ameliorates disease progression and enhances survival, making BLyS an attractive therapeutic target in human disease. However, several unresolved issues remain, including what is the contributory role of APRIL (a tumor-necrosis-factor superfamily member related to BLyS) in the 'autoimmunogenic' effects of BLyS, identification of the 'optimal' BLyS antagonist, and identification of those SLE patients most likely to benefit from BLyS antagonist therapy.
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PMID:SLE--systemic lupus erythematosus: a BLySful, yet BAFFling, disorder. 1272 79

By substituting the heavy chain constant region of IgM and IgD with that of IgG, IgA or IgE, immunoglobulin class switching endows antibodies with novel effector functions that enhance the ability of the immune system to effectively clear invading pathogens. Plasmacytoid dendritic cells critically link innate immunity with adaptive immunity by producing massive amounts of type 1 IFN in response to viruses. We have recently found that type 1 IFN triggers class switching by inducing myeloid dendritic cells to upregulate the expression of BAFF and APRIL, two powerful B cell-activating molecules. In this paper, we propose that IFN-producing plasmacytoid dendritic cells modulate class switching by activating B cells through both T cell-dependent and T cell-independent pathways. A better understanding of these pathways may facilitate the development of novel antiviral vaccine strategies and aid in identifying new therapies for antibody-mediated autoimmune disorders, such as lupus.
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PMID:Plasmacytoid dendritic cells and the regulation of immunoglobulin heavy chain class switching. 1617 7

The objective of this study was to investigate the interaction between levels of BAFF (B-cell activation factor of the tumour necrosis factor [TNF] family) and APRIL (a proliferation-inducing ligand) and B-cell frequencies in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) treated with the B-cell-depleting agent rituximab. Ten patients with SLE were treated with rituximab in combination with cyclophosphamide and corticosteroids. They were followed longitudinally up to 6 months after B-cell repopulation. Nine patients with RA, resistant or intolerant to anti-TNF therapy, treated with rituximab plus methotrexate were investigated up to 6 months after treatment. The B-cell frequency was determined by flow cytometry, and serum levels of BAFF and APRIL were measured by enzyme-linked immunosorbent assays. BAFF levels rose significantly during B-cell depletion in both patient groups, and in patients with SLE the BAFF levels declined close to pre-treatment levels upon B-cell repopulation. Patients with SLE had normal levels of APRIL at baseline, and during depletion there was a significant decrease. In contrast, patients with RA had APRIL levels 10-fold higher than normal, which did not change during depletion. At baseline, correlations between levels of B cells and APRIL, and DAS28 (disease activity score using 28 joint counts) and BAFF were observed in patients with RA. In summary, increased BAFF levels were observed during absence of circulating B cells in our SLE and RA patient cohorts. In spite of the limited number of patients, our data suggest that BAFF and APRIL are differentially regulated in different autoimmune diseases and, in addition, differently affected by rituximab treatment.
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PMID:Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis. 1709 41

B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response.
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PMID:Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity. 1847 19

This article is an update on the clinical and research data available on systemic lupus erythematosus (SLE) and intravenous immunoglobulin (IVIg) therapy that includes some studies performed under the umbrella of the European Working Party on SLE. Various mechanisms of IVIg may play a role, some synergistically, in the modulation of SLE. Recently it has been suggested that IVIg also suppresses the expansion of autoreactive B lymphocytes through signalling of the FcgRIIB, idiotype-mediated inhibition of B cell receptors and neutralisation of cytokines such as the B cell survival factors (B cell activation factor (BAFF and APRIL). In case reports and in open trials, high-dose IVIg (2 g/kg over a 5-day period) has consistently been shown to be a beneficial and safe adjunct therapeutic agent for over 20 manifestations in patients with SLE. It can be given as a first choice of therapy in some cases, for example, in neurological involvement and in those patients who refuse certain immunosuppressive agents such as cyclophosphamide, or in patients who have concomitant infections. Furthermore, IVIg may have a steroid-sparing effect although this characteristic needs further investigation. Specific IVIg (an anti-idiotype to anti-DNA, phosphorylcholine and antiphospholipids) has been shown to be effective in experimental murine models. Hence, extractable IVIg that is directed to the specific pathogenic immunoglobulins will enable the more specific therapy for patients with lupus.
Lupus 2009 Sep
PMID:Intravenous immunoglobulins in systemic lupus erythematosus: from the bench to the bedside. 1967 87

Atacicept, a recombinant fusion protein of the TACI receptor and human IgG, is an inhibitor of B-Lymphocyte Stimulator (BLyS) and APRIL, potent stimulators of B cell maturation, proliferation, and survival. Pharmacokinetics (PKs) and biological activity of intravenous (iv) and subcutaneous (sc) atacicept are described here for patients with systemic lupus erythematosus in two randomized, double-blind, placebo-controlled, Phase Ib studies. Study 1: Six cohorts of eight patients received sc atacicept (single dose: 0.3, 1, 3, or 9 mg/kg; four weekly doses: 1 or 3 mg/kg), or placebo (3:1 ratio). Study 2: Four cohorts of six patients received iv atacicept (single dose: 3, 9, or 18 mg/kg; multiple dose: 2 x 9 mg/kg), or matching placebo (5:1 ratio). PK profiles were determined through serum atacicept and atacicept-BLyS complex, and biological activity through IgA, IgG, and IgM levels. PK profiles of atacicept were influenced by saturable binding between atacicept and its ligands, and were consistent and predictable across doses and regimens. Atacicept's biological activity was compatible with its presumed mechanism of action. Bioavailability was approximately 30-40% following sc or iv administration and similar doses yielded similar biological activity irrespective of administration route. This observation may have a mechanistic foundation and may inform dosing regimen design for future studies.
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PMID:Pharmacokinetics and immunoglobulin response of subcutaneous and intravenous atacicept in patients with systemic lupus erythematosus. 1974 3

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

The aim of the present study is to assess serum APRIL levels in SLE patients versus rheumatoid arthritis (RA) patients and normal control and to correlate serum APRIL levels in SLE patients with disease activity indices. Serum APRIL levels was measured in 40 SLE patients, 20 patients with RA and 20 healthy volunteers who served as control group. Disease activity in SLE patients was assessed by the British Isles Lupus Assessment Group (BILAG) index and SLE disease activity index (SLEDAI), and results were correlated with serum APRIL levels. Significantly higher serum APRIL levels was observed in SLE patients compared to RA patients and normal controls (p=0.003 and p < or = 0.001, respectively). Positive correlations were found between serum APRIL levels and total BILAG index (r=0.486 and p=0.001), BILAG musculoskeletal score (r=0.848 and p < or = 0.001) and BILAG cardiorespiratory score (r=0.326 and 0.04). Serum APRIL was higher in SLE patients compared to RA patients and normal control subjects and positively correlates with BILAG index and higher levels may be associated with musculoskeletal manifestations of the disease. APRIL antagonism could be a potential therapeutic target in SLE.
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PMID:Raised serum level of APRIL in patients with systemic lupus erythematosus: correlations with disease activity indices. 2011 34


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