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BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells. OBJECTIVES: This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD. METHODS: NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours. RESULTS: This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13-induced attenuation of tPA expression in cultured cells (P < .01). CONCLUSIONS: RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13-induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.
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Asma Induzida por Aspirina , Pólipos Nasais , Rinite , Sinusite , Humanos , Pólipos Nasais/metabolismo , Rinite/metabolismo , Ativador de Plasminogênio Tecidual , Interleucina-13 , Fibrinólise , Tretinoína/farmacologia , Células Endoteliais/metabolismo , Sinusite/metabolismo , Asma Induzida por Aspirina/complicações , Doença Crônica , FibrinaRESUMO
BACKGROUND: Polyps from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) contain increased levels of autoreactive antibodies, B cells and fibrin deposition. Anti-phospholipid antibodies (APA) are autoantibodies known to cause thrombosis but have not been implicated in chronic rhinosinusitis (CRS). OBJECTIVE: To compare APA levels (anti-cardiolipin, anti-phosphatidylethanolamine (anti-PE), and anti-ß2 -glycoprotein (anti-B2GP)) in nasal polyp (NP) tissue with tissue from control and CRS without nasal polyp (CRSsNP) patients, we tested whether NP antibodies affect coagulation, and correlate APAs with anti-dsDNA IgG and markers of coagulation. METHODS: Patient specimens were assayed for APA IgG, anti-dsDNA IgG and thrombin-anti-thrombin (TaT) complex by ELISA. Antibodies from a subset of specimens were tested for modified activated partial thromboplastin time (aPTT) measured on an optical-mechanical coagulometer. RESULTS: Anti-cardiolipin IgG in NP was 5-fold higher than control tissue (p < .0001). NP antibodies prolonged aPTT compared to control tissue antibodies at 400 µg/mL (36.7 s vs. 33.8 s, p = .024) and 600 µg/mL (40.9 s vs. 34.7 s, p = .0037). Anti-PE IgG antibodies were increased in NP (p = .027), but anti-B2GP IgG was not significantly higher (p = .084). All APAs correlated with anti-dsDNA IgG levels, which were also elevated (R = .77, .71 and .54, respectively, for anti-cardiolipin, anti-PE, and anti-B2GP; all p < .001), but only anti-cardiolipin (R = .50, p = .0185) and anti-PE (R = 0.45, p = .037) correlated with TaT complex levels. CONCLUSIONS: APA IgG antibodies are increased in NP and correlate with autoreactive tissue antibodies. NP antibodies have in vitro anti-coagulant activity similar to those observed in anti-phospholipid syndrome, suggesting that they may have pro-coagulant effects in polyp tissue.
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Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Humanos , Imunoglobulina G , Pólipos Nasais/complicaçõesRESUMO
BACKGROUND: Increased activation of the coagulation cascade and diminished fibrinolysis combine to promote fibrin deposition and polyp formation in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). More information is needed concerning mechanisms of coagulation in CRSwNP. OBJECTIVE: We investigated the mechanisms as well as the initiation and regulation of coagulation cascade activation in CRS. METHODS: Samples were collected from 135 subjects with CRSwNP, 80 subjects with chronic CRS without nasal polyps (NP), and 65 control subjects. The levels of activated factor X (FXa), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex, tissue factor (TF), and TF pathway inhibitor (TFPI) were monitored in CRS by real-time PCR, ELISA, immunohistochemistry, or immunofluorescence. Heteromeric complexes of TF with activated factor VII (FVII) and TF with activated FVII and FXa were assessed by coimmunoprecipitation and Western blotting. RESULTS: Increased levels of FXa, F1+2, and thrombin-antithrombin complex were detected in NP tissue compared to uncinate tissue from CRS and control subjects. Although free TF protein levels were not increased in NP, immunoprecipitation of TF in NP tissue revealed increased complexes of TF with FVII. Local expression of FVII was detected in sinonasal mucosa, and the ratio of TFPI to FXa was lower in NP tissue. CONCLUSION: The coagulation cascade is associated with NP compared to control and uncinate tissue from CRS patients, and TF and FVII are produced locally in sinonasal mucosa in patients. TF and FVII can activate the extrinsic coagulation pathway, suggesting that this pathway may activate fibrin deposition in CRSwNP. Reduced formation of the complex of FXa and TFPI in NP may reduce natural suppression of the extrinsic coagulation pathway in CRSwNP.
