B Lineage Cells and IgE in Allergic Rhinitis and CRSwNP and the Role of Omalizumab Treatment

Abstract

Background

Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) are two prevalent nasal diseases where both type 2 inflammation and immunoglobulin E (IgE) may play important roles. Although they can exist independently or comorbidly, subtle but important differences exist in immunopathogenesis.

Objective

To summarize current knowledge of pathophysiological roles of B lineage cells and IgE in AR and CRS with nasal polyps (CRSwNP).

Methods

Searched PubMed database, reviewed AR and CRSwNP-related literature, and discussed disease diagnosis, comorbidity, epidemiology, pathophysiology, and treatment. Similarities and differences in B-cell biology and IgE are compared in the 2 conditions.

Results

Both AR and CRSwNP have evidence for pathological type 2 inflammation, B-cell activation and differentiation, and IgE production. However, distinctions exist in the clinical and serological profiles at diagnosis, as well as treatments utilized. B-cell activation in AR may more frequently be regulated in the germinal center of lymphoid follicles, whereas CRSwNP may occur via extrafollicular pathways although controversies remain in these initial activating events. Oligoclonal and antigen-specific IgE maybe predominate in AR, but polyclonal and antigen-nonspecific IgE may predominate in CRSwNP. Omalizumab has been shown efficacious in treating both AR and CRSwNP in multiple clinical trials but is the only Food and Drug Administration-approved anti-IgE biologic to treat CRSwNP or allergic asthma. Staphylococcus aureus frequently colonizes the nasal airway and has the ability to activate type two responses including B-cell responses although the extent to which it modulates AR and CRSwNP disease severity is being investigated.

Conclusion

This review highlights current knowledge of the roles of B cells and IgE in the pathogenesis of AR and CRSwNP and a small comparison between the 2 diseases. More systemic studies should be done to elevate the understanding of these diseases and their treatment.

Introduction

Allergic Rhinitis

Allergic rhinitis (AR) is characterized by inflammation of the nasal mucosal membranes with component symptoms of sneezing, nasal itching, congestion, and/or discharge following allergen exposure with further confirmation of corresponding allergen-specific immunoglobulin E (IgE)-mediated hypersensitivity, preferably via skin prick test or serum testing. ¹ However, a subgroup of patients, especially those who have local AR may test negative despite appropriate allergic symptoms. A nasal provocation test and/or basophil activation test are advocated for those individuals although the access to these testing modalities remains limited. ² AR affects up to approximately 10%-40% of the worldwide population depending on geographic diversity and shows an upward trend over the decades. AR often begins early in life, more common in males before puberty but becomes more common in females after puberty. AR significantly lowers the quality of life (QoL), degrades at-work productivity, and impairs social functions. ³

As an atopic disease, AR is a manifestation of an exaggerated IgE immune response to otherwise harmless substances in the environment ⁴ such as dust mite or pet dander. Similarly, AR is thus frequently comorbid or predisposes patients to other atopic diseases like allergic conjunctivitis, asthma, chronic sinusitis, atopic dermatitis, and food allergies.^5,6 AR can also be characterized as seasonal (intermittent) and perennial (persistent)^1,7 depending on the persistence of an allergen in a patient's inhaled environment. Of note, AR is present in up to 80% of asthma patients. In addition to genetic and environmental predisposition, there is evidence that epigenetic modification in AR may play a role difference noted in DNA methylation of peripheral blood mononuclear cells (PBMCs) in grass allergic patients ⁸ and in nasal epithelial brushes from patients with rhinitis and asthma. ⁹ AR is thought to result from an overactive response of T helper 2 (Th2) lymphocytes that initiate a systemic and IgE-driven reaction.

Chronic Rhinosinusitis With Nasal Polyp

Chronic rhinosinusitis (CRS) is a condition characterized by chronic inflammation of the nose and paranasal sinuses and upper airways for a duration of at least 3 months with at least 2 symptoms of nasal congestion, anterior or posterior nasal drainage, facial pressure or pain and anosmia. Further careful nasal clinical examination or endoscopy is required to identify the presence of polyps, middle meatal discharge or edema and to differentiate the 2 significant disease phenotypes— chronic rhinosinusitis with nasal polyps (CRSwNP) if nasal polyps are present or chronic rhinosinusitis without nasal polyp (CRSsNP) if no nasal polyps are visualized.^10–13

