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1.
J Allergy Clin Immunol ; 150(5): 1114-1124.e3, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35728655

RESUMEN

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.


Asunto(s)
Asma Inducida por Aspirina , Pólipos Nasales , Rinitis , Sinusitis , Humanos , Pólipos Nasales/metabolismo , Rinitis/metabolismo , Activador de Tejido Plasminógeno , Interleucina-13 , Fibrinólisis , Tretinoina/farmacología , Células Endoteliales/metabolismo , Sinusitis/metabolismo , Asma Inducida por Aspirina/complicaciones , Enfermedad Crónica , Fibrina
2.
J Allergy Clin Immunol ; 150(2): 467-476.e1, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35271862

RESUMEN

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.


Asunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Coagulación Sanguínea , Enfermedad Crónica , Fibrina , Humanos , Pólipos Nasales/metabolismo , Rinitis/metabolismo , Sinusitis/metabolismo , Tromboplastina
3.
Clin Exp Allergy ; 52(8): 954-964, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35253284

RESUMEN

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.


Asunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Enfermedad Crónica , Humanos , Inmunoglobulina G , Pólipos Nasales/complicaciones
4.
J Allergy Clin Immunol ; 148(2): 439-449.e5, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33819512

RESUMEN

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.


Asunto(s)
Asma/inmunología , Basófilos/inmunología , Inhibidores de la Ciclooxigenasa/efectos adversos , Pólipos Nasales/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Adulto , Asma/inducido químicamente , Asma/patología , Basófilos/patología , Enfermedad Crónica , Inhibidores de la Ciclooxigenasa/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pólipos Nasales/inducido químicamente , Pólipos Nasales/patología , Rinitis/inducido químicamente , Rinitis/patología , Sinusitis/inducido químicamente , Sinusitis/patología
5.
J Allergy Clin Immunol ; 147(2): 600-612, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32371071

RESUMEN

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.


Asunto(s)
Araquidonato 15-Lipooxigenasa/inmunología , Asma Inducida por Aspirina/inmunología , Trastornos Respiratorios/inmunología , Adulto , Araquidonato 15-Lipooxigenasa/metabolismo , Asma Inducida por Aspirina/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Respiratorios/metabolismo
6.
Ann Allergy Asthma Immunol ; 126(2): 127-134, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33065294

RESUMEN

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.


Asunto(s)
Asma Inducida por Aspirina/inmunología , Inmunoglobulinas/inmunología , Pólipos Nasales/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Linfocitos B/inmunología , Enfermedad Crónica , Humanos
8.
Mucosal Immunol ; 13(1): 86-95, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31641233

RESUMEN

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.


Asunto(s)
Inflamación/inmunología , Linfocitos/inmunología , Pólipos Nasales/inmunología , Ligando RANK/metabolismo , Rinitis/inmunología , Sinusitis/inmunología , Células Th2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Enfermedad Crónica , Citocinas/metabolismo , Femenino , Humanos , Inmunidad Innata , Masculino , Persona de Mediana Edad , Células Th2/metabolismo , Adulto Joven
9.
J Allergy Clin Immunol ; 144(6): 1566-1574.e6, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31562871

RESUMEN

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.


Asunto(s)
Carboxipeptidasa B2/inmunología , Líquido del Lavado Nasal/inmunología , Pólipos Nasales/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Adulto , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pólipos Nasales/patología , Rinitis/patología , Sinusitis/patología
10.
J Allergy Clin Immunol Pract ; 7(8): 2812-2820.e3, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31128376

RESUMEN

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.


Asunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Adulto , Anciano , Asma/epidemiología , Asma/inmunología , Enfermedad Crónica , Comorbilidad , Proteína Catiónica del Eosinófilo/inmunología , Femenino , Glicoproteínas/inmunología , Humanos , Interferón gamma/inmunología , Interleucina-17/inmunología , Lisofosfolipasa/inmunología , Masculino , Persona de Mediana Edad , Pólipos Nasales/epidemiología , Pólipos Nasales/inmunología , Trastornos del Olfato/epidemiología , Trastornos del Olfato/inmunología , Fenotipo , Rinitis/epidemiología , Rinitis/inmunología , Sinusitis/epidemiología , Sinusitis/inmunología , Adulto Joven
12.
J Allergy Clin Immunol ; 141(5): 1553-1560, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29731101

RESUMEN

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.


Asunto(s)
Anticuerpos/inmunología , Linfocitos B/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Enfermedad Crónica , Humanos
13.
J Allergy Clin Immunol ; 140(6): 1562-1571.e5, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28625807

RESUMEN

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.