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Pólipos Nasais , Rinite , Sinusite , Coagulação Sanguínea , Doença Crônica , Fibrina , Humanos , Pólipos Nasais/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , TromboplastinaRESUMO
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to cyclooxygenase-1 enzyme inhibitors. The underlying mechanisms contributing to AERD pathogenesis are not fully understood, but AERD is characterized by an enhanced type 2 inflammatory phenotype. Basophils are potent type 2 effector cells, but their involvement in AERD pathophysiology remains unclear. OBJECTIVE: We sought to characterize the systemic and local basophil responses in patients with AERD compared with patients with CRSwNP. METHODS: Sinonasal tissues including inferior turbinate and/or nasal polyps (NPs) and peripheral blood were collected from controls, patients with AERD, and patients with CRSwNP. Expression of cell surface (CD45, FcεRI, CD203c), activation (CD63), and intracellular (2D7) markers associated with basophils was characterized using flow cytometry. Clinical data including Lund-Mackay scores and pulmonary function were obtained. RESULTS: The mean number of basophils (CD45+CD203c+FcεRI+CD117-) detected in AERD NPs (147 ± 28 cells/mg tissue) was significantly elevated compared with that detected in CRSwNP NPs (69 ± 20 cells/mg tissue; P = .01). The number of circulating basophils was significantly elevated in patients with AERD (P = .04). Basophils in NPs had significantly higher CD203c and CD63 mean fluorescence intensity compared with blood in both conditions (P < .01). Basophils from AERD NPs had lower expression of the granule content marker 2D7 compared with those from matched blood (P < .01) or NPs of patients with CRSwNP (P = .06), suggesting ongoing degranulation. Basophil 2D7 mean fluorescence intensity significantly correlated with pulmonary function (r = 0.62; P = .02) and inversely correlated with sinonasal inflammation (r = -0.56; P = .004). CONCLUSIONS: Increased basophil numbers and extent of ongoing degranulation in NPs of patients with AERD compared with patients with CRSwNP may contribute to the exaggerated disease pathogenesis and severity unique to AERD.
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Asma/imunologia , Basófilos/imunologia , Inibidores de Ciclo-Oxigenase/efeitos adversos , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , Asma/induzido quimicamente , Asma/patologia , Basófilos/patologia , Doença Crônica , Inibidores de Ciclo-Oxigenase/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/induzido quimicamente , Pólipos Nasais/patologia , Rinite/induzido quimicamente , Rinite/patologia , Sinusite/induzido quimicamente , Sinusite/patologiaRESUMO
OBJECTIVE: Local activation of B cells and antibody production are important for protective and pathogenic immune responses. Furthermore, there is evidence that local activation of B cells and antibody production are important for pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and a severe subset of CRSwNP, aspirin-exacerbated respiratory disease (AERD). This review summarizes these findings and the potential role of B cells and antibodies in disease pathogenesis. DATA SOURCES: Published literature from PubMed searches. STUDY SELECTIONS: Studies relevant to B cell development and the roles of B cells and antibodies in the pathogenesis of CRSwNP and AERD. RESULTS: Formation of tertiary lymphoid structures plays a key role in the local activation of B cells and antibody production. This process is important for fighting infections, but it also contributes to autoimmune disease. Furthermore, there is evidence to support a role for local B cell activation and antibody production in a variety of allergic diseases. Nasal polyp tissues from patients with CRSwNP and AERD have elevated levels of activated B cell subsets and locally produced antibodies. These locally produced antibodies may contribute to disease pathogenesis in a variety of ways, including activation of innate effector cells, whereas locally activated B cells may contribute to pathogenesis through the activation of T cells. CONCLUSION: More studies are needed to determine the role of B cells and antibodies in driving disease in these patients. However, targeting the processes that drive local B cell activation and antibody production may provide new therapeutic approaches and could help to reduce chronic inflammation.
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Asma Induzida por Aspirina/imunologia , Imunoglobulinas/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Linfócitos B/imunologia , Doença Crônica , HumanosRESUMO
BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD. OBJECTIVE: Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD. METHODS: Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence. RESULTS: The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P < .05) or controls (P < .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r = 0.56; P < .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P < .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO+ epithelium in NPs from patients with AERD. CONCLUSIONS: Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD.
