ENT Research focus 2020

Is there an upregulation of B and T cell interactions in nasal polyposis?

Yes, a special aspect of nasal polyps in comparison to infected nasal tissue in CRSwNP is a very high production of IgE.

These high local IgE levels differ from serum IgE levels in patients with CRSwNP, which underscores the importance of local IgE production.

What is the predictive value of IgE in nose Polyps?

Specific IgE antibodies against Staphylococcus aureus enterotoxins are increased in nasal polyps and have a predictive value for concomitant asthma bronchiale.

What is the importance of local B cells in chronic infectious diseases of the nasal mucous?

  • HPF, high-power field
  • CRSwNP, chronic rhinosinusitis with nasal polyps
  • CCL, chemokine ligand; CRSsNP, chronic rhinosinusitis without nasal polyps
  • ECRS, Eosinophilic chronic rhinosinusitis
  • ESS, endoscopic sinus surgery
  • IL, interleukin
  • ROC, receiver operating characteristic
  • AUC, area under the curve
  • TSLP, Thymic stromal-derived lymphopoietin
  • TH2, T helper 2
  • ELISA, enzyme-linked immunosorbent assay
  • ILC2, innate lymphoid cells
  • BAFF, B cell activating factor
  • tPA, tissue plasminogen activator.

The condition is estimated to affect about 12% of the U.S. population.5 CRSwNP patients tend to exhibit elevated levels of eosinophils and interleukins.

Atopy and asthma are common comorbidities and seem to share pathophysiology with CRS, which can result in significant healthcare costs and diminished quality of life.

The recommendation by the American Academy of Otolaryngology-Head and Neck Surgery Foundation for initial treatment is saline nasal irrigation and/or intranasal corticosteroids.

For those with persistent symptoms, medical treatment (systemic corticosteroids, anti-inflammatory antibiotics) and sinonasal surgery are options.

However, there are patients who are refractory to medical treatment and are candidates for surgery; some patients still suffer after surgery (recalcitrant).

Several biologics are under investigation for CRS. Chronic rhinosinusitis with nasal polyps (CRSwNP), one of the most prevalent chronic illnesses, affects 4-10% of the global population ( Fokkens et al., 2012 ; Hamilos, 2007 ; Hsu and Peters, 2011 ; Sreeparvathi et al., 2017 ).

CRSwNP is characterized by chronic inflammation of the nasal mucosa and paranasal sinuses that persists for a minimum of 12 weeks ( Hamilos, 2007 ; Hsu and Peters, 2011 ; Sreeparvathi et al., 2017 ).

Based on whether the prevalence of eosinophil tissue infiltration in NP exceeds 10% of the total inflammatory cells, two subtypes can be distinguished: eosinophilic and non-eosinophilic CRSwNP (E-CRSwNP and NE-CRSwNP, respectively)( Grgić et al., 2015 ; Sreeparvathi et al., 2017 ).

E-CRSwNP is characterized by high eosinophilic infiltration in the polyps, which predicts higher risk for polyp recurrence after surgical treatment and poor prognosis ( Akdis et al., 2013 ; Payne et al., 2011 ). A direct correlation between NP and eosinophil/neutrophil counts has been reported ( Kim et al., 2015 ; Shah et al., 2016 ).

Considering the involvement of severe eosinophilic inflammation in E-CRSwNP, there is a need for more aggressive treatments and surgical therapies ( Derycke et al., 2014 ). While various studies have been conducted to clarify the different cellular and molecular characteristics of chronic inflammation in E-CRSwNP and NE-CRSwNP, the molecular mechanisms underlying the differences remain largely unknown ( Chen et al., 2018 , Chin and Harvey, 2013 ).

T helper 1 (TH1) cells in patients with CRSsNP and TH2 cells in patients with CRSwNP are dominant.

What markers are known in nasal polyps?

immunoreactivity of the chemokine ligand (CCL) eotaxin subfamily comprising eotaxin-1 (CCL11), eotaxin-2 (CCL24), and eotaxin-3 (CCL26) are upregulated.

Staphylococcus aureus enterotoxin B stimulation of dispersed nasal polyp cells induced significant interleukin 17A (IL-17A) synthesis ( 16 ). Thymic stromal-derived lymphopoietin (TSLP) was significantly increased in eosinophilic CRSwNP, and the expression of IL-33 was enhanced in epithelial cells in both eosinophilic and non-eosinophilic CRSwNP compared with controls.

(E) After stimulated with hypoxia (1% O2), different IL-17A secretion levels from four types of epithelial cells derived from inferior turbinate (IT) of control, inferior turbinate (IT) of chronic rhinosinusitis with nasal polyps (CRS), eosinophilic (Eos) and noneosinophilic (Non-Eos) chronic rhinosinusitis with nasal polyps NP(CRS) groups were examined by ELISA. Figure 2: IL-5, TSLP, IL-17A and IL-17A receptor (IL-17AR )expression in epithelial cells derived from all four groups: inferior turbinate (IT) of control, inferior turbinate (IT) of chronic rhinosinusitis with nasal polyps (CRS)eosinophilic (Eos) and noneosinophilic (Non-Eos) chronic rhinosinusitis with nasal polyps NP(CRS) groups.

