Antiviral Adaptor MAVS Promotes Murine Lupus With a B Cell Autonomous Role

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by increased production of autoantibodies, which commonly target nuclear antigens, and concomitant deposition of immune complexes that cause inflammation in tissues. SLE is often associated with increased systemic expression of type I interferons, in some cases due to dysregulation in nucleic acid-sensing innate pathways. There is strong genetic evidence for a link between cytoplasmic RNA sensing pathways (RIG-I/MDA5) and SLE, both in human patients and murine models, however questions still remain regarding pathway initiation, cell types involved and downstream effects. Here we show that MAVS, an essential adaptor for RIG-I/MDA5 signaling, is necessary for all symptoms of autoimmune disease that develop spontaneously in the lupus model FcγRIIB−/− mice. This effect was independent of type I interferon signaling, TLR7 expression or STING, all three factors that have been connected to autoimmunity. Mixed bone marrow reconstitution experiments showed reduced occurrence in autoimmune germinal centers and diminished autoantibody production by MAVS-deficient B cells. Thus, MAVS plays a B cell intrinsic role in autoreactive B cell activation that is independent of its anti-viral functions and independent of elevated type I interferon expression.
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research

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Roche today announced data from the phase II NOBILITY study, investigating the safety and efficacy of Gazyva ® (obinutuzumab) for adults with proliferative lupus nephritis.1 The study met the primary endpoint with Gazyva, in combination with standard of care (mycophenolate mofetil or mycophenolic acid and corticosteroids), demonstrating superiority compared to placebo plus standard of care.
Source: Roche Media News - Category: Pharmaceuticals Source Type: news
Abstract B cells are essential to the adaptive immune system for providing the humoral immunity against cohorts of pathogens. The presentation of antigen to the B cell receptor (BCR) leads to the initiation of B cell activation, which is a process sensitive to the stiffness features of the substrates presenting the antigens. Mechanosensing of the B cells, potentiated through BCR signaling and the adhesion molecules, efficiently regulates B cell activation, proliferation and subsequent antibody responses. Defects in sensing of the antigen-presenting substrates can lead to the activation of autoreactive B cells in a...
Source: Advances in Immunology - Category: Allergy & Immunology Authors: Tags: Adv Immunol Source Type: research
In conclusion, a polypharmacology approach of combining established, prolongevity drug inhibitors of specific nodes may be the most effective way to target the nutrient-sensing network to improve late-life health. Deletion of p38α in Neurons Slows Neural Stem Cell Decline and Loss of Cognitive Function in Mice https://www.fightaging.org/archives/2019/10/deletion-of-p38%ce%b1-in-neurons-slows-neural-stem-cell-decline-and-loss-of-cognitive-function-in-mice/ Researchers here provide evidence for p38α to be involved in the regulation of diminished neural stem cell activity with age. It is thought...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Sterile inflammation arises without external cause, such as infection or injury, and chronic sterile inflammation is a characteristic of aging. Inflammatory signaling becomes constant and pronounced in tissues, and the immune system is constantly roused to action. Processes, such as regeneration from injury, that depend upon a clear cycle of inflammation that starts, progresses, and resolves are significantly disrupted. It is no exaggeration to say that the downstream consequences of chronic inflammation accelerate the progression of all of the common age-related conditions. It is of great importance in atherosclerosis and...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs
Conclusion As a critical regulator of inflammation and cell survival, the NFκB pathway is a promising target for diagnosing and treating kidney diseases. For modulation of the NFκB pathway in the clinic, a number of molecules can effectively inhibit NFκB signaling by targeting the receptors, associated adaptors, IKKs, IκBs and transcriptional regulators (144). There is further clinical evidence on small-molecule inhibitors of IKKα and NIK from recent trials on anti-cancer therapies (145). These clinical trials showed that the cancer-selective pharmacodynamic response of DTP3, the co-inhibitor...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
This study was supported in part by the Projects: Redes Internacionales (REDI170651) (to AH and MI); Proyecto interno Universidad Autónoma de Chile (DIUA 134-2018) and by the Pilot Research Grant (PP-1805-30965) from the National Multiple Sclerosis Society (to AH); Proyecto Genera-Autónoma N°UA 17-04 and FONDECYT de Inicio N° 11160592, CONICYT (to NE) and Proyecto Vicerrectoría de Investigación, Pontificia Universidad Católica de Chile Puente P1802 (to CL). Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or fina...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Publication date: 23 October 2018Source: Cell Reports, Volume 25, Issue 4Author(s): Katerina Gkirtzimanaki, Eleni Kabrani, Dimitra Nikoleri, Alexander Polyzos, Athanasios Blanas, Prodromos Sidiropoulos, Antonis Makrigiannakis, George Bertsias, Dimitrios T. Boumpas, Panayotis VerginisSummaryInterferon α (IFNα) is a prompt and efficient orchestrator of host defense against nucleic acids but upon chronicity becomes a potent mediator of autoimmunity. Sustained IFNα signaling is linked to pathogenesis of systemic lupus erythematosus (SLE), an incurable autoimmune disease characterized by aberrant self-DNA sens...
Source: Cell Reports - Category: Cytology Source Type: research
Abstract: Fogo selvagem or endemic pemphigus foliaceus is an autoimmune acantholytic anti-cadherin bullous disease that primarily affects seborrheic areas, which might disseminate. Brazil has the world's largest number of patients, mainly in the Central-West region, but the disease has also been reported in other South American countries. It affects young people and adults who have been exposed to rural areas, with occurrence of familial cases. Anti-desmoglein-1 autoantibodies are directed against desmosomal structures, with loss of adhesion of the upper layers of the epidermis, causing superficial blisters. The etiology i...
Source: Anais Brasileiros de Dermatologia - Category: Dermatology Source Type: research
AbstractPurpose of ReviewSystemic lupus erythematosus (SLE) is a multisystem autoimmune disease known for its clinical heterogeneity. Over time, new insights into the complex genetic origin of SLE have started to explain some of this clinical variability. These findings, reviewed here, have also yielded important understanding in the immune mechanisms behind SLE pathogenesis.Recent FindingsSeveral new monogenic disorders with lupus-like phenotype have been described. These can be organized into physiologic pathways that parallel mechanisms of disease in SLE. Examples include genes important for DNA damage repair (e.g.,TREX...
Source: Current Rheumatology Reports - Category: Rheumatology Source Type: research
Aicardi–Goutières syndrome (AGS) provides a monogenic model of nucleic acid-mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of either RNA:DNA hybrid or genome-embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid-sensing pathway. Here, we establish Rnaseh2bA174T/A174T knock-in mice as a subclinical model of disease, identifyi...
Source: EMBO Journal - Category: Molecular Biology Authors: Tags: Immunology Articles Source Type: research
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