The prevalence of CRS-appropriate symptoms varies globally with 8% in China, 10.9% in Europe, and 11.9% in the United States. ¹⁴ CRSwNP prevalence is estimated to be 1%-4% in the general population in the United States. However, about 30% of the CRS cases requiring endoscopic sinus surgery (ESS) are for the CRSwNP phenotype and CRSwNP has a higher postsurgical revision rate due to polyp recurrence.^15–17 Uncontrolled CRSwNP results in decreased patients’ QoL and significantly causes an economic burden on surgical interventions.^12,18

Like AR, CRSwNP is more common among males and is often comorbid with asthma in Western countries. However, unlike AR, CRSwNP most commonly affects adult males when compared to CRSsNP which has a slight female dominance. ¹⁹ Also, unlike AR, CRSwNP frequently begins in adulthood, and comorbid asthma is more often adult in onset.^7,20,21 The frequency of asthma is reported to be as high as 38% in AR, 36% in CRSsNP, and 56% in CRSwNP, and even higher in refractory CRSwNP.^12,15,21

The Clinical Associations Between AR and CRSwNP

Although AR and CRSwNP have been elegantly reviewed by Bousquet ⁵ and Schleimer, ¹¹ respectively, this review will try to highlight the differences that exist between these conditions with a specific focus on B cells and IgE. Since AR and CRSwNP share common definitional symptoms of nasal congestion and rhinorrhea, accurate diagnosis with endoscopy and IgE testing is required despite potential symptomatic cues with AR less associated with facial pressure, purulent nasal discharge, or severe olfactory loss and correspondingly CRSwNP not characterized by nasal itch or sneezing. The duration of symptoms also differs with AR symptoms varying in duration from intermittent (<4 days/week) to persistent (>4 days/week) with symptom-free intervals, ²² whereas CRS symptoms persist daily for more than 12 weeks. Nonetheless, the symptomatic overlap requires careful diagnosis involving history ascertainment and the use of clinician objective diagnostics including nasal endoscopy or computed tomography to differentiate these entities.

AR and CRSwNP do share some predispositional commonalities. A higher mean number of positive skin tests is found in refractory CRSwNP than among AR patients, ²³ and an overall higher rate of atopy is reported in CRSwNP than in the general population. ¹⁵ However, these studies did not find differences in the rate of atopic sensitization to any individual allergen between tested groups. There does not seem to be a strong association between the presence of AR and CRSwNP disease severity. Pearlman et al demonstrated no difference between allergic and nonallergic patients based on the mean Lund–Mackay score not affected by allergenic stimuli. ²⁴ Li et al found no difference in allergic and nonallergic patients regarding disease severity or polyp recurrence. ²⁵ In CRSwNP, asthma comorbidity affects disease severity and increases rates of polyp recurrence and the need for revision surgery following ESS, ²⁶ whereas AR does not appear to modify disease severity.^14,27 Taken all together these studies suggest an association between AR and CRSwNP as comorbidities but not in disease severity.

B Cells and Immunoglobulin Production in AR

Although inflammation in both AR and CRSwNP likely involves an interaction of mucosal cells, including epithelial cells, eosinophils, basophils, neutrophils, mast cells, T cells, and B cells, and their responses to stimuli from the airway like allergens, antigens, or microbes. This review focuses on B lineage cells which uniquely can serve as antigen-presenting cells and immune cells capable of both innate and adaptive responses due to their ability to generate Igs. The ability to generate Ig confers B lineage cells an unparalleled ability to influence cellular and humoral immunity through the ability of Ig to: (1) alter antigen-binding affinity through somatic hypermutation (SHM, introducing mutations to rearranged Ig genes); (2) undergo class switch recombination (CSR, changing the constant region to another to form different Fc-mediated effectors); (3) be expanded through clonal expansion (amplify the number of clones), and cellular differentiation into plasma cells (PCs) all at the mucosal interface; (4) form memory responses among post-CSR and SHM cells; and (5) influence cellular immunity through the presence of isotype-specific Ig receptors (eg, FcεRI for IgE on mast cells) that are present on multiple immune cell types. The CSR and SHM processes alter somatic DNA in B lineage cells, following stimulation of surface Igs on B lineage cells, also termed B-cell receptor (BCR), with further modulation by signals from co-stimulatory factors including innate pattern recognition receptors like the toll-like receptor, cytokine receptors like the B-cell-activating factor (BAFF) receptor family, and CD40 that recognize its ligand CD40L on other immune cells. ²⁸

