Neuroprotective protein ADNP-dependent histone remodeling complex promotes T helper 2 immune cell differentiation.

Type 2 immune responses are critical in tissue homeostasis, anti-helminth immunity, and allergy. T helper 2 (Th2) cells produce interleukin-4 (IL-4), IL-5, and IL-13 from the type 2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand transcriptional regulation of Th2 cell differentiation, we performed CRISPR-Cas9 screens targeting 1,131 TFs. We discovered that activity-dependent neuroprotector homeobox protein (ADNP) was indispensable for immune reactions to allergen. Mechanistically, ADNP performed a previously unappreciated role in gene activation, forming a critical bridge in the transition from pioneer TFs to chromatin remodeling by recruiting the helicase CHD4 and ATPase BRG1. Although GATA3 and AP-1 bound the type 2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type 2 cytokine expression. Our results demonstrate an important role for ADNP in promoting immune cell specialization.

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch.

Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.

Tissue-Resident Group 2 Innate Lymphoid Cells Differentiate by Layered Ontogeny and In Situ Perinatal Priming.

The perinatal period is a critical window for distribution of innate tissue-resident immune cells within developing organs. Despite epidemiologic evidence implicating the early-life environment in the risk for allergy, temporally controlled lineage tracing of group 2 innate lymphoid cells (ILC2s) during this period remains unstudied. Using complementary fate-mapping approaches and reporters for ILC2 activation, we show that ILC2s appeared in multiple organs during late gestation like tissue macrophages, but, unlike the latter, a majority of peripheral ILC2 pools were generated de novo during the postnatal window. This period was accompanied by systemic ILC2 priming and acquisition of tissue-specific transcriptomes. Although perinatal ILC2s were variably replaced across tissues with age, the dramatic increases in tissue ILC2s following helminth infection were mediated through local expansion independent of de novo generation by bone marrow hematopoiesis. We provide comprehensive temporally controlled fate mapping of an innate lymphocyte subset with notable nuances as compared to tissue macrophage ontogeny.

Nmes1 is a novel regulator of mucosal response influencing intestinal healing potential.

The initiation of tissue remodeling following damage is a critical step in preventing the development of immune-mediated diseases. Several factors contribute to mucosal healing, leading to innovative therapeutic approaches for managing intestinal disorders. However, uncovering alternative targets and gaining mechanistic insights are imperative to enhance therapy efficacy and broaden its applicability across different intestinal diseases. Here we demonstrate that Nmes1, encoding for Normal Mucosa of Esophagus-Specific gene 1, also known as Aa467197, is a novel regulator of mucosal healing. Nmes1 influences the macrophage response to the tissue remodeling cytokine IL-4 in vitro. In addition, using two murine models of intestinal damage, each characterized by a type 2-dominated environment with contrasting functions, the ablation of Nmes1 results in decreased intestinal regeneration during the recovery phase of colitis, while enhancing parasitic egg clearance and reducing fibrosis during the advanced stages of Schistosoma mansoni infection. These outcomes are associated with alterations in CX3CR1+ macrophages, cells known for their wound-healing potential in the inflamed colon, hence promising candidates for cell therapies. All in all, our data indicate Nmes1 as a novel contributor to mucosal healing, setting the basis for further investigation into its potential as a new target for the treatment of colon-associated inflammation.

Helminth infection induces a distinct subset of CD101hi lung tissue-infiltrating eosinophils that are differentially regulated by type 2 cytokines.

Eosinophils play divergent roles in health and disease, contributing to both immunoregulatory and proinflammatory responses. Helminth infection is strongly associated with eosinophilia and the induction of the type 2 cytokines interleukin (IL)-5, IL-4 and IL-13. This study aimed to elucidate the heterogeneity of pulmonary eosinophils in response to helminth infection and the roles of IL-5, IL-4 and IL-13 in driving pulmonary eosinophil responses. Using the murine helminth model Nippostrongylus brasiliensis (Nb), we characterize a subtype of eosinophils, defined by high expression of CD101, that is induced in the lungs of Nb-infected mice and are phenotypically distinct from lung eosinophils that express low levels of CD101. Strikingly, we show that the two eosinophil subtypes have distinct anatomical localization within the lung: CD101low eosinophils are predominantly localized in the lung vasculature, whereas Nb-induced CD101hi eosinophils are predominantly localized in the extravascular lung niche. We show that CD101hi eosinophils are also induced across other models of pulmonary infection and inflammation, including a nonlung-migrating helminth infection, house dust mite-induced allergic inflammation and influenza infection. Furthermore, we demonstrate that the induction of CD101hi tissue eosinophils is independent of IL-5 and IL-4 signaling, but is dependent on intact IL-13 signaling. These results suggest that IL-13 produced during helminth infection and other disease states promotes a pulmonary tissue-infiltrating program in eosinophils defined by high expression of CD101.