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Araquidonato 15-Lipoxigenase/imunologia , Asma Induzida por Aspirina/imunologia , Transtornos Respiratórios/imunologia , Adulto , Araquidonato 15-Lipoxigenase/metabolismo , Asma Induzida por Aspirina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Respiratórios/metabolismoRESUMO
Background: Food specific immunoglobulin E (sIgE) levels are associated with the development of allergic responses and are used in the clinical evaluation of food allergy. Food sIgG4 levels have been associated with tolerance or clinical nonresponsiveness, particularly in interventional studies. Objective: We aimed to characterize food-specific antibody responses and compare responses with different foods in food allergy. Methods: Serum sIgA, sIgG4, and sIgE to whole peanut, egg white, and wheat, along with total IgE were measured in 57 children. Children with food allergy, children with natural tolerance, and controls were studied. The Mann-Whitney test or Kruskall Wallis test with the Dunn correction were used for statistical analysis. Results: As expected, total IgE levels were highest in the subjects with food allergy compared with the subjects who were nonallergic (p < 0.001) or the subjects who were naturally tolerant (p < 0.001). Peanut sIgE levels were higher in subjects with peanut allergy compared with the subjects who were naturally tolerant (p < 0.0001) and the control subjects (p < 0.03). Interestingly, peanut sIgG4 levels were also highest in children with peanut allergy compared with subjects who were naturally tolerant and control subjects (p = 0.28 and p < 0.001, respectively). Subjects with peanut allergy alone had comparable egg white sIgE levels to children with egg white allergy. In addition, the subjects with peanut allergy alone also had higher levels of egg white and wheat sIgE compared with the control subjects (p < 0.02 and p = 0.001, respectively). In contrast, the subjects with egg white allergy did not demonstrate elevated peanut or wheat sIgE levels. Conclusion: These novel findings suggested that IgE production is dysregulated in patients with peanut allergy, who are much less likely to outgrow their allergy, and suggest that the mechanisms that drive more persistent forms of food allergy may be distinct from more transient forms of food allergy.
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Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation with accumulation of activated group 2 innate lymphoid cells (ILC2s) and elevation of thymic stromal lymphopoietin (TSLP). A member of the TNF superfamily (TNFSF), TNFSF15, is known to induce the production of type 2 cytokines in ILC2s. Although ILC2s have been implicated in CRSwNP, the presence and role of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP has not been elucidated. Here, we investigate the involvement of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP. We found that receptor activator of NF-κB (RANK) ligand (RANK-L (TNFSF11)) was significantly elevated in nasal polyps (NPs), and that the receptor of RANK-L, RANK, was expressed on ILC2s in human peripheral blood and NPs. An agonistic antibody against RANK induced production of type 2 cytokines in human ILC2s, and TSLP significantly enhanced this reaction. The membrane-bound RANK-L was detected mainly on CD45 + immune cells, including TH2 cells in NPs. The co-culture of NP-derived ILC2s and TH2 cells significantly enhanced production of type 2 cytokines, and anti-RANK-L monoclonal antibody suppressed this enhancement. In conclusion, RANK-L, together with TSLP, may play an inductive role in the ILC2-mediated type 2 inflammation in CRSwNP.
Assuntos
Inflamação/imunologia , Linfócitos/imunologia , Pólipos Nasais/imunologia , Ligante RANK/metabolismo , Rinite/imunologia , Sinusite/imunologia , Células Th2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Doença Crônica , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Células Th2/metabolismo , Adulto JovemRESUMO
BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease subdivided based on the presence or absence of nasal polyps (NPs). Histologic features of chronic rhinosinusitis with nasal polyps (CRSwNP) include inflammatory cell infiltration and excessive fibrin deposition in NPs. Thrombin-activatable fibrinolysis inhibitor (TAFI) is an enzyme that plays an antifibrinolytic role in the body. The significance of TAFI has been documented in patients with chronic inflammatory diseases, including chronic lung disease; however, it has not been evaluated in the pathogenesis of NPs. OBJECTIVE: The objective of this study was to evaluate the potential role of TAFI in the pathogenesis of NPs. METHODS: Nasal lavage fluid was collected from control subjects and patients with CRS. We measured levels of thrombin/anti-thrombin complex (TATc) and TAFI protein using an ELISA. RESULTS: TATc levels in nasal lavage fluid were significantly increased in patients with CRSwNP and patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared with control subjects, and TAFI levels in nasal lavage fluid were also significantly increased in patients with CRSwNP compared with those in control subjects and patients with CRSsNP. There was a significant correlation between TATc and TAFI levels in nasal lavage fluid. Interestingly, patients with CRS and asthma showed increased TATc and TAFI levels in nasal lavage fluid compared with those in patients with CRS without asthma, especially patients with CRSwNP. CONCLUSIONS: Increased TATc and TAFI levels in nasal passages of patients with CRSwNP might participate in fibrin deposition in NPs and might play a role in the pathogenesis of CRSwNP and asthma.