Conceptually, AR symptoms are thought to occur when allergen-specific IgE on effector cells like mast cells and basophils binds to allergen resulting in histamine release. A series of immune events is required for the generation of allergen-specific IgE and are thought to heavily involve the Th2 adaptive immune responses (Figure 1). Allergens, either directly through intrinsic protease activity or indirectly via innate pattern recognition receptors, can cause epithelial cells to secrete alarmins like interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). The nasal mucosa resident dendritic cells (DCs) take up allergens and present the allergen to the naïve CD4 + T cells in draining lymph nodes. Evidence suggests that prior DC exposure to these epithelial alarmins, best described with TSLP, causes DCs to influence naïve CD4 + T cells to differentiate into allergen-specific Th2 cells that secrete cytokines IL-5, IL-13, and IL-4. ²⁹ In PBMCs from AR patients, evidence suggests a balance shift from T regulatory cells to Th2 cells compared to healthy control. ³⁰ Activated Th2 cells further interact with cognate allergen-specific B cells which in the presence of IL-4 and possibly IL-13 class switch to IgE.^5,31

Figure 1.

Molecular mechanisms in type 2 inflammation in AR and CRSwNP. Inhaled allergens, viruses, Staphylococcus aureus, and other bacteria disrupt the epithelial barrier, triggering the release of cytokines IL-25, IL-33, and TSLP, which activate ILC2s. DCs interact with CD4+ naïve T cells and promote their differentiation to Th2 cells. Both Th2 cells and ILC2s secret IL-4, IL-5, and IL-13, inducing basophil and mast degranulation, and eosinophil activation. B-cell activation via GC: in the dark zone, SHM, CRS, and clonal expansion occur, while in the light zone, CD40L+  Th2 cells interact with CD40+ B cells to facilitate their activation and differentiation into IgE expressing plasmablast cells or SLPC. Alternatively, activated naïve B cells undergo activation and differentiation into PC to express IgE or SE-IgE in an extrafollicular pathway. IgG4 and IgA B cells undergo local class switch to IgE B cells. Local autoantibodies against complement activation, hypercoagulability, and fibrin deposition secretion are found in CRSwNP. Exposure to S. aureus and/or its secreted virulent factors SpA and SE cause antigen-specific IgE production. Figure created using BioRender (https://biorender.com/). Abbreviations: AR, allergic rhinitis; Bas, basophil; CRSwNP, chronic rhinosinusitis with nasal polyp; CSR, class switch recombination; DC, dendritic cells; EBI2, Epstein–Barr virus-induced protein 2; GC, germinal center; Ig, immunoglobulin; IL, interleukin; ILC2, group 2 innate lymphoid cells; PC, plasma cells; SE, staphylococcal enterotoxins; SHM, somatic hypermutation; SLPC, short-lived plasma cells; SpA, staphylococcal protein A; Tfh, T follicular cells; Th2, T helper 2; TSLP, thymic stromal lymphopoietin.

Type 2 cytokines, especially IL-4, released from Th2 cells, activate and expand cognate allergen-specific B cell and further promote CSR into IgE. IgE binds to mast cells and basophils via crosslinks with the high-affinity IgE receptor (FcεRI) on the surface of basophils and mast cells. On B cells, IgE further binds to FcεRII, a low-affinity receptor compared to FcεRI. The binding of IgE to FcεRII increases the allergen-presenting activity of B cells. ³² Another study reported that T–B cell interactions are mediated by FcεRII expressed on class-switched memory B cells, which could be induced by Th2 T follicular helper cells via IL-4. ³³ When these allergen-specific IgE primed cells encounter allergen, degranulation of these cells releases allergic mediators including histamine, leukotrienes, and prostaglandins, causing hypersensitivities such as plasma infiltration and vascular permeability. These mediators also have direct effects on sensory nerve responses and may mediate some of the nasal itch, sneezing, and excess mucus secretion seen in AR. ³⁴