IL-4/STAT6 axis observed to reverse proliferative defect in SCA3 patient-derived neural progenitor cells.

Spinocerebellar ataxia 3 (SCA3) is an incurable, neurodegenerative genetic disorder that leads to progressive cerebellar ataxia and other parkinsonian-like pathologies because of loss of cerebellar neurons. The role of an expanded polyglutamine aggregate on neural progenitor cells is unknown. Here, we show that SCA3 patient-specific induced neural progenitor cells (iNPCs) exhibit proliferative defects. Moreover, SCA3 iNPCs have reduced autophagic expression compared to control. Furthermore, although SCA3 iNPCs continue to proliferate, they do not survive subsequent passages compared to control iNPCs, indicating the likelihood that SCA3 iNPCs undergo rapid senescence. Exposure to interleukin-4 (IL-4), a type 2 cytokine produced by immune cells, resulted in an observed increase in expression of autophagic programs and a reduction in the proliferation defect observed in SCA3 iNPCs. Our results indicate a previously unobserved role of SCA3 disease ontology on the neural stem cell pool and a potential therapeutic strategy using IL-4 to ameliorate or delay disease pathology in the SCA3 neural progenitor cell population.

Local type 2 immunity in eosinophilic gastritis.

BACKGROUND: Eosinophilic gastritis (EoG) associates with type 2 immunity. However, the type 2 cytokine cellular source, gastric T-cell composition, and gastric T-cell relationship (or relationships) with disease pathology remain understudied. OBJECTIVE: We defined gastric T-cell populations and their association with histologic and endoscopic EoG pathology. METHODS: Gastric biopsy samples (n = 6 EoG, n = 7 control) were subjected to histologic, endoscopic, and flow cytometry analyses. In a complementary cohort (n = 83 EoG), IL4, IL5, and IL13 mRNA levels were correlated with EoG pathologic parameters. RESULTS: Gastric biopsy samples contained CD3+ T cells that were mainly CD8+; the CD8/CD4 ratio was comparable in EoG and control biopsy samples (5.7 ± 3.0 and 4.3 ± 0.6, respectively; P = .28). Gastric regulatory T (CD3+CD4+FOXP3+) and TH2 (CD3+CD4+GATA3+) cell levels were increased in EoG versus controls (2-fold, P < .05 and 10-fold, P < .001, respectively) and correlated with gastric eosinophil levels (r = 0.63, P < .05 and r = 0.85, P < .001, respectively), endoscopic pathology (r = 0.56, P < .01; r = 0.84, P < .001, respectively), and histopathology (r = 0.72, P < .01; r = 0.82, P < .01, respectively). Cytokine-positive, most notably IL-4+, TH2 cell levels strongly correlated with histologic and endoscopic scores (r = 0.82, P < .0001 and r = 0.78, P < .0001, respectively). In an independent EoG cohort (n = 83), bulk gastric IL4, IL5, and IL13 mRNA levels correlated with histologic score (r = 0.22, P < .005; r = 0.54, P < .0001; and r = 0.36, P < .0001, respectively) and endoscopic score (r = 0.27, P < .001; r = 0.40, P < .0001; and r = 0.35, P < .0001, respectively). CONCLUSIONS: EoG is a TH2 cell-associated disease featuring increased gastric type 2 cytokine-producing CD3+CD4+GATA3+TH2 cells that strongly correlate with disease pathologies.

IL-4 receptor alpha blockade dampens allergic inflammation and upregulates IL-17A expression to promote Saureus clearance in antigen sensitized mouse skin.

