Toll-Like Receptor Signaling Drives Btk-Mediated Autoimmune Disease.


:Bruton's tyrosine kinase (Btk) is a signaling molecule involved in development and activation of B cells through B-cell receptor (BCR) and Toll-like receptor (TLR) signaling. We have previously shown that transgenic mice that overexpress human Btk under the control of the CD19 promoter (CD19-hBtk) display spontaneous germinal center formation, increased cytokine production, anti-nuclear autoantibodies (ANAs), and systemic autoimsmune disease upon aging. As TLR and BCR signaling are both implicated in autoimmunity, we studied their impact on splenic B cells. Using phosphoflow cytometry, we observed that phosphorylation of ribosomal protein S6, a downstream Akt target, was increased in CD19-hBtk B cells following BCR stimulation or combined BCR/TLR stimulation, when compared with wild-type (WT) B cells. The CD19-hBtk transgene enhanced BCR-induced B cell survival and proliferation, but had an opposite effect following TLR9 or combined BCR/TLR9 stimulation. Although the expression of TLR9 was reduced in CD19-hBtk B cells compared to WT B cells, a synergistic effect of TLR9 and BCR stimulation on the induction of CD25 and CD80 was observed in CD19-hBtk B cells. In splenic follicular (Fol) and marginal zone (MZ) B cells from aging CD19-hBtk mice BCR signaling stimulated in vitro IL-10 production in synergy with TLR4 and particularly TLR9 stimulation, but not with TLR3 and TLR7. The enhanced capacity of CD19-hBtk Fol B cells to produce the pro-inflammatory cytokines IFNγ and IL-6 compared with WT B cells was however not further increased following in vitro BCR or TLR9 stimulation. Finally, we used crosses with mice deficient for the TLR-associated molecule myeloid differentiation primary response 88 (MyD88) to show that TLR signaling was crucial for spontaneous formation of germinal centers, increased IFNγ, and IL-6 production by B cells and anti-nuclear autoantibody induction in CD19-hBtk mice. Taken together, we conclude that high Btk expression does not only increase B cell survival following BCR stimulation, but also renders B cells more sensitive to TLR stimulation, resulting in increased expression of CD80, and IL-10 in activated B cells. Although BCR-TLR interplay is complex, our findings show that both signaling pathways are crucial for the development of pathology in a Btk-dependent model for systemic autoimmune disease.


Front Immunol


Frontiers in immunology


Rip J,de Bruijn MJW,Appelman MK,Pal Singh S,Hendriks RW,Corneth OBJ




Has Abstract


2019-01-30 00:00:00








  • Human Lymphoid Stromal Cells Contribute to Polarization of Follicular T Cells Into IL-4 Secreting Cells.

    abstract::Fibroblastic reticular cells (FRCs) are the specialized lymphoid stromal cells initially identified as triggering T-cell recruitment and dynamic motion in secondary lymphoid organs. Interestingly, FRCs also display antigen presentation capacities and support lymphocyte survival. CXCR5+CD4+ follicular T cells are impor...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Misiak J,Jean R,Rodriguez S,Deleurme L,Lamy T,Tarte K,Amé-Thomas P

    更新日期:2020-10-02 00:00:00

  • Fate of a Naive T Cell: A Stochastic Journey.

    abstract::The homeostasis of T cell populations depends on migration, division and death of individual cells (1). T cells migrate between spatial compartments (spleen, lymph nodes, lung, liver, etc.), where they may divide or differentiate, and eventually die (2). The kinetics of recirculation influences the speed at which loca...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: de la Higuera L,López-García M,Castro M,Abourashchi N,Lythe G,Molina-París C

    更新日期:2019-03-06 00:00:00

  • MTBVAC: Attenuating the Human Pathogen of Tuberculosis (TB) Toward a Promising Vaccine against the TB Epidemic.

    abstract::Bacille Calmette-Guérin (BCG) is a live-attenuated strain of Mycobacterium bovis developed a century ago by repeated subculture. It remains the only vaccine against tuberculosis (TB) in use today, and it offers variable protection against the respiratory forms of TB responsible for transmission. The principal genetic ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Gonzalo-Asensio J,Marinova D,Martin C,Aguilo N

    更新日期:2017-12-15 00:00:00

  • Mechanisms of Graft-versus-Host Disease Prevention by Post-transplantation Cyclophosphamide: An Evolving Understanding.

    abstract::Post-transplantation cyclophosphamide (PTCy) has been highly successful at preventing severe acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). The clinical application of this approach was based on extensive studies in major histocompatibility complex (MHC)-m...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Nunes NS,Kanakry CG

    更新日期:2019-11-29 00:00:00

  • Role of T Cell-To-Dendritic Cell Chemoattraction in T Cell Priming Initiation in the Lymph Node: An Agent-Based Modeling Study.