Since the generation of specific IgE and its effect on mast cell priming are definitional to AR, understanding how antigen-specific IgE expressing B cells generated is fundamental to understanding IgE as well as the condition. In the classical pathway for antigen-specific B-cell activation and differentiation, high affinity and antigen-specific B cells are generated in tightly regulated T-cell and B-cell interactions in a germinal center (GC) of a secondary lymphoid organ. Local SHM, clonal expansion, and CSR are present in nasal mucosa of AR evidenced by IgE V_H region. ³⁵ B cells generated in a GC response either become memory B cells or undergo plasma cell differentiation, switching to short-lived PCs (SLPC) with reduced proliferation, and increased apoptosis, and some switch to long-lived PC (LLPC). There is evidence that allergen-specific IgG  +  memory B cells (CD19 ⁺ CD20 ⁺ CD27 ⁺ CD38⁻) can rapidly switch isotypes to IgE  +  plasmablasts (CD19 ⁺ CD20^lowCD27 ⁺ CD38⁺) which is short lived, evaluated by IgE simultaneous drops as well as IgE transcripts decreases in serum. ³⁶ In addition, significantly more IgE  +  B cells and IgE  +  PCs are found in the nasal mucosa in AR patients than in the nonallergic controls. ³⁷ Finally, there is also evidence however that local CSR to IgE may occur outside GC in AR given the expression of germline and epsilon circle transcripts (DNA byproducts of CSR) in the nasal mucosa of grass pollen AR patients. This final process is least understood experimentally. Some B cells have even been elucidated to have regulatory immune effects in AR. Peripheral antigen-specific CD38 + B cells in AR patients facilitate conversion of regulatory T cells into Th17 cells by expressing IL-6, compromising allergen-specific immunotherapy. ³⁸ In addition, peripheral blood regulatory B cells (CD19 ⁺ CD73⁻CD25^+/hiCD71⁺) have been demonstrated to be reduced in AR patients because it inhibits type 2 response by producing IL-10, ³⁹ in consistent with another finding that IL-10 producing Bregs (CD19 ⁺ CD24^hiCD27⁺) in total B cells in peripheral blood are reduced in AR, and more extensively in AR with asthma. ⁴⁰

B Cells and Immunoglobulin Production in CRSwNP

Similar to AR, CRSwNP is a complex inflammatory disease with interplays of innate and adaptive immune cells. Strong evidence implicates dysregulation of type 2 inflammation in sinonasal mucosa with the accumulation of group 2 innate lymphoid cells (ILC2s), Th2 cells, M2 macrophages, mast cells, basophils, and eosinophils in nasal polyp (NP) tissue (Figure 1). ILC2s secrete IL-5, IL-13 in NP tissue but not blood ILC2, and strongly skew the nasal immune response.^41,42 It should be noted that while elevated type 2 inflammation can be detected in upwards of 90% of Western CRSwNP, with Chinese CRSwNP studies report a significant proportion as high as 58% as mixed type 1 (interferon γ driven) and type 3 (IL-17a driven) inflammation.^10–13

Besides type 2 inflammation, ample evidence shows that B-cell activation and IgE expression are also dysregulated in CRSwNP (Table 1). In NP tissue, B cells are 1.7-fold higher in compared to the adjacent uncinate tissue (UT) and almost 25-fold higher than in non-CRS UT. The difference is further magnified among plasmablasts, given that the number of plasmablasts in NP tissue is 2.3-fold higher than polyp patient-derived UT and more than 100-fold higher than normal UT. ⁴⁸ The plasmablasts having a CD19 ⁺ CD27 ⁺ CD38^hi surface phenotype are found at significantly increased frequency in NP tissue even when compared to secondary lymphoid organs like tonsils. Notably, these plasmablasts also display dramatically increased expression of Epstein–Barr virus-induced protein 2 (EBI2), a chemotactic receptor, in both gene and protein expression compared to those in tonsils. ⁵⁰ The abundance of B lineage cells and PCs in CRSwNP may result in increased tissue-produced antibodies. Antibody isotypes including IgG1, IgG2, IgG4, IgM, IgA1, IgA2, and IgE but particularly IgG4 and IgE are increased in NP tissue compared to polyp patient-derived UT or serum.

Table 1.

Key B Lineage Cell Findings in AR and CRSwNP.