Asunto(s)
Linfocitos B/inmunología , Inmunoglobulina D/metabolismo , Mucosa Nasal/inmunología , Pólipos Nasales/inmunología , Sistema Respiratorio/patología , Rinitis/inmunología , Sinusitis/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Anciano , Antígenos CD19/metabolismo , Células Cultivadas , Enfermedad Crónica , Femenino , Humanos , Interleucina-2/metabolismo , Masculino , Persona de Mediana Edad , Regulación hacia Arriba , Adulto Joven
14.
Curr Allergy Asthma Rep ; 17(7): 49, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28623534

RESUMEN

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.


Asunto(s)
Rinitis/inmunología , Sinusitis/inmunología , Inmunidad Adaptativa , Enfermedad Crónica , Humanos , Rinitis/clasificación , Rinitis/tratamiento farmacológico , Sinusitis/clasificación , Sinusitis/tratamiento farmacológico
15.
Immun Inflamm Dis ; 5(3): 233-243, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28474861

RESUMEN

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.


Asunto(s)
Inmunidad Innata , Linfocitos , Pólipos Nasales , Rinitis , Sinusitis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Citocinas/inmunología , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-7/inmunología , Linfocitos/inmunología , Linfocitos/patología , Masculino , Persona de Mediana Edad , Pólipos Nasales/inmunología , Pólipos Nasales/patología , Rinitis/inmunología , Rinitis/patología , Sinusitis/inmunología , Sinusitis/patología
16.
Laryngoscope ; 127(10): 2210-2218, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28322448

RESUMEN

OBJECTIVE: To evaluate if molecular markers of eosinophilia in olfactory-enriched mucosa are associated with olfactory dysfunction. STUDY DESIGN: Cross-sectional study of tissue biopsies from 99 patients, and an additional 30 patients who underwent prospective olfactory testing prior to sinonasal procedures. METHODS: Tissue biopsies were processed for analysis of inflammatory markers using quantitative real time polymerase chain reaction (qRT-PCR). Ipsilateral olfactory performance was assessed using the Sniffin' Sticks (Burghart, Wedel, Germany) threshold component and the University of Pennsylvania Smell Identification Test (Sensonics, Haddon Heights, NJ). Age-adjusted data was correlated with inflammatory marker expression and clinical measures of obstruction from computed tomography and endoscopy. RESULTS: Gene expression of the eosinophil marker CLC (Charcot Leyden crystal protein) was elevated in superior turbinate (ST) tissue in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) compared to ST and inferior turbinate tissue in CRS without nasal polyps (CRSsNP) and control patients (all P < 0.001, respectively). CLC in ST tissue was correlated with IL-5 and eotaxin-1 expression (all P < 0.001; P = 0.65, and 0.49, respectively). CLC expression was strongly correlated with eosinophilic cationic protein levels (P < 0.001; r = -0.76), and ST CLC expression was inversely related to olfactory threshold (P = 0.002, r = -0.57) and discrimination scores (P = 0.05, r = -0.42). In multiple linear regression of CLC gene expression, polyp status, and radiographic and endoscopic findings with olfactory threshold, CLC was the only significantly correlated variable (P < 0.05). CONCLUSION: Markers of eosinophils are elevated in the ST of patients with CRSwNP and correlate with olfactory loss. These findings support the hypothesis that olfactory dysfunction in CRS correlates local eosinophil influx into the olfactory cleft. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2210-2218, 2017.


Asunto(s)
Eosinofilia/complicaciones , Trastornos del Olfato/etiología , Rinitis/complicaciones , Sinusitis/complicaciones , Adulto , Anciano , Quimiocina CCL11/análisis , Enfermedad Crónica , Estudios Transversales , Proteína Catiónica del Eosinófilo/sangre , Eosinofilia/sangre , Eosinofilia/patología , Femenino , Glicoproteínas/análisis , Humanos , Interleucina-5/análisis , Lisofosfolipasa/análisis , Masculino , Persona de Mediana Edad , Pólipos Nasales/sangre , Pólipos Nasales/complicaciones , Pólipos Nasales/patología , Estudios Prospectivos , Rinitis/sangre , Rinitis/patología , Sinusitis/sangre , Sinusitis/patología , Cornetes Nasales/patología , Adulto Joven
17.
J Allergy Clin Immunol Pract ; 5(4): 1061-1070.e3, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28286156