    abstract::The adaptive immune response is initiated in lymph nodes by contact between antigen-bearing dendritic cells (DCs) and antigen-specific T cells. A selected number of naïve T cells that recognize a specific antigen may proliferate into expanded clones, differentiate, and acquire an effector phenotype. Despite growing ex...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Azarov I,Peskov K,Helmlinger G,Kosinsky Y

    更新日期:2019-06-11 00:00:00

  • Endothelial Basement Membrane Laminins as an Environmental Cue in Monocyte Differentiation to Macrophages.

    abstract::Monocyte differentiation to macrophages is triggered by migration across the endothelial barrier, which is constituted by both endothelial cells and their underlying basement membrane. We address here the role of the endothelial basement membrane laminins (laminins 411 and 511) in this monocyte to macrophage switch. C...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Li L,Song J,Chuquisana O,Hannocks MJ,Loismann S,Vogl T,Roth J,Hallmann R,Sorokin L

    更新日期:2020-10-30 00:00:00

  • Fungal Infection in the Brain: What We Learned from Intravital Imaging.

    abstract::Approximately 1.2 billion people suffer from fungal diseases worldwide. Arguably, the most serious manifestation occurs when pathogenic fungi infect the brain, often causing fatal meningoencephalitis. For most fungi, infection occurs via the vascular route. The organism must first be arrested in the brain microvascula...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Shi M,Mody CH

    更新日期:2016-08-02 00:00:00

  • Stability and Maintenance of Foxp3+ Treg Cells in Non-lymphoid Microenvironments.

    abstract::Foxp3+ Treg cells are indispensable for maintaining self-tolerance in secondary lymphoid organs (SLOs). However, Treg cells are also recruited to non-lymphoid tissues (NLTs) during inflammation. Recent advances in the understanding of Treg cell biology provided us with molecular mechanisms-both transcriptional and epi...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Korn T,Muschaweckh A

    更新日期:2019-11-14 00:00:00

  • Imaging the Bone-Immune Cell Interaction in Bone Destruction.

    abstract::Bone is a highly dynamic organ that is continuously being remodeled by the reciprocal interactions between bone and immune cells. We have originally established an advanced imaging system for visualizing the in vivo behavior of osteoclasts and their precursors in the bone marrow cavity using two-photon microscopy. Usi...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Hasegawa T,Kikuta J,Ishii M

    更新日期:2019-03-26 00:00:00

  • Hypomorphic Mutations in the BCR Signalosome Lead to Selective Immunoglobulin M Deficiency and Impaired B-cell Homeostasis.

    abstract::B cell activation via the B cell receptor (BCR) signalosome involves participation of signaling molecules such as BTK and BLNK. Genetic defects in these molecules are known to impair B cell differentiation and subsequently lead to agammaglobulinemia. Here we identified novel mutations in BTK and BLNK in two unrelated ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Geier CB,Sauerwein KMT,Leiss-Piller A,Zmek I,Fischer MB,Eibl MM,Wolf HM

    更新日期:2018-12-18 00:00:00

  • How the Interplay Between the Commensal Microbiota, Gut Barrier Integrity, and Mucosal Immunity Regulates Brain Autoimmunity.

    abstract::The intestinal barrier provides the host with a strong defense line against the external environment playing also a pivotal role in the crosstalk between the gut microbiota and the immune system. Notably, increasing lines of evidence concerning autoimmune disorders such as Multiple Sclerosis (MS) report an imbalance i...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Antonini M,Lo Conte M,Sorini C,Falcone M

    更新日期:2019-08-16 00:00:00

  • Interleukin-2 production by dendritic cells and its immuno-regulatory functions.

    abstract::Dendritic cells (DCs) are uniquely potent antigen presenting cells that acquire microbial products and prime adaptive immune responses against pathogens. Furthermore, DCs also play a key role in induction and maintenance of tolerance. Although numerous studies have assessed the diverse functions of DCs, many unanswere...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Zelante T,Fric J,Wong AY,Ricciardi-Castagnoli P

    更新日期:2012-06-18 00:00:00

  • Recent Advances in Immune Cell Therapy for Glioblastoma.

    abstract::Glioblastoma (GBM) is the most malignant form of astrocytoma with short survival and a high recurrence rate and remains a global problem. Currently, surgery, chemotherapy, radiotherapy, and other comprehensive treatments are the main treatment modalities, but patients still have a poor prognosis mainly due to the infi...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Kang X,Zheng Y,Hong W,Chen X,Li H,Huang B,Huang Z,Tang H,Geng W

    更新日期:2020-10-21 00:00:00

  • Computational Biology: Modeling Chronic Renal Allograft Injury.

