013 Unabated type I interferon expedites B-cell autoimmunity and anti-drug antibody formation during anti-TNF therapy

2021 ◽  
Vol 141 (10) ◽  
pp. S151
Author(s):  
A. Mennella ◽  
A. Mylonas ◽  
J. Chen ◽  
A. Nidegger ◽  
M. Gilliet ◽  
...  
Keyword(s):  
B Cell ◽  
Antibody Formation ◽  
Type I Interferon ◽  
Type I

scholarly journals Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+Macrophage Function during Viral Infection

2015 ◽  
Vol 89 (9) ◽  
pp. 4748-4759 ◽  
Author(s):  
Haifeng C. Xu ◽  
Jun Huang ◽  
Vishal Khairnar ◽  
Vikas Duhan ◽  
Aleksandra A. Pandyra ◽  
...  
Keyword(s):  
B Cells ◽  
Viral Infection ◽  
B Cell ◽  
Viral Infections ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Production ◽  
Immune Priming ◽  
Adaptive Immune ◽  
Deficient Mice

ABSTRACTThe B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169+macrophage compartment. Consequently,Baffr−/−mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells inBaffr−/−animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169+cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.IMPORTANCEViruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169+macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.

A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis

2019 ◽  
Vol 101 ◽  
pp. 1-16 ◽  
Author(s):  
Martina Severa ◽  
Fabiana Rizzo ◽  
Sundararajan Srinivasan ◽  
Marco Di Dario ◽  
Elena Giacomini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cell ◽  
Type I Interferon ◽  
Type I ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific

scholarly journals Influenza Virus-Induced Type I Interferon Leads to Polyclonal B-Cell Activation but Does Not Break Down B-Cell Tolerance

2007 ◽  
Vol 81 (22) ◽  
pp. 12525-12534 ◽  
Author(s):  
Anne Woods ◽  
Fanny Monneaux ◽  
Pauline Soulas-Sprauel ◽  
Sylviane Muller ◽  
Thierry Martin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Production ◽  
B Cell Activation ◽  
B Cell Tolerance

ABSTRACT The link between infection and autoimmunity is not yet well understood. This study was designed to evaluate if an acute viral infection known to induce type I interferon production, like influenza, can by itself be responsible for the breakdown of immune tolerance and for autoimmunity. We first tested the effects of influenza virus on B cells in vitro. We then infected different transgenic mice expressing human rheumatoid factors (RF) in the absence or in the constitutive presence of the autoantigen (human immunoglobulin G [IgG]) and young lupus-prone mice [(NZB × NZW)F1] with influenza virus and looked for B-cell activation. In vitro, the virus induces B-cell activation through type I interferon production by non-B cells but does not directly stimulate purified B cells. In vivo, both RF and non-RF B cells were activated in an autoantigen-independent manner. This activation was abortive since IgM and IgM-RF production levels were not increased in infected mice compared to uninfected controls, whether or not anti-influenza virus human IgG was detected and even after viral rechallenge. As in RF transgenic mice, acute viral infection of (NZB × NZW)F1 mice induced only an abortive activation of B cells and no increase in autoantibody production compared to uninfected animals. Taken together, these experiments show that virus-induced acute type I interferon production is not able by itself to break down B-cell tolerance in both normal and autoimmune genetic backgrounds.

scholarly journals Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus

2009 ◽  
Vol 11 (4) ◽  
pp. R112 ◽  
Author(s):  
Donna L Thibault ◽  
Kareem L Graham ◽  
Lowen Y Lee ◽  
Imelda Balboni ◽  
Paul J Hertzog ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
B Cell ◽  
Murine Model ◽  
Type I Interferon ◽  
Type I ◽  
Toll Like Receptors ◽  
Autoantibody Production ◽  
Interferon Receptor ◽  
Cell Expression

scholarly journals B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

2021 ◽  
Vol 12 ◽  
Author(s):  
Kenneth Green ◽  
Thomas R. Wittenborn ◽  
Cecilia Fahlquist-Hagert ◽  
Ewa Terczynska-Dyla ◽  
Nina van Campen ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Type I Interferon ◽  
Affinity Maturation ◽  
Antibody Responses ◽  
Type I ◽  
Cell Responses ◽  
B Cell Responses ◽  
Sting Pathway ◽  
Humoral Responses

Germinal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signals driving B cell participation in GC responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an important mediator of type I interferon and proinflammatory cytokine responses during infection and cellular stress. Recent studies have reported important roles for STING in B cell responses, including an impact on GC B cells and downstream antibody responses, which could have great consequences for vaccine design and understanding STING-associated interferonopathies. GCs are also involved in untoward reactions to autoantigens in a plethora of autoimmune disorders, and it is generally thought that these responses coopt the mechanisms used in foreign antigen-directed GCs. Here, we set out to investigate the importance of the cGAS-STING pathway in autoreactive B cell responses. In a direct competition scenario in a murine mixed bone marrow chimera model of autoreactive GCs, we find that B cell intrinsic deficiency of cGAS, STING, or the type I interferon receptor IFNAR, does not impair GC participation, whereas Toll-like receptor (TLR)-7 deficiency mediates a near-complete block. Our findings suggest that physiological B cell responses are strictly sustained by signals linked to BCR-mediated endocytosis. This wiring of B cell signals may enable appropriate antibody responses, while at the same time restricting aberrant antibody responses during infections and in autoimmune or autoinflammatory settings.

scholarly journals B-Cell Compartmental Features and Molecular Basis for Therapy in Autoimmune Disease

2021 ◽  
Vol 8 (6) ◽  
pp. e1070
Author(s):  
Chao Zhang ◽  
Tian-Xiang Zhang ◽  
Ye Liu ◽  
Dongmei Jia ◽  
Pei Zeng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Type I Interferon ◽  
Type I ◽  
Autoantibody Production ◽  
Interferon Pathway ◽  
Proinflammatory Activity ◽  
Cell Subpopulations ◽  
Molecular Landscape

Background and ObjectivesTo assess the molecular landscape of B-cell subpopulations across different compartments in patients with neuromyelitis optica spectrum disorder (NMOSD).MethodsWe performed B-cell transcriptomic profiles via single-cell RNA sequencing across CSF, blood, and bone marrow in patients with NMOSD.ResultsAcross the tissue types tested, 4 major subpopulations of B cells with distinct signatures were identified: naive B cells, memory B cells, age-associated B cells, and antibody-secreting cells (ASCs). NMOSD B cells show proinflammatory activity and increased expression of chemokine receptor genes (CXCR3 and CXCR4). Circulating B cells display an increase of antigen presentation markers (CD40 and CD83), as well as activation signatures (FOS, CD69, and JUN). In contrast, the bone marrow B-cell population contains a large ASC fraction with increased oxidative and metabolic activity reflected by COX genes and ATP synthase genes. Typically, NMOSD B cells become hyperresponsive to type I interferon, which facilitates B-cell maturation and anti–aquaporin-4 autoantibody production. The pool of ASCs in blood and CSF were significantly elevated in NMOSD. Both CD19− and CD19+ ASCs could be ablated by tocilizumab, but not rituximab treatment in NMOSD.DiscussionB cells are compartmentally fine tuned toward autoreactivity in NMOSD and become hyperreactive to type I interferon. Inhibition of type I interferon pathway may provide a new therapeutic avenue for NMOSD.

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