RESUMEN

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) comprises the triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and intolerance to inhibitors of the cyclooxygenase-1 (COX-1) enzyme. The prevalence of AERD remains unclear, and few studies have compared the clinical characteristics of patients with AERD to those with CRSwNP alone, asthma alone, or both CRSwNP and asthma. OBJECTIVE: To determine the prevalence of AERD within a tertiary care setting, and to identify unique clinical features that could distinguish these patients from those with both CRSwNP and asthma or with CRSwNP alone. METHODS: Electronic medical records of patients at Northwestern in Chicago, Illinois, were searched by computer algorithm and then manual chart review to identify 459 patients with CRSwNP alone, 412 with both CRSwNP and asthma, 171 with AERD, and 300 with asthma only. Demographic and clinical features including sex, atopy, and sinus disease severity were characterized. RESULTS: The prevalence of AERD among patients with CRSwNP was 16%. Patients with AERD had undergone 2-fold more sinus surgeries (P < .001) and were significantly younger at the time of their first surgery (40 ± 13 years) than were patients with CRSwNP (43 ± 14 years; P < .05). Atopy was significantly more prevalent in patients with AERD (84%) or asthma (85%) than in patients with CRSwNP (66%, P < .05). More patients with AERD (13%) had corticosteroid-dependent disease than patients with both CRSwNP and asthma (4%, P < .01) or asthma (1%, P < .001). CONCLUSIONS: AERD is common among patients with CRSwNP; even though patients with AERD have CRSwNP and asthma, the clinical course of their disease is not the same as of patients who have CRSwNP and asthma but are tolerant to COX-1 inhibitors.


Asunto(s)
Asma Inducida por Aspirina/epidemiología , Asma/epidemiología , Pólipos Nasales/epidemiología , Rinitis/epidemiología , Sinusitis/epidemiología , Adulto , Anciano , Aspirina/efectos adversos , Aspirina/uso terapéutico , Asma/fisiopatología , Asma Inducida por Aspirina/diagnóstico , Asma Inducida por Aspirina/fisiopatología , Asma Inducida por Aspirina/terapia , Enfermedad Crónica , Comorbilidad , Inhibidores de la Ciclooxigenasa/efectos adversos , Inhibidores de la Ciclooxigenasa/uso terapéutico , Femenino , Humanos , Illinois/epidemiología , Masculino , Persona de Mediana Edad , Pólipos Nasales/fisiopatología , Prevalencia , Pruebas de Función Respiratoria , Rinitis/diagnóstico por imagen , Rinitis/fisiopatología , Sinusitis/diagnóstico por imagen , Sinusitis/fisiopatología , Tomografía Computarizada por Rayos X
18.
J Allergy Clin Immunol ; 140(3): 720-729, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28238741

RESUMEN

BACKGROUND: Microparticles (MPs) are submicron-sized shed membrane vesicles released from activated or injured cells and are detectable by flow cytometry. MP levels have been used as biomarkers to evaluate cell injury or activation in patients with pathological conditions. OBJECTIVE: We sought to compare MP types and levels in nasal lavage fluids (NLFs) from controls and patients with chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD). METHODS: We collected NLFs from patients with CRSsNP (n = 33), CRSwNP (n = 45), and AERD (n = 31) and control (n = 24) subjects. Standardized flow cytometry methods were used to characterize the following MP types: endothelial MPs, epithelial MPs (epithelial cell adhesion molecule [EpCAM](+)MPs, E-cadherin(+)MPs), platelet MPs (CD31(+)CD41(+)MPs), eosinophil MPs (EGF-like module-containing mucin-like hormone receptor-like 1[EMR1](+)MPs), mast cell MPs (high-affinity IgE receptor [FcεRI](+)c-kit(+)MPs), and basophil MPs (CD203c(+)c-kit(-)MPs). Basophil activation was evaluated by the mean fluorescence intensity of CD203c on basophil MPs. RESULTS: Activated mast cell MPs (CD137(+) FcεRI(+)c-kit(+)MPs) were significantly increased in NLFs of controls compared with NLFs of patients with CRSsNP (2.3-fold; P < .02), CRSwNP (2.3-fold; P < .03), and AERD (7.4-fold; P < .0001). Platelet MPs (3.5-fold; P < .01) and basophil MPs (2.5-fold; P < .05) were increased only in patients with AERD. Mean fluorescence intensity of CD203c on MPs was increased in patients with CRSwNP (P < .002) and AERD (P < .0001), but not in patients with CRSsNP. EpCAM(+)MPs in patients with CRSwNP were no different from control (P = .91) and lower than those in patients with CRSsNP (P < .02) and AERD (P < .002). CONCLUSIONS: Based on released MPs, mast cells, platelets, and basophils were more highly activated in patients with AERD than in patients with CRS. Epithelial injury was lower in patients with CRSwNP than in patients with CRSsNP and AERD. MP analysis may help identify phenotypes of CRS, and in distinguishing AERD from CRSwNP.