    abstract::New approaches are needed to develop more effective interventions to prevent long-term rejection of organ allografts. Computational biology provides a powerful tool to assess the large amount of complex data that is generated in longitudinal studies in this area. This manuscript outlines how our two groups are using m...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Stegall MD,Borrows R

    更新日期:2015-08-03 00:00:00

  • Erythromycin treatment hinders the induction of oral tolerance to fed ovalbumin.

    abstract::The mucosal immune system is constantly exposed to antigen, whether it be food antigen, commensal bacteria, or harmful antigen. It is essential that the mucosal immune system can distinguish between harmful and non-harmful antigens, and initiate an active immune response to clear the harmful antigens, while initiating...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Lambert SE,Kinder JM,Then JE,Parliament KN,Bruns HA

    更新日期:2012-07-18 00:00:00

  • Chemokines in Physiological and Pathological Bone Remodeling.

    abstract::The bone matrix is constantly remodeled by bone-resorbing osteoclasts and bone-forming osteoblasts. These two cell types are fundamentally different in terms of progenitor cells, mode of action and regulation by specific molecules, acting either systemically or locally. Importantly, there is increasing evidence for an...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Brylka LJ,Schinke T

    更新日期:2019-09-13 00:00:00

  • Isatuximab Acts Through Fc-Dependent, Independent, and Direct Pathways to Kill Multiple Myeloma Cells.

    abstract::Isatuximab is a monoclonal antibody targeting the transmembrane receptor and ectoenzyme CD38, a protein highly expressed on hematological malignant cells, including those in multiple myeloma (MM). Upon binding to CD38-expressing MM cells, isatuximab is thought to induce tumor cell killing via fragment crystallizable (...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Zhu C,Song Z,Wang A,Srinivasan S,Yang G,Greco R,Theilhaber J,Shehu E,Wu L,Yang ZY,Passe-Coutrin W,Fournier A,Tai YT,Anderson KC,Wiederschain D,Bahjat K,Adrián FJ,Chiron M

    更新日期:2020-08-14 00:00:00

  • Early Resistance of Non-virulent Mycobacterial Infection in C57BL/6 Mice Is Associated With Rapid Up-Regulation of Antimicrobial Cathelicidin Camp.

    abstract::Early clearance of tuberculosis is the successful eradication of inhaled bacteria before the development of an adaptive immune response. We previously showed, by utilizing a non-virulent mycobacteria infection model, that C57BL/6 mice are more efficient than BALB/c in their control of bacterial growth in the lungs dur...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Adam L,López-González M,Björk A,Pålsson S,Poux C,Wahren-Herlenius M,Fernández C,Spetz AL

    更新日期:2018-09-03 00:00:00

  • Leveraging Multilayered "Omics" Data for Atopic Dermatitis: A Road Map to Precision Medicine.

    abstract::Atopic dermatitis (AD) is a complex multifactorial inflammatory skin disease that affects ~280 million people worldwide. About 85% of AD cases begin in childhood, a significant portion of which can persist into adulthood. Moreover, a typical progression of children with AD to food allergy, asthma or allergic rhinitis ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Ghosh D,Bernstein JA,Khurana Hershey GK,Rothenberg ME,Mersha TB

    更新日期:2018-12-12 00:00:00

  • The Soluble Form of Toll-Like Receptor 2 Is Elevated in Serum of Multiple Sclerosis Patients: A Novel Potential Disease Biomarker.

    abstract::Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system. It was previously shown that toll-like receptor (TLR)-2 signaling plays a key role in the murine experimental autoimmune encephalomyelitis (EAE) model of MS, and that TLR2-stimulation of regulatory T cells (...

    journal_title:Frontiers in immunology

    pub_type: 临床试验,杂志文章


    authors: Hossain MJ,Morandi E,Tanasescu R,Frakich N,Caldano M,Onion D,Faraj TA,Erridge C,Gran B

    更新日期:2018-03-14 00:00:00

  • Human Gut Symbiont Roseburia hominis Promotes and Regulates Innate Immunity.

    abstract:OBJECTIVE:Roseburia hominis is a flagellated gut anaerobic bacterium belonging to the Lachnospiraceae family within the Firmicutes phylum. A significant decrease of R. hominis colonization in the gut of ulcerative colitis patients has recently been demonstrated. In this work, we have investigated the mechanisms of R. h...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Patterson AM,Mulder IE,Travis AJ,Lan A,Cerf-Bensussan N,Gaboriau-Routhiau V,Garden K,Logan E,Delday MI,Coutts AGP,Monnais E,Ferraria VC,Inoue R,Grant G,Aminov RI

    更新日期:2017-09-26 00:00:00

  • Antibacterial Fusion Proteins Enhance Moraxella catarrhalis Killing.