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Carboxipeptidase B2/imunologia , Líquido da Lavagem Nasal/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Adulto , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/patologia , Rinite/patologia , Sinusite/patologiaRESUMO
BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by mucosal inflammation in the nose and paranasal sinuses. Inflammation in CRS is also heterogeneous and is mainly characterized by type 2 (T2) inflammation, but subsets of patients show type 1 (T1) and type 3 (T3) inflammation. Whether inflammatory endotypes are associated with clinical phenotypes has yet to be explored in detail. OBJECTIVE: To identify associations between inflammatory endotypes and clinical presentations in CRS. METHODS: We compared 121 patients with nonpolypoid CRS (CRSsNP) and 134 patients with polypoid CRS (CRSwNP) and identified inflammatory endotypes using markers including IFN-γ (T1), eosinophil cationic protein (T2), Charcot-Leyden crystal galectin (T2), and IL-17A (T3). We collected clinical parameters from medical and surgical records and examined whether there were any associations between endotype and clinical features. RESULTS: The presence of nasal polyps, asthma comorbidity, smell loss, and allergic mucin was significantly associated with the presence of T2 endotype in all patients with CRS. The T1 endotype was significantly more common in females, and the presence of pus was significantly associated with T3 endotype in all patients with CRS. We further analyzed these associations in CRSsNP and CRSwNP separately and found that smell loss was still associated with T2 endotype and pus with the T3 endotype in both CRSsNP and CRSwNP. Importantly, patients with CRS with T2 and T3 mixed endotype tended to have clinical presentations shared by both T2 and T3 endotypes. CONCLUSIONS: Clinical presentations are directly associated with inflammatory endotypes in CRS. Identification of inflammatory endotypes may allow for more precise and personalized medical treatments in CRS.
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Pólipos Nasais , Rinite , Sinusite , Adulto , Idoso , Asma/epidemiologia , Asma/imunologia , Doença Crônica , Comorbidade , Proteína Catiônica de Eosinófilo/imunologia , Feminino , Glicoproteínas/imunologia , Humanos , Interferon gama/imunologia , Interleucina-17/imunologia , Lisofosfolipase/imunologia , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/epidemiologia , Pólipos Nasais/imunologia , Transtornos do Olfato/epidemiologia , Transtornos do Olfato/imunologia , Fenótipo , Rinite/epidemiologia , Rinite/imunologia , Sinusite/epidemiologia , Sinusite/imunologia , Adulto JovemRESUMO
Biliary atresia (BA) is a neonatal cholestatic liver disease that is the leading cause of pediatric liver transplantation, however, the mechanism of disease remains unknown. There are two major forms of BA: isolated BA (iBA) comprises the majority of cases and is thought to result from an aberrant immune response to an environmental trigger, whereas syndromic BA (BASM) has associated malformations and is thought to arise from a congenital insult. To determine whether B cells in BA biliary remnants are antigen driven, we examined the immunoglobulin (Ig) repertoire of diseased tissue from each BA group. Deep sequencing of the Ig chain DNA was performed on iBA and BASM biliary remnants and lymph nodes obtained from the Childhood Liver Disease Research Network (ChiLDReN) repository. Statistical analysis of the Ig repertoire provided measures of Ig clonality and the Ig phenotype. Our data demonstrate that B cells infiltrate diseased iBA and BASM biliary remnant tissue. The Ig repertoires of iBA and BASM disease groups were oligoclonal supporting a role for an antigen-driven immune response in both sub-types. These findings shift the current understanding of BA and suggest a role for antigen stimulation in early iBA and BASM disease pathogenesis.