Asunto(s)
Asma Inducida por Aspirina/patología , Micropartículas Derivadas de Células , Líquido del Lavado Nasal/citología , Pólipos Nasales/patología , Rinitis/patología , Sinusitis/patología , Adulto , Biomarcadores , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad
19.
Int Forum Allergy Rhinol ; 7(6): 609-614, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28236375

RESUMEN

BACKGROUND: The unconventional toll-like receptor (TLR) CD180 is implicated in chronic inflammatory diseases; however, its role in chronic rhinosinusitis (CRS) has yet to be investigated. Here we study the expression of CD180, its homologue TLR4 and myeloid differentiation factor 1 (MD1) on mucosal and systemic immune cell populations in relation to serum immunoglobulin G (IgG) levels. METHODS: A total of 70 patients were recruited to the study. Mucosal and peripheral blood samples were prospectively collected from CRS patients and non-CRS controls without evidence of sinus disease. The expression of TLR4, MD1, and CD180 was investigated using qualitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, and flow cytometry. Serum IgG levels were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: CRS with nasal polyps (CRSwNP) patients had significantly increased messenger RNA (mRNA) expression of CD180 and MD1 compared to controls (5.54-fold and 2.1-fold, respectively, p < 0.01). B cells lacking CD180 were lower in CRSwNP tissue compared to CRS without nasal polyps (CRSsNP) and controls (21.07 ± 6.41 vs 41.61 ± 7.82 vs 40.06 ± 8.06; p < 0.01) but higher in blood (39.18 ± 8.3 vs 17.95 ± 7.82 and 12.49 ± 4.92; p ≤ 0.05). CONCLUSION: Changes in mucosal and peripheral CD180-expressing B cells were identified in CRSwNP patients compared to CRSsNP and controls. This suggests a role for these cells in the dysregulated immune response in these patients.


Asunto(s)
Antígenos CD/inmunología , Linfocitos B/inmunología , Pólipos Nasales/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Antígenos CD/genética , Antígenos de Superficie/genética , Antígenos de Superficie/inmunología , Enfermedad Crónica , Humanos , Inmunoglobulina G/sangre , Mucosa Nasal/inmunología , Pólipos Nasales/genética , ARN Mensajero/metabolismo , Rinitis/sangre , Sinusitis/sangre , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología
20.
J Allergy Clin Immunol ; 140(1): 89-100.e2, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27979430

RESUMEN

BACKGROUND: Complement plays a major role in inflammatory diseases, but its involvement and mechanisms of activation in patients with chronic rhinosinusitis (CRS) are not known. OBJECTIVES: After earlier studies discovering autoantibodies in patients with CRS, we sought to investigate the nature, extent, and location of complement activation in nasal tissue of patients with CRS. Specifically, we were interested in whether antibody-mediated activation through the classical pathway was a major mechanism for complement activation in patients with CRS. METHODS: Nasal tissue was obtained from patients with CRS and control subjects. Tissue homogenates were analyzed for complement activation products (ELISA-C5b-9, C4d, activated C1, and C5a) and major complement-fixing antibodies (Luminex). Tissue sections were stained for C5b-9, C4d, and laminin. Antibodies were purified with protein A/G columns from nasal polyps (NP), matching patient serum, and control serum and assayed for basement membrane binding by means of ELISA. RESULTS: C5b-9 levels were significantly increased in NP tissue compared with uncinate tissue (UT) of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and those with chronic rhinosinusitis without nasal polyps (CRSsNP; P < .01). Similarly, C4d levels were increased in NPs compared with UT of patients with CRSwNP, patients with CRSsNP, and control subjects (P < .05). Activated C1 levels were also increased in NP tissue compared with UT of patients with CRSsNP and control subjects (P < .05) and correlated with levels of C5a (P < .01), local immunoglobulins (especially IgM, P < .0001), and anti-double-stranded DNA IgG (P < .05). Immunofluorescence showed that C5b-9 and C4d deposition occurred linearly along the epithelial basement membrane. NP tissue extracts had significantly more anti-basement membrane antibodies than sera from patients with CRSwNP and control subjects (P < .0001). CONCLUSION: Levels of C5b-9, C4d, and activated C1 were significantly increased locally in NP tissue. C5b-9 and C4d were almost universally deposited linearly along the basement membrane of NP tissue. Furthermore, activated C1 levels were best correlated with local immunoglobulin and C5a levels. Together, these data suggest that the classical pathway plays a major role in complement activation in patients with CRS.


Asunto(s)
Vía Clásica del Complemento , Mucosa Nasal/inmunología , Pólipos Nasales/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Adulto , Anciano , Anticuerpos Antinucleares/inmunología , Enfermedad Crónica , Eosinofilia/inmunología , Femenino , Humanos , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Adulto Joven
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