BACKGROUND: Skin colonization with Staphylococcus aureus aggravates atopic dermatitis and exaggerates allergic skin inflammation in mice. IL-4 receptor α (IL-4Rα) blockade is beneficial in atopic dermatitis and reduces Saureus skin colonization through unknown mechanisms. The cytokine IL-17A restrains Saureus growth. OBJECTIVES: This study sought to examine the effect of IL-4Rα blockade on Saureus colonization at sites of allergic skin inflammation in mice and determine the mechanism involved. METHODS: BALB/c mice were epicutaneously sensitized with ovalbumin (OVA). Immediately after, PSVue 794-labeled S aureus strain SF8300 or saline was applied and a single dose of anti-IL-4Rα blocking antibody, a mixture of anti-IL-4Rα and anti-IL-17A blocking antibodies, or IgG isotype controls were administered intradermally. Saureus load was assessed 2 days later by in vivo imaging and enumeration of colony forming units. Skin cellular infiltration was examined by flow cytometry and gene expression by quantitative PCR and transcriptome analysis. RESULTS: IL-4Rα blockade decreased allergic skin inflammation in OVA-sensitized skin, as well as in OVA-sensitized and Saureus-exposed skin, evidenced by significantly decreased epidermal thickening and reduced dermal infiltration by eosinophils and mast cells. This was accompanied by increased cutaneous expression of Il17a and IL-17A-driven antimicrobial genes with no change in Il4 and Il13 expression. IL-4Rα blockade significantly decreased Saureus load in OVA-sensitized and S aureus-exposed skin. IL-17A blockade reversed the beneficial effect of IL-4Rα blockade on Saureus clearance and reduced the cutaneous expression of IL-17A-driven antimicrobial genes. CONCLUSIONS: IL-4Rα blockade promotes Saureus clearance from sites of allergic skin inflammation in part by enhancing IL-17A expression.

IL-21 induces pyroptosis of Treg cells via Akt-mTOR-NLRP3-caspase 1 axis in eosinophilic chronic rhinosinusitis.

BACKGROUND: Regulatory T (Treg) cells, which prevent inflammation-induced eosinophil infiltration, are deficient in nasal polyps (NPs) in patients with eosinophilic chronic rhinosinusitis (ECRS). It is concomitant with loss of Foxp3 after certain inflammatory stimuli. OBJECTIVE: We sought to determine the inflammatory cytokines involved in inducing the loss of Treg cells in NPs. METHODS: The abundance of cytokines in ECRS patients or mice were tested using ELISA, immunochemistry, immunofluorescence, quantitative reverse transcription PCR (qPCR), and/or flow cytometry. Expression of eosinophil cationic protein (ECP), CD4+ T cells, IL-4, and IL-17A and eosinophils in nasal mucosa of mouse model was investigated by immunochemistry, immunofluorescence, and hematoxylin and eosin staining. The percentage and death of induced Treg (iTreg) cells, source of IL-21 in NPs from ECRS and non-ECRS patients, and abundance of different systemic phenotypes of CD4+ T cells in a mouse model were studied by flow cytometry. Western blot analysis, scanning, and transmission electronic microscopy were used to detect pyroptosis of iTreg cells. RESULTS: IL-21 was highly expressed in nasal mucosa of ECRS patients and mice, causing pyroptosis and preventing development of iTreg cells in vitro. The elevated IL-21 in NPs from ECRS patients was mainly produced by CD3+ T cells, including T follicular helper, T peripheral helper, TH2, and TH17 cells and CD3+CD4- T cells. T peripheral helper cells and CD3+CD4- T cells were the predominant source of IL-21 in NPs from non-ECRS patients. Blocking IL-21/IL-21R signaling significantly reduced the number of eosinophils and CD4+ T cells along with ECP, IL-4, and IL-17A expression in the nasal mucosa of ECRS mice. It also increased Treg cell percentage and systemically decreased TH2 and TH17 ratios. Akt-mTOR inhibition prevented IL-21-induced pyroptosis in human and mouse iTreg cells. CONCLUSION: Elevated IL-21 drives pyroptosis and prevents Treg cell development in ECRS patients. IL-21 induced pyroptosis via activating Akt-mTOR-NLRP3-caspase 1 signaling.

Single-Domain Antibodies-Novel Tools to Study and Treat Allergies.