    abstract::Moraxella catarrhalis is a human-specific commensal of the respiratory tract and an opportunistic pathogen. It is one of the leading cause of otitis media in children and of acute exacerbations in patients with chronic obstructive pulmonary disease, resulting in significant morbidity and economic burden. Vaccines and ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Laabei M,Colineau L,Bettoni S,Maziarz K,Ermert D,Riesbeck K,Ram S,Blom AM

    更新日期:2020-09-02 00:00:00

  • Increased TNF-α/IFN-γ/IL-2 and Decreased TNF-α/IFN-γ Production by Central Memory T Cells Are Associated with Protective Responses against Bovine Tuberculosis Following BCG Vaccination.

    abstract::Central memory T cell (Tcm) and polyfunctional CD4 T cell responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB); however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by CD4 T cell effect...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Maggioli MF,Palmer MV,Thacker TC,Vordermeier HM,McGill JL,Whelan AO,Larsen MH,Jacobs WR Jr,Waters WR

    更新日期:2016-10-17 00:00:00

  • From the Cradle to the Grave: The Role of Macrophages in Erythropoiesis and Erythrophagocytosis.

    abstract::Erythropoiesis is a highly regulated process where sequential events ensure the proper differentiation of hematopoietic stem cells into, ultimately, red blood cells (RBCs). Macrophages in the bone marrow play an important role in hematopoiesis by providing signals that induce differentiation and proliferation of the e...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Klei TR,Meinderts SM,van den Berg TK,van Bruggen R

    更新日期:2017-02-02 00:00:00

  • NOD-Like Receptors in Lung Diseases.

    abstract::The lung is a particularly vulnerable organ at the interface of the body and the exterior environment. It is constantly exposed to microbes and particles by inhalation. The innate immune system needs to react promptly and adequately to potential dangers posed by these microbes and particles, while at the same time avo...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Chaput C,Sander LE,Suttorp N,Opitz B

    更新日期:2013-11-21 00:00:00

  • Pulmonary Exposure to Magnéli Phase Titanium Suboxides Results in Significant Macrophage Abnormalities and Decreased Lung Function.

    abstract::Coal is one of the most abundant and economic sources for global energy production. However, the burning of coal is widely recognized as a significant contributor to atmospheric particulate matter linked to deleterious respiratory impacts. Recently, we have discovered that burning coal generates large quantities of ot...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: McDaniel DK,Ringel-Scaia VM,Morrison HA,Coutermarsh-Ott S,Council-Troche M,Angle JW,Perry JB,Davis G,Leng W,Minarchick V,Yang Y,Chen B,Reece SW,Brown DA,Cecere TE,Brown JM,Gowdy KM,Hochella MF Jr,Allen IC

    更新日期:2019-11-28 00:00:00

  • Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D.

    abstract::Bi-allelic null mutations affecting UNC13D, STXBP2, or STX11 result in defects of lymphocyte cytotoxic degranulation and commonly cause familial hemophagocytic lymphohistiocytosis (FHL) in early life. Patients with partial loss of function are increasingly being diagnosed after presenting with alternative features of ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Gray PE,Shadur B,Russell S,Mitchell R,Buckley M,Gallagher K,Andrews I,Thia K,Trapani JA,Kirk EP,Voskoboinik I

    更新日期:2017-08-09 00:00:00

  • Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies.

    abstract::Severe combined immunodeficiency (SCID) and other severe non-SCID primary immunodeficiencies (non-SCID PID) can be treated by allogeneic hematopoietic stem cell (HSC) transplantation, but when histocompatibility leukocyte antigen-matched donors are lacking, this can be a high-risk procedure. Correcting the patient's o...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审


    authors: Ott de Bruin LM,Volpi S,Musunuru K

    更新日期:2015-05-21 00:00:00

  • Germline Amino Acid Diversity in B Cell Receptors is a Good Predictor of Somatic Selection Pressures.

    abstract::The diversity of the immune repertoire is important for the adaptive immune system's ability to detect pathogens. Much of this diversity is generated in two steps, first through the recombination of germline gene segments and second through hypermutation during an immune response. While both steps are to some extent b...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章


    authors: Schwartz GW,Hershberg U

    更新日期:2013-11-08 00:00:00

  • Different Innate and Adaptive Immune Responses to SARS-CoV-2 Infection of Asymptomatic, Mild, and Severe Cases.

    abstract::SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focused on patients with m...

    journal_title:Frontiers in immunology

    pub_type: 临床试验,杂志文章,多中心研究


    authors: Carsetti R,Zaffina S,Piano Mortari E,Terreri S,Corrente F,Capponi C,Palomba P,Mirabella M,Cascioli S,Palange P,Cuccaro I,Milito C,Zumla A,Maeurer M,Camisa V,Vinci MR,Santoro A,Cimini E,Marchioni L,Nicastri E,Palmi

    更新日期:2020-12-16 00:00:00