Also HIF1α protein expression in epithelial cells and the lamina propria in the inferior turbinate (IT) of control, inferior turbinate (IT) of chronic rhinosinusitis with nasal polyps (CRS), eosinophilic (Eos) and noneosinophilic (Non-Eos) chronic rhinosinusitis with nasal polyps NP(CRS) groups. Three groups of tissue samples were collected: inferior turbinate (IT)and NP from individuals with chronic rhinosinusitis with NPs (CRSwNP), and control IT. A positive relationship was detected between HIF1α, HIF2α protein expression in epithelial cells and endoscope score in NP samples, while there was a negative correlation between HIF1α expression and degree of eosinophil infiltration. We have shown that the B-cell activating factor of the TNF family (BAFF, also called BLys, or TNFSF13B) is highly elevated in nasal polyp tissue in CRSwNP in comparison to CRSsNP, control and unaffected tissue in CRSwNP 6 We found that BAFF is produced by epithelial cells and could be induced by stimulation with several cytokines and innate immune activators 7 BAFF is a potent stimulator of B-cell proliferation and class switching in B-cells, and mice over-expressing BAFF manifest systemic autoimmunity .

In addition to BAFF, we have also found nasal polyps contain elevated levels of the cytokine IL6 and chemokines such as BLC (CXCL13) and SDF-1a which are known to play a role in B-cell recruitment and plasma cell differentiation 10 , 11 We have proposed that these findings may account for the increased levels of IgA and IgG present in nasal polyp tissue, germinal-center like pseudofollicles and consistently high numbers of B cells and plasma cells 10 , 12 At present, the nature of the antigen specificity of these B cells and their roles in pathogenesis of nasal polyposis remain unclear.

Aureus can be identified very specifically that is found intracellularly only the tissue of CRSwNP patients.

The Aureus germ can also be present as small colony variant”, a sleeping variant with low metabolism, or replicate in epithelial cells of nasal polyps 140 Those findings confirm the persisting character of Staph. (A) Amount of B cells in nasal polyps compared to peripheral blood mononuclear cells (PBMC) in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). (A) CD19+ CD20+ B cells and CD19- CD20+ plasma cells in peripheral blood mononuclear cells (PBMC) compared to nasal polyps in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP).

(A) Detection of CD45+ lymphocytes in peripheral blood mononuclear cells (PBMC) and nasal polyps in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). In this study, we obtained uncinate process (UP) mucosa tissues from control subjects and inflamed UP tissues from the patients with CRS, including those of the chronic rhinosinusitis without nasal polyps (CRSsNP) and CRSwNP groups. This led to the approval of other phase II clinical trials that are currently still ongoing, which hopefully could bring promising data (Table 1). Since CRSwNP is usually characterized by an intense Eosinophilic inflammation and high interleukin (IL)-5 levels in nasal polyp’s tissue 9, a potential new treatment strategy in patients with difficult-to-control nasal polyps could be antagonizing the effect of IL-5 with monoclonal antibodies.

The strong induction of eotaxin-3 from nasal tissue, high levels of eotaxin-3 in nasal polyp , and its expression of endothelial cells could keep the plasma high levels of eotaxin-3 in the patients with ECRS. The diagnosis of sinus disease was based on patient history, clinical examination, and nasal endoscopy according to the guidelines of the European Position Paper on Rhinosinusitis and Nasal Polyps. Our study excluded patients who received systemic or topical corticosteroids before surgery, patients whose information on systemic or topical corticosteroids was unknown, patients who were followed up for <28 days after surgery, patients whose white blood cell count was 10,000/μl or more, and patients from whom there was no pathological specimen.

This disease is divided into 2 subgroups, chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) ( 1 ). Nasal polyps have negative effects on many aspects of the quality of life (physical health, general health, social functioning, sleep, mental health, and workplace absenteeism) due to nasal obstruction, olfactory disturbance, rhinorrhea, and symptoms caused by lower airway involvement ( 2 , 3 ). In patients 80-90% of the nasal polyps are characterized by prominent eosinophilia.

Why is the clinical classification of CRSwNP according to the degree of eosinophilic infiltration in nasal polyps is controversial?

Materials and Methods: Mucosal tissues from 97 patients with chronic rhinosinusitis (CRS) were obtained from the nasal polyps during surgery. One study showed that superantigen from colonized S. aureus leads to activation of T cells and B cells within NP tissue, which results in infiltration of locally produced polyclonal IgE and eosinophils.

Our recently developed animal model of NP had also established the role of S. aureus superantigen in the pathogenesis of NP. S. aureus enterotoxin B when applied at low dose induced nasal polypoid lesion with an increased eosinophilic infiltration in ovalbumin sensitized murine model.

Staphylococcal super-antigens skew inflammation towards Th2-type inflammation 34 , and CRSwNP revealed high concentrations of IL-5 and IL-13

Originally, these cytokines were thought to be generated only in Th2 cells, but now they are known to also be produced from innate lymphoid cell 2” (ILC2) and that ILC2 levels are increased in CRSwNP.