IgE-mediated allergies represent a major health problem in the modern world. Apart from allergen-specific immunotherapy (AIT), the only disease-modifying treatment, researchers focus on biologics that target different key molecules such as allergens, IgE, or type 2 cytokines to ameliorate allergic symptoms. Single-domain antibodies, or nanobodies, are the newcomers in biotherapeutics, and their huge potential is being investigated in various research fields since their discovery 30 years ago. While they are dominantly applied for theranostics of cancer and treatment of infectious diseases, nanobodies have become increasingly substantial in allergology over the last decade. In this review, we discuss the prerequisites that we consider to be important for generating useful nanobody-based drug candidates for treating allergies. We further summarize the available research data on nanobodies used as allergen monitoring and detection probes and for therapeutic approaches. We reflect on the limitations that have to be addressed during the development process, such as in vivo half-life and immunogenicity. Finally, we speculate about novel application formats for allergy treatment that might be available in the future.

Altered expression of S100 fused-type proteins in an atopic dermatitis skin model.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with elevated interleukin (IL)-4 and IL-13 signatures and extensive barrier dysfunction, which is correlated with the downregulation of filaggrin (FLG). FLG is a member of the S100 fused-type protein family and this family also includes cornulin (CRNN), filaggrin-2 (FLG2), hornerin (HRNR) repetin (RPTN), trichohyalin (TCHH) and trichohyalin-like 1 (TCHHL1). The present study aimed to examine the effects of IL-4 and IL-13 and the downregulation of FLG on the expression of S100 fused-type proteins using a three-dimensional (3D) AD skin model by immunohistochemical study and quantitative polymerase chain reaction. In the 3D AD skin model, which was generated by a stimulation of recombinant IL-4 and IL-13, the expression of FLG, FLG2, HRNR and TCHH was decreased, while that of RPTN was increased in comparison to the 3D control skin. In the FLG knockdown (KD) 3D skin model, which was generated using FLG siRNA, the expression of HRNR was increased. The expression of the other proteins did not differ to a statistically significant extent. The expression of fused-S100 type protein family members may differ in AD skin. This suggests that these proteins play different roles in the pathogenesis of AD.

The role of IL-4 derived from follicular helper T (TFH) cells and type 2 helper T (TH2) cells.

IL-4 is known to be the quintessential regulatory cytokine, playing a role in a vast number of immune and non-immune functions. This cytokine is commonly secreted by type 2 helper T (TH2) cells and follicular helper T (TFH) cells after antigenic sensitization. TH2 cells have been classically thought to be the major contributor to B-cell help as a source of IL-4 responsible for class-switch recombination to IgG1 in mice (IgG4 in humans) and to IgE in mice and humans. Recent in vivo observations have shown that IgE and IgG1 antibody responses are mainly controlled by IL-4-secreting TFH cells but not by classical TH2 cells. IL-4 is distinctively regulated in these two T-cell subsets by the GATA-3-mediated HS2 enhancer in TH2 cells and the Notch-mediated conserved non-coding sequence 2 (CNS-2) enhancer in TFH cells. Moreover, the IL-4 derived from TFH cells has an essential role in germinal center (GC) formation in the secondary lymphoid organs during humoral immune responses.

Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema.

Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity, and impaired innate host defense. One important aspect of innate airway epithelial host defense to nonmicrobial triggers is the secretion of alarmins such as IL-33 and activation of type 2 inflammation, which were previously found to depend on activation of the NADPH oxidase (NOX) homolog DUOX1, and redox-dependent signaling pathways that promote alarmin secretion. Here, we demonstrate that normal aging of C57BL/6J mice resulted in markedly decreased lung innate epithelial type 2 responses to exogenous triggers such as the airborne allergen Dermatophagoides pteronyssinus, which was associated with marked downregulation of DUOX1, as well as DUOX1-mediated redox-dependent signaling. DUOX1 deficiency was also found to accelerate age-related airspace enlargement and decline in lung function but did not consistently affect other features of lung aging such as senescence-associated inflammation. Intriguingly, observations of age-related DUOX1 downregulation and enhanced airspace enlargement due to DUOX1 deficiency in C57BL/6J mice, which lack a functional mitochondrial nicotinamide nucleotide transhydrogenase (NNT), were much less dramatic in C57BL/6NJ mice with normal NNT function, although the latter mice also displayed impaired innate epithelial injury responses with advancing age. Overall, our findings indicate a marked aging-dependent decline in (DUOX1-dependent) innate airway injury responses to external nonmicrobial triggers, but the impact of aging on DUOX1 downregulation and its significance for age-related senile emphysema development was variable between different C57BL6 substrains, possibly related to metabolic alterations due to differences in NNT function.

