Cytokines and their role in immune pathogenesis of allergy
DOI: 10.32364/2587-6821-2021-5-1-32-37
A.S. Simbirtsev
State Research Institute of Especially Purified Bioproducts, St. Petersburg, Russian Federation
Allergy is characterized by inadequate hyperimmune response to one or several antigens with the properties of allergens. A specific pattern of abnormal synthesis of some cytokines (principal molecular mediators of the initiation, development, and regulation of allergic inflammation) has an important pathogenic role in allergy.
In recent years, it is generally accepted that allergic disorders are accounted for by impaired immune regulation resulting from increased imbalanced activation of allergen-specific T helper 2 cell clones. Allergic type of immune response is currently referred to as type 2 immune response which normally provides humoral immunity, anthelmintic protection etc. However