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Atresia Biliar/classificação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Imunoglobulinas/genética , Linfócitos B/imunologia , Atresia Biliar/imunologia , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Análise de Sequência de DNA/métodosAssuntos
Anafilaxia/induzido quimicamente , Histamina/farmacologia , Imidazóis/farmacologia , Prurido/induzido quimicamente , Animais , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Humanos , Camundongos Knockout , Lavagem Peritoneal , Receptores Histamínicos H1/genética , Receptores Histamínicos H1/imunologia , Receptores Histamínicos H2/genética , Receptores Histamínicos H2/imunologiaAssuntos
Epitélio/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Biomarcadores , Chicago , Doença Crônica , Epitélio/patologia , Humanos , Inflamação/patologia , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Pólipos Nasais/etiologia , Pólipos Nasais/metabolismo , Pólipos Nasais/patologia , Rinite/etiologia , Rinite/metabolismo , Rinite/patologia , Sinusite/etiologia , Sinusite/metabolismo , Sinusite/patologiaRESUMO
Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the nose and sinuses that affects up to 12% of the population in Europe and the United States. This complex disease is likely driven by multiple environmental, genetic, and inflammatory mechanisms, and recent studies suggest that B cells might play a critical role in disease pathogenesis. B cells and their antibodies have undisputed roles in health and disease within the airway mucosae. Deficient or inadequate B-cell responses can lead to susceptibility to infectious disease in the nose, whereas excess antibody production, including autoantibodies, can promote damaging inflammation. Thus, patients with B-cell defects often have either chronic or recurrent acute infections, and this can be associated with nonpolypoid CRS. In contrast, many patients with CRS with nasal polyps, which is less likely to be driven by pathogens, have excess production of local immunoglobulins, including autoreactive antibodies. These B-cell responses activate complement in many patients and likely contribute to immunopathogenic responses. A better understanding of the B cell-associated mechanisms that drive disease in patients with CRS should be a high priority in the quest to understand the pathogenesis of this disease.
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Anticorpos/imunologia , Linfócitos B/imunologia , Rinite/imunologia , Sinusite/imunologia , Doença Crônica , HumanosRESUMO
PURPOSE OF REVIEW: This review summarizes recent findings on mast cell biology with a focus on IgE-independent roles of mast cells in regulating allergic responses. RECENT FINDINGS: Recent studies have described novel mast cell-derived molecules, both secreted and membrane-bound, that facilitate cross-talk with a variety of immune effector cells to mediate type 2 inflammatory responses. Mast cells are complex and dynamic cells that are persistent in allergy and are capable of providing signals that lead to the initiation and persistence of allergic mechanisms.
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Comunicação Celular/imunologia , Hipersensibilidade/imunologia , Mastócitos/fisiologia , Animais , Reações Cruzadas , Humanos , Imunoglobulina E/imunologia , Inflamação/imunologiaRESUMO
BACKGROUND: IgD is an enigmatic antibody isotype best known when coexpressed with IgM on naive B cells. However, increased soluble IgD (sIgD) levels and increased IgD+IgM- B-cell populations have been described in the human upper respiratory mucosa. OBJECTIVE: We assessed whether levels of sIgD and IgD+ B cell counts are altered in nasal tissue from patients with chronic rhinosinusitis (CRS). We further characterized IgD+ B-cell populations and explored clinical and local inflammatory factors associated with tissue sIgD levels. METHODS: sIgD levels were measured by means of ELISA in nasal tissues, nasal lavage fluid, sera, and supernatants of dissociated nasal tissues. IgD+ cells were identified by using immunofluorescence and flow cytometry. Inflammatory mediator levels in tissues were assessed by using real-time PCR and multiplex immunoassays. Bacterial cultures from the middle meatus were performed. Underlying medical history and medicine use were obtained from medical records. RESULTS: sIgD levels and numbers of IgD+ cells were significantly increased in uncinate tissue (UT) of patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared with that of control subjects (4-fold, P < .05). IgD+ cells were densely scattered in the periglandular regions of UT from patients with CRSsNP. We also found that IgD+CD19+CD38bright plasmablast numbers were significantly increased in tissues from patients with CRSsNP compared with control tissues (P < .05). Among numerous factors tested, IL-2 levels were increased in UT from patients with CRSsNP and were positively correlated with tissue IgD levels. Additionally, supernatants of IL-2-stimulated dissociated tissue from patients with CRSsNP had significantly increased sIgD levels compared with those in IL-2-stimulated dissociated control tissue ex vivo (P < .05). Tissue from patients with CRS with preoperative antibiotic use or those with pathogenic bacteria showed higher IgD levels compared with tissue from patients without these variables (P < .05). CONCLUSION: sIgD levels and IgD+CD19+CD38bright plasmablast counts were increased in nasal tissue of patients with CRSsNP. IgD levels were associated with increased IL-2 levels and the presence of pathogenic bacteria. These findings suggest that IgD might contribute to enhancement mucosal immunity or inflammation or respond to bacterial infections in patients with CRS, especially CRSsNP.