The magnitude of airway remodeling is not altered by distinct allergic inflammatory responses in BALB/c versus C57BL/6 mice but matrix composition differs.

Allergic airway inflammation is heterogeneous with variability in immune phenotypes observed across asthmatic patients. Inflammation has been thought to directly contribute to airway remodeling in asthma, but clinical data suggest that neutralizing type 2 cytokines does not necessarily alter disease pathogenesis. Here, we utilized C57BL/6 and BALB/c mice to investigate the development of allergic airway inflammation and remodeling. Exposure to an allergen cocktail for up to 8 weeks led to type 2 and type 17 inflammation, characterized by airway eosinophilia and neutrophilia and increased expression of chitinase-like proteins in both C57BL/6 and BALB/c mice. However, BALB/c mice developed much greater inflammatory responses than C57BL/6 mice, effects possibly explained by a failure to induce pathways that regulate and maintain T-cell activation in C57BL/6 mice, as shown by whole lung RNA transcript analysis. Allergen administration resulted in a similar degree of airway remodeling between mouse strains but with differences in collagen subtype composition. Increased collagen III was observed around the airways of C57BL/6 but not BALB/c mice while allergen-induced loss of basement membrane collagen IV was only observed in BALB/c mice. This study highlights a model of type 2/type 17 airway inflammation in mice whereby development of airway remodeling can occur in both BALB/c and C57BL/6 mice despite differences in immune response dynamics between strains. Importantly, compositional changes in the extracellular matrix between genetic strains of mice may help us better understand the relationships between lung function, remodeling and airway inflammation.

Possible involvement of type 2 cytokines in alloknesis in mouse models of menopause and dry skin.

Alloknesis, an abnormal itch sensation induced by innocuous stimuli, is a key phenomenon in the vicious itch-scratch cycle in patients with atopic dermatitis. Dry skin and pruritus, including alloknesis, are major health problems in peri- and post-menopausal women. We recently reported permeability barrier dysfunction in ovariectomized (OVX) mice-a model of menopause-and found that the dysfunction was related to dry skin. However, the mechanism of the itch remains unknown. Therefore, we examined touch- and pruritogen-evoked alloknesis and epidermal innervation in OVX mice and acetone, diethyl ether and water (AEW)-treated mice, for the experimental dry skin model. Both alloknesis and epidermal innervation were comparable in OVX and AEW mice. Neutralizing antibodies against IL-4 and IL-13 inhibited alloknesis in both OVX and AEW mice as early as 30 min after intradermal administration. Comparable values close to the measurement limit of IL-4 were found in the skin of HRT and Sham mice as well as AEW and the control mice, but the levels of IL-4 were within the measurement limit in OVX mice. We could not detect mRNAs of IL-4 or IL-13 in any groups of mice. On the other hand, the number of eosinophils and basophils was increased in OVX and AEW mice. These results suggest that impaired barrier function in cooperation with type 2 cytokines derived from eosinophils and basophils in the skin or with endogenous type 2 cytokine may trigger the development of alloknesis, and thus, these cytokines could be a therapeutic target for sensitive skin.

Role of type 2 innate lymphoid cell and its related cytokines in tumor immunity.

Type 2 innate lymphoid cells (ILC2s) have multiple functions that can respond to allergic diseases, parasite infection, metabolic homeostasis, tissue repair, and adipose metabolism homeostasis. In these diseases, ILC2s can be activated by various inflammatory cytokines released by damaged cells. Activated ILC2s produce different type 2 cytokines, including interleukin (IL)-4, IL-5, IL-9, and IL-13, which involved in the pathogenesis of many diseases. In recent years, the relationship between ILC2s and tumor diseases has attracted more and more attention. The role of ILC2s in tumor immunity depends on its surface molecules and cytokine context. This review aims to conclude tumorigenic and antitumorigenic roles of ILC2s, and the characters of ILC2s-related cytokines in tumor diseases to provide a comprehensive overview of the impact of ILC2s in tumor immunity.

Interleukin-16 aggravates ovalbumin-induced allergic inflammation by enhancing Th2 and Th17 cytokine production in a mouse model.