Key findings in AR
KleinJan et al 37	IgE is produced locally in the nasal mucosa of AR patients evidenced by significantly increased IgE+ B cells and plasma cells compared to nonallergic controls, and the plasma cells are allergen-specific
Coker et al 35	Local somatic hypermutation, clonal expansion, and class switch recombination are present in the nasal mucosa of AR patients evidenced by RT-PCR of IgE VH region
Wu et al 43	IgE repertoires measured on AR patients inside of grass pollen season are more diverse and mutated than those taken outside of the pollen season or from healthy control; clonal relatedness between IgE and IgG is found and associated with a GC reaction
De Schryver et al44	Summarized evidence for local IgE+ B cells and IgE production are increased in the nasal mucosa in both AR and CRSwNP
Kamekura et al 40	IL-10-producing Bregs (CD19+CD24hiCD27+) in total B cells in blood are reduced in AR
Kim et al 39	Regulatory B cells (CD19+CD73−CD25+/hiCD71+) are reduced in AR patients, which is hypothesized to inhibit type 2 response by producing IL-10
Hoof et al 36	Human mucosal IgG memory B cells could locally class switch to short-lived IgE plasmablasts after specific allergen exposure in AR, supported by high IgE transcript levels in sorted plasmablasts (CD19+CD20lowCD27+CD38+). Both IgG+ memory B cells and IgE+ preplasmablast transcriptomes encoded antigen-specific antibodies
Tian et al 38	Antigen-specific CD38+ B cells are increased in AR patients, and their expression of IL-6 converts regulatory T cells to TH17 cells
Allen 45	Summarized evidence that serum IgE is produced by SLPC in AR especially in seasonal AR with allergen re-exposure and some are made by LLPC
Key findings in CRSwNP
Tan et al 46	Anti-dsDNA IgG and IgA autoantibodies are elevated in CRSwNP, and the presence of anti-dsDNA antibodies is associated with the need for repeated surgery
Gevaert et al 47	Local IgE and the frequency of class switching to IgE are increased in NP compared with AR and normal controls, supported by increased RAG1 and RAG2 in NP, which are correlated with Staphylococcus aureus enterotoxin-specific IgE
Hulse et al 48	In NP tissue, B cells and plasma cells are increased compared to UT and control; local increases in antibody levels are found but not in blood. EBI2 expression is increased and positively correlated with plasma cell markers (CD138, CH25H, and Blimp-1)
Tsybikov et al 49	Anticytokines IL-5 and IL-17A autoantibodies are detected in nasal secretions in CRSwNP
Feldman et al 50	Increased antibody-secreting cells in CRSwNP than tonsil by ELISpot, and ILC2s directly induced EBI2 expression on B cells in vitro. B-cell activation and differentiation might be GC independent, but extrafollicular responses
Lau et al 51	Higher frequency of local tertiary lymphoid organs is found in recalcitrant chronic rhinosinusitis compared to CRSsNP and control patients
Bai. et al 51	Anti-dsDNA specific ASCs are increased in both frequency and abundance in CRSwNP
Buchheit et al 52	Local IgE and IgG4 antibodies increased in AERD patients compared to CRSwNP, which is attributed to plasma cells expressing IL-5Rα
De Schryver et al 53	Local anti-dsDNA IgG is found but not in the serum in CRSwNP
Corrado et al 54	Extrafollicular IgE ASC formation at the nasal mucosa is through activated IgD naïve B cells locally direct and indirect (IgG and IgA to IgE) class switch to IgE
Bachert et al 55	Elevated IgE in nasal tissue of CRSwNP is independent of allergy, and they are derived from many different B-cell clones. S. aureus enterotoxins are thought to act as superantigens to induce polyclonal IgE production via B-cell and T-cell activation
Bai et al 56	Anti-dsDNA-IgG is highly increased in NPs compared to ethmoid from CRSwNP, and the level of dsDNA-IgG is predictive of polyp recurrence

Abbreviations: AERD, aspirin-exacerbated respiratory disease; AR, allergic rhinitis; CRSsNP, chronic rhinosinusitis without nasal polyp; CRSwNP, chronic rhinosinusitis with nasal polyp; dsDNA, double-stranded DNA; EBI2, Epstein–Barr virus-induced protein 2; GC, germinal center; Ig, immunoglobulin; IL, interleukin; ELISpot, enzyme-linked immunosorbent spot; ILC2, group 2 innate lymphoid cells; ASCs, antibody secreting cells; LLPC, long-lived plasma cells; NP, nasal polyp; RAG, recombination activating gene; RT-PCR, reverse transcription polymerase chain reaction; SLPC, short-lived plasma cells; UT, uncinate tissue.

As discussed in B-cell responses in AR, antigen-specific B-cell responses typically develop in the GC of lymphoid follicles. However, B cells are known to have two fate decisions in the lymphoid follicles, either migrating to the extrafollicular areas, where they differentiate into plasmablast and PCs for rapid antibody production or localizing into the GC region of the follicle. The extrafollicular activation mechanism, in particular, may play an important role in the activation of B cells in CRSwNP and the generation of antigen-nonspecific IgE-producing cells. There is contradictory evidence for GC formation in CRSwNP with no tertiary lymphoid structure found in two systematic studies of polyp tissue,^50,54 but other studies reported the formation of tertiary lymphoid structures in NP.^47,57,58 In contrast, evidence for an extrafollicular origin of CRSwNP B cells includes: the expression of EBI2, also an oxysterol receptor, that guides B-cell migration to the extrafollicular regions in secondary lymphoid organs is highly expressed on CRSwNP B cells.^59–64 Despite the lack of GCs, some of the activation machinery typically associated with GC-activated B cells are found in CRSwNP B cells including gene expression of the recombination activating gene and activation-induced cytidine deaminase as well as germline gene transcripts and epsilon circle transcripts (evidence for local CSR to IgE).^{44,47,50,65,66} Recently, using heavy chain sequencing, Corrado et al ⁵⁴ reported that an extrafollicular-activated mucosal IgD  +  activated naïve-like B cells may be the progenitor of IgE antibody secreting cells. These lines of evidence suggest that local activation, proliferation, CSR, and maturation into IgE PCs may occur directly within NP tissue.

Extrafollicular-activated B cells are also less tightly regulated than the GC pathway and permit the activation of autoreactive B cells with resultant production of autoantibodies. ⁶⁷ We find an abundance of IgG autoantibodies to a variety of autoantigens including double-stranded DNA (dsDNA), phospholipids, and basement membrane proteins with NP tissue that are common in the serum of autoimmune diseases like systemic lupus erythematosus.^46,49,51,68 We have recently also found that this phenomenon has prognostic implications for patients with CRSwNP with evidence that anti-dsDNA IgG antibodies were a prospective biomarker for recurrent NP following ESS. ⁵⁶ In addition, complement is highly activated in NP tissue and complement neo-epitopes specific to the classical antibody-activated pathway are particularly elevated in NP tissue. ⁶⁹ However, thus far, we have not found evidence for IgE autoreactivity or anti-IgE IgG in NP tissue although these are relatively difficult to detect given the substantially lower amount of IgE relative to common isotypes like IgG. ⁵³

In addition to atypical activation mechanisms in CRSwNP, elevated cytokines like BAFF in NP tissue ⁷⁰ and serum ⁷¹ may also play a role in B-cell activation and differentiation to PCs. BAFF serves as a potent stimulator of B-cell proliferation and activation in NP. Elevated IL-6 is also found in NP tissue and may drive B cells to undergo plasma cell differentiation in sinonasal tissues. ⁷² Recently, Buchheit et al illustrated an increase in IgE and IgG4 antibodies in patients with aspirin-exacerbated respiratory disease (AERD) NP tissue compared to non-AERD CRSwNP which they attributed to PCs expressing IL-5Rα suggesting IL-5 may influence IgE production. ⁵²

IgE Specificity and Systemic Versus Local Elevation in AR and CRSwNP

IgE in AR is definitionally oligoclonal and allergen-specific and detectable by systemic testing like skin prick tests or serum.^5,43 In contrast, the clonality of IgE in CRSwNP is thought to be polyclonal^44,55 and to date, a dominant specificity has not been established. The fundamental mechanisms leading to the differences in clinical presentation and these differences in B-cell phenotypes and IgE specificity is an area of active research but may have to do with the nature of the antibody-secreting cells. IgE repertories measured on AR patients inside of grass pollen season are more diverse and mutated than those taken outside of the pollen season or from healthy control, and the IgE and IgG are found related, suggesting the clonal switch is associated with a GC reaction. ⁴³ Allen has summarized evidence that serum IgE in AR is produced by SLPC especially in seasonal AR with allergen re-exposure, as well as some contribution by LLPC. ⁴⁵ In patients with grass pollen AR, serum IgE antibodies specific for grass pollen allergens are reported to derive from IgG  +  memory B cells that undergo CSR to IgE  +  plasmablasts after mucosal allergen exposure. ³⁶ Even though hypersensitivity in AR is thought to be systemic, local IgE may still contribute as allergen-specific IgE is found to predominate the total IgE in the nasal mucosa unlike that in the blood. ⁷³ Similarly, allergen-specific IgE is found to be produced locally in the nasal mucosa in the seasonal AR and perennial AR but not in the nonallergic controls. ³⁷

It is believed that a large fraction of the IgE produced in CRSwNP may be produced locally within NP tissue. Local total IgE and IgE-secreting cells are significantly higher in NP tissue than in healthy nasal tissue, and IgE correlated with eosinophilic infiltration in NP.^74,75 CRSwNP sinus tissue has been shown to have a higher frequency of polyclonal IgE response, as well as cockroach and plantain-specific IgE but no other tested common inhalant antigens compared to CRSsNP sinus tissue. ⁷⁶ Separately, another study found positivity and level of serum staphylococcal enterotoxin B-IgE (SEB-IgE) is significantly higher in CRSwNP compared to CRSsNP and healthy controls. ⁷⁷

Staphylococcal-specific IgE Antibodies

Staphylococcus aureus is one of the most frequently found bacteria which colonizes approximately 20%-30% of sinonasal cavity in Europe and the US general population, ⁷⁸ and is more frequent in AR and asthma, ⁷⁹ and CRSwNP. ⁸⁰ The presence of S. aureus can be assessed directly by bacterial growth in culture or indirectly through secreted virulence factors including S. aureus enterotoxin A and B (SE, A and B), serine protease-like proteins, or staphylococcal protein A (SpA) or serum-specific IgE. Experimentally, the SE has been shown to exacerbate type 2 immune skewing.^81,82 It is believed that S. aureus induces antigen-specific IgE in AR and polyclonal IgE in CRSwNP; however, the pathophysiological mechanism of S. aureus or SE is not clear. SE is reported to activate T cells and release Th2 cytokines, while SpA activates B cells via crosslinking BCR with heavy chain V_H3 regions ⁸³ and further induces polyclonal IgE production in V_H3-positive B cells in culture with healthy adult and lupus patients’ blood, ⁸⁴ or binding to V_H3-positive IgE, which can induce mast cell degranulation in an antigen-nonspecific way, but no unambiguous evidence of SpA-induced IgE in the human upper airway.

AR has been documented to have associations with S. aureus or its enterotoxin SE. AR patients are more likely to have S. aureus colonization (eg, 44% in perennial AR) than controls (20%), ⁸⁵ as well as higher local or systemic SE-IgE than controls.^79,86 Increased total serum IgE^87,88 and increased SE-IgE^88,89 are found in AR patients with sensitization to SE than without. However, the association between S. aureus or its enterotoxin SE and severity is debatable. The severity using nasal symptom scores is reported as not correlated with sensitization to SE. ⁸⁷ In contrast, the higher prevalence and concentration of serum SE-IgE antibodies are related to more severe symptoms in AR with or without asthma, ⁸⁹ and higher levels of serum eosinophil cationic protein are found in AR with sensitization to SE than people who have not SE specific. ⁸⁸ In addition, nasal symptoms scores among cases were significantly higher in SA carriers compared to noncarriers. ⁸⁵

In CRSwNP, S. aureus by nasal swab culture has been variably reported with some studies reporting 33%, similar to non-CRS controls, ⁹⁰ whereas others reported near universal prevalence. ⁹¹ In contrast to the above, no higher prevalence of S. aureus in CRSwNP than in CRSsNP or control, assessed by bacterial culture of nasal tissue or lavages.^92,93 There is no clear causation of either S. aureus or its enterotoxin SE causing the host immune response. ⁹⁴ In contrast, studies that evaluated S. aureus exposure via SE-IgE have shown increased polyclonal and SE-specific IgE in CRSwNP tissue but not in blood or CRSsNP tissue^80,95,96 and elevated nasal tissue SE-IgE is correlated with increased Th2 cytokines in eosinophilic CRSwNP with comorbid asthma. ⁹⁶ Other studies find SEB-IgE level is not unique to the CRSwNP phenotype and is elevated in CRSsNP, even though both are higher than non-CRS. ⁹⁷ In contrast, NP patients in China have lower rates of serum SE-IgE or (<5%) compared to Europe and Oceania (26%). ⁹⁸ Despite differences in the prevalence of SE and SE-IgE, no correlation was found between SE and severity in CRSwNP or CRSsNP. ⁹⁰

Thus, the influence of S. aureus and its secreted virulence factors as well as IgE specific to its enterotoxins appears elevated though not universal in CRSwNP and remains an area of investigation in the condition.

Evidence for the Efficacy of Omalizumab in AR and CRSwNP

In recent years, several clinical trials have evaluated the efficacy and safety of biologics targeting type 2 inflammation in treating AR and CRSwNP. Omalizumab, a humanized anti-IgE monoclonal antibody, was first approved by the Food and Drug Administration (FDA) for the treatment of severe allergic asthma, ⁹⁹ subsequently for refractory chronic spontaneous urticaria, ¹⁰⁰ and CRSwNP.^101–103 It was developed to block the binding of free IgE to high-affinity receptors on effector cells including mast cells and basophils but may also facilitate the dissociations between inflammatory complexes. Omalizumab is the only FDA-approved anti-IgE biologic that targets and blocks IgE. Omalizumab also has been reported for off-label use in AR and other allergies. ¹⁰⁴

While the mechanistic study of omalizumab's effects is ongoing, it is generally accepted that omalizumab interferes with the high-affinity binding between IgE and FcεRI on mast cells and basophils (Figure 1). IgE binding to the α-chain of FcεRI is mediated through the Fc region of IgE, and omalizumab can bind and crosslink IgE-Fc_. A crystal structure of omalizumab Fab fragments and IgE-Fc mutants revealed that omalizumab-mediated inhibition of IgE binding to FcεRI might be through IgE:CD23 complex. ¹⁰⁵ Omalizumab can also bind to free IgE and reduces immune cells or facilitate the dissociations of IgE from FcεRI ¹⁰⁶ and CD23. ¹⁰⁷ In addition, omalizumab is also associated with decreased expression of FcεRI on basophils, mast cells, and DCs.^108,109 Not surprisingly, reduced serum IgE levels, eosinophils, basophils, mast cells, and B cells have been noted following omalizumab treatment. Furthermore, omalizumab induces anergy in membrane IgE-bearing B cells to decrease B cell producing IgE, ¹¹⁰ induces apoptosis in eosinophils, ¹¹¹ and reduces serum eosinophil count. ¹¹² Interestingly, an in vitro study of omalizumab on human tonsillar B cells showed a reduced number of IgE  +  B cells, which is attributable to the decreased IgE synthesis by human B cells by targeting membrane IgE-bearing B cells. ¹¹⁰

Although not currently approved for the treatment of AR, the efficacy of omalizumab in the treatment of AR has been evaluated in several randomized control trials (RCTs), indicating that it significantly improved nasal and ocular symptom scores and QoL and reduced the need for medication based on a meta-analysis of 12 RCTs of AR patients.^113,114 Preseason omalizumab use significantly reduced the symptom, resulting in improved QoL in seasonal AR patients. ¹¹⁵ Evidence of the efficacy of omalizumab in CRSwNP has been established in successful Phase 3 RCTs. ⁵⁵ In CRSwNP and comorbid asthma, omalizumab binds free tissue and serum IgE and significantly reduces the NP score and severity independent of the presence of allergy. ¹¹⁶ Two Phase III RCTs, POLYP1 and POLYP2, indicate that nasal polyp burden, nasal and CRS-specific symptoms are improved after 4 weeks of post omalizumab use and last for 24 weeks of the treatment period. ¹⁰²

Other biologics for treating AR and CRSwNP are also under studies and evaluations. Dupilumab and mepolizumab, together with omalizumab, have been approved in the United States for CRSwNP treatment. Dupilumab, a monoclonal antibody that binds to IL-4Rα, inhibiting IL-4 and IL-13, has shown significantly greater improvement in symptoms in CRSwNP compared to placebo. ¹¹⁷ Reduced total IgE levels have been reported in NP tissue following dupilumab treatment and provide insight into the role IL-4 and IL-13 may play in driving tissue IgE production. ¹¹⁸ Similarly, mepolizumab, an approved anti-IL-5 monoclonal antibody, reduced SE-IgE, is reported in a CRSwNP study. ¹¹⁹ With further ongoing clinical trials of these agents and other anti-type 2 agents, further insights may be gained in the relationship of the various aspects of type 2 inflammation and their relevance to the B lineage cells and IgE production that are found in abundance in CRSwNP.

Conclusions

Research has shed new insights into the role B lineage cells and the IgE they produce in the pathogenesis of AR and CRSwNP. To date, IgE has served as a useful tool for diagnosis of AR and the treatment of AR and CRSwNP as evidenced by the success of anti-IgE biologics in clinical trials. However, the similarities and contrasts in mechanisms leading to the activation of B cells and excess IgE production in both AR and CRSwNP is an area of active investigation and may lead to an improved understanding of how to better prevent and treat these common and chronic nasal inflammatory conditions.