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Linfócitos B/imunologia , Imunoglobulina D/metabolismo , Mucosa Nasal/imunologia , Pólipos Nasais/imunologia , Sistema Respiratório/patologia , Rinite/imunologia , Sinusite/imunologia , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Idoso , Antígenos CD19/metabolismo , Células Cultivadas , Doença Crônica , Feminino , Humanos , Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Regulação para Cima , Adulto JovemRESUMO
Chronic rhinosinusitis (CRS) is a prevalent disease that is associated with significant costs and quality of life impairments. Currently, patients are classified into subgroups based on clinical characteristics, most often the presence or absence of nasal polyps. However, despite medical and surgical treatment, many of these patients continue to have symptoms. Recent efforts have focused on gaining a more complete understanding of the inflammatory mechanisms that drive pathogenesis in CRS, and it is becoming clear that the inflammatory processes in CRS are quite complex. As our understanding of these complex phenotypes improves, it may become possible to classify patients into endotypes based on unique inflammatory patterns within the sinus mucosa. This information may also lead to the identification of appropriate targeted therapies for different endotypes. This review will discuss our current understanding of endotypes in CRS along with the unique adaptive immune responses that may contribute to these different endotypes and, finally, some potential targeted therapeutics for the next generation of CRS treatment strategies.
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Rinite/imunologia , Sinusite/imunologia , Imunidade Adaptativa , Doença Crônica , Humanos , Rinite/classificação , Rinite/tratamento farmacológico , Sinusite/classificação , Sinusite/tratamento farmacológicoRESUMO
BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is characterized by type 2 inflammation with high levels of Th2 cytokines. Although T helper cytokines are released from T cells, innate lymphoid cells (ILC) are also known to produce high levels of the same cytokines. However, the presence of various types of ILC in CRS is poorly understood. OBJECTIVE: The objective of this study was to fully characterize the presence of all ILC subsets in CRS and to identify phenotypical differences of group 2 ILC (ILC2) in CRSwNP compared to ILC2 from non-type 2 inflamed areas. METHODS: We investigated the presence of ILC subsets in peripheral blood mononuclear cells (PBMC) from healthy subjects, tonsil tissue, ethmoid tissue from control subjects and patients with non-polypoid CRS (CRSsNP) and CRSwNP, as well as nasal polyp (NP) tissue from CRSwNP by flow cytometry. Sorted ILC2 were cultured in the presence and absence of IL-33 and production of IL-5 and IL-13 was assessed by Luminex. RESULTS: We found that all ILC subsets were present in NP but ILC2 were dominant and significantly elevated compared to PBMC, tonsil, CRSsNP, and normal sinus tissue. We also found that inducible T-cell co-stimulator (ICOS) and side scatter were increased and CD127 was down-regulated in ILC2 from NP compared to blood or tonsil ILC2. Thymic stromal lymphopoietin, IL-7, and IL-33 were able to down-regulate expression of CD127 and increase side scatter in blood ILC2. Furthermore, sorted NP ILC2 but not blood ILC2 spontaneously released type 2 cytokines including IL-5 and IL-13. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggest that ILC2 are not only elevated but also activated in CRSwNP in vivo and that ILC2 may play important roles in the type 2 inflammation in CRSwNP.