Asthma is a chronic inflammatory disease that involves a variety of cytokines and cells. Interleukin-16 (IL-16) is highly expressed during allergic airway inflammation and is involved in its development. However, its specific mechanism of action remains unclear. In the present study, we used an animal model of ovalbumin (OVA)-induced allergic asthma with mice harboring an IL-16 gene deletion to investigate the role of this cytokine in asthma, in addition to its underlying mechanism. Increased IL-16 expression was observed during OVA-induced asthma in C57BL/6J mice. However, when OVA was used to induce asthma in IL-16-/- mice, a diminished inflammatory reaction, decreased bronchoalveolar lavage fluid (BALF) eosinophil numbers, and the suppression of OVA-specific IgE levels in the serum and BALF were observed. The results also demonstrated decreased levels of T helper type 2 (Th2) and Th17 cytokines upon OVA-induced asthma in IL-16-/- mice. Hence, we confirmed that IL-16 enhances the lung allergic inflammatory response and suggest a mechanism possibly associated with the up-regulation of IgE and the promotion of Th2 and Th17 cytokine production. This work explored the mechanism underlying the regulation of IL-16 in asthma and provides a new target for the clinical treatment of asthma.

Endotypes of severe allergic asthma patients who clinically benefit from anti-IgE therapy.

BACKGROUND: Omalizumab, a recombinant monoclonal anti-IgE antibody, was developed for the treatment of severe allergic asthma. Not all these patients respond to omalizumab. OBJECTIVE: This study aimed to evaluate whether the proinflammatory cytokine profiles in the severe allergic asthma patients were different between who responded and nonresponded to omalizumab therapy. METHODS: A prospective study was conducted to examine type 2 cytokines and epithelium-derived cytokines in the bronchial tissues by immunohistochemistry, Western blot and PCR analysis among patients with severe allergic asthma before and after omalizumab therapy. RESULTS: Fourteen of 23 patients with unstable severe allergic asthma improved their asthma control after 4 months of omalizumab treatment (Responders), while nine failed to improve (Non-Responders). Most of Responders were type 2-high endotype (12/14) with upregulated expression of IL-33, IL-25 and TSLP in their bronchial tissues, while most of Non-Responders were type 2-low endotype (8/9). Repeated bronchoscopic biopsy was done in nine responders after omalizumab treatment and showed a decline in IL-13, IL-33, IL-25 and TSLP expression in the bronchial tissues. Among 14 Responders who continued omalizuamb treatments to a total 12 months, six patients achieved a well control of asthma (ACT ≥ 23), while eight patients required additional treatment for asthma symptoms and had more rhinosinusitis comorbidities and a mixed eosinophilic and neutrophilic inflammation in their bronchial tissues. CONCLUSION: Most of the severe allergic asthma patients who benefited from omalizumab treatment were IL-33, IL-25 and TSLP aggravated type 2-high endotype. Rhinosinusitis or with a mixed eosinophilic and neutrophilic airway inflammation should be evaluated in patients who partially responded to omalizumab treatment.

Advances in rhinitis and rhinosinusitis in 2015.

The last year has seen great progress in the understanding of upper airway disease and in its management. For allergic rhinitis, authors focused on the prediction of and effect on the natural course of disease. New evidence was published for the disease-modifying effect of allergen immunotherapy in terms of avoidance of new sensitizations and prevention of asthma in either randomized or real-life studies. Specifically, for patients with house dust mite allergies, which are often underestimated and difficult to diagnose, the efficacy of SQ house dust mite sublingual immunotherapy tablets has been demonstrated in patients with allergic rhinitis and asthma. For the first time, allergen immunotherapy significantly reduced asthma exacerbations. In patients with chronic rhinosinusitis, a novel endotyping approach purely based on T helper cell biomarkers has been developed and has shown clinical relevance through associations with asthma comorbidity and recurrence after surgery. Severe nasal polyposis with high risk for asthma comorbidity and disease recurrence is characterized by type 2 inflammatory patterns, including IgE antibodies to staphylococcal superantigens; several studies using biologic agents have targeted exactly this spectrum of mediators. This goes in parallel with new knowledge on even more type 2 mediators derived from epithelial cells, which will expand the number of possible candidates for innovative intervention.