Evidence of a role for B cell–activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps

Kato, Atsushi; Peters, Anju T.; Suh, Lydia; Carter, Roderick; Harris, Kathleen E.; Chandra, Rakesh; Conley, David B.; Grammer, Leslie C.; Kern, Robert C.; Schleimer, Robert P.

doi:10.1016/j.jaci.2008.03.002

Cited by 165 publications

(186 citation statements)

References 45 publications

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“…In addition, our group has previously shown that B cell-activating factor (BAFF) of the TNF family, a key B cell survival factor, is highly expressed in NP tissue from patients with CRSwNPs (8). We also reported increased levels of autoantigen-specific antibodies in NP tissue (9,10).…”

Section: Clinical Relevancementioning

confidence: 83%

A Recently Established Murine Model of Nasal Polyps Demonstrates Activation of B Cells, as Occurs in Human Nasal Polyps

Kim

Lee²,

Carter³

et al. 2016

Am J Respir Cell Mol Biol

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Animal model systems are invaluable for examining human diseases. Our laboratory recently established a mouse model of nasal polyps (NPs) and investigated similarities and differences between this mouse model and human NPs. We especially focus on the hypothesis that B cell activation occurs during NP generation in the murine model. After induction of ovalbumin-induced allergic rhinosinusitis, 6% ovalbumin and Staphylococcus aureus enterotoxin B (10 ng) were instilled into the nasal cavity of mice three times per week for 8 weeks. The development of structures that somewhat resemble NPs (which we will refer to as NPs) was confirmed by hematoxylin and eosin staining. The mRNA and protein levels of various inflammatory cell markers and mediators were measured by real-time PCR in nasal tissue and by ELISA in nasal lavage fluid (NLF), respectively. Total Ig isotype levels in NLF were also quantitated using the Mouse Ig Isotyping Multiplex kit (EMD Millipore, Billerica, MA) on a Luminex 200 instrument (Life Technologies, Grand Island, NY). Similar to human NPs, there were significant increases in gene expression of inflammatory cell markers, such as CD19, CD138, CD11c, and mast cell protease-6 in nasal tissue samples of the NP group compared with those of the control group. In further investigations of B cell activation, mRNA expressions of B cell activating factor and a proliferation-inducing ligand were found to be significantly increased in mouse NP tissue. B cell-activating factor protein concentration and IgA and IgG 1 levels in NLF were significantly higher in the NP group compared with the control group. In this study, the NP mouse model demonstrated enhanced B cell responses, which are reminiscent of B cell responses in human NPs. Clinical RelevanceThe present study demonstrates that the nasal polyp (NP) mouse model revealed enhanced B cell responses, reminiscent of human NPs. This mouse model may enhance our understanding of the pathophysiology of NPs and provide a model to test therapeutic targets in vivo.Chronic rhinosinusitis (CRS) is one of most common chronic diseases worldwide. CRS can be categorized into two types: CRS with nasal polyps (NPs; CRSwNPs) and CRS without NPs (CRSsNPs). The pathogenesis of NPs is incompletely understood, and lack of an in vivo animal model for NPs has been a major hurdle in investigating NP pathogenesis and testing new treatment modalities. Animal model systems are invaluable in vivo models for examining a variety of human diseases and aid in the

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Section: Clinical Relevancementioning

confidence: 83%

A Recently Established Murine Model of Nasal Polyps Demonstrates Activation of B Cells, as Occurs in Human Nasal Polyps

Kim

Lee²,

Carter³

et al. 2016

Am J Respir Cell Mol Biol

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“…528 In addition to host defense molecules, ECs respond to PRR stimulation with the secretion of cytokines and chemokines that foster inflammation and attract and activate innate effector cells. 362,515,[529][530][531][532] In addition, the EC cytokines play a key role in shaping any subsequent adaptive immune response. Cytokine crosstalk between ECs, innate lymphoid cells (ILCs), and dendritic cells matches the appropriate innate and adaptive response to particular foreign stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…288,556 These observations suggest that host defects in CRS will be centered in the airway mucosa, giving rise to the "immune barrier hypothesis," which proposes that genetic and epigenetic variation in the coordinated mechanical barrier and/or the innate immune response of the sinonasal epithelium manifests as CRS. 530 Diminished innate host defense coupled with a porous barrier should theoretically lead to altered microbial colonization, accentuated barrier damage, and a compensatory adaptive immune response. 491,528 Although somewhat distinct, CRSsNP and CRSwNP both exhibit innate immune and mechanical barrier defects.…”

Section: Discussionmentioning

confidence: 99%

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

Orlandi

Kingdom

Hwang

et al. 2016

Int Forum Allergy Rhinol

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557

888

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Background:The body of knowledge regarding rhinosinusitis (RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS). Methods:Evidence-based reviews with recommendations (EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR) was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus. Results:The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS) with and without nasal polyps (CRSwNP and CRSsNP), recurrent acute RS (RARS), acute exacerbation of CRS (AE-CRS), and pediatric RS. Conclusion:As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too o en the foundation upon which these recommendations are based is comprised of lowerlevel evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed. C 2016 ARS-AAOA, LLC. Key Words:rhinosinusitis; chronic rhinosinusitis; acute rhinosinusitis; recurrent acute rhinosinusitis; evidence-based medicine; systematic review; endoscopic sinus surgery List of Abbreviations Used

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“…Immunohistochemistry was performed as described previously (15). Briefly, blocked sections were incubated with antihuman fibrin antibody (Sekisui Diagnostics, Stamford, CT) or antihuman t-PA antibody (Sigma, St. Louis, MO) at 4 8 C overnight.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression

Takabayashi

Kato²,

Peters³

et al. 2013

Am J Respir Crit Care Med

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148

205

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Rationale: Nasal polyps (NPs) are characterized by intense edema or formation of pseudocysts filled with plasma proteins, mainly albumin. However, the mechanisms underlying NP retention of plasma proteins in their submucosa remain unclear. Objectives: We hypothesized that formation of a fibrin mesh retains plasma proteins in NPs. We assessed the fibrin deposition and expression of the components of the fibrinolytic system in patients with chronic rhinosinusitis (CRS). Methods:We assessed fibrin deposition in nasal tissue from patients with CRS and control subjects by means of immunofluorescence. Fibrinolytic components, d-dimer, and plasminogen activators were measured using ELISA, real-time PCR, and immunohistochemistry. We also performed gene expression and protein quantification analysis in cultured airway epithelial cells. Measurements and Main Results: Immunofluorescence data showed profound fibrin deposition in NP compared with uncinate tissue (UT) from patients with CRS and control subjects. Levels of the cross-linked fibrin cleavage product protein, d-dimer, were significantly decreased in NP compared with UT from patients with CRS and control subjects, suggesting reduced fibrinolysis (P , 0.05). Expression levels of tissue plasminogen activator (t-PA) mRNA and protein were significantly decreased in NP compared with UT from patients with CRS and control subjects (P , 0.01). Immunohistochemistry demonstrated clear reduction of t-PA in NP, primarily in the epithelium and glands. Th2 cytokine-stimulated cultured airway epithelial cells showed down-regulation of t-PA, suggesting a potential Th2 mechanism in NP. Conclusions: A Th2-mediated reduction of t-PA might lead to excessive fibrin deposition in the submucosa of NP, which might contribute to the tissue remodeling and pathogenesis of CRS with nasal polyps.

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Evidence of a role for B cell–activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps

Abstract: Overproduction of BAFF in nasal polyps may contribute to the pathogenesis of CRSwNP via the local induction of IgA and activation of eosinophils.

Cited by 165 publications

References 45 publications

A Recently Established Murine Model of Nasal Polyps Demonstrates Activation of B Cells, as Occurs in Human Nasal Polyps

A Recently Established Murine Model of Nasal Polyps Demonstrates Activation of B Cells, as Occurs in Human Nasal Polyps

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

Excessive Fibrin Deposition in Nasal Polyps Caused by Fibrinolytic Impairment through Reduction of Tissue Plasminogen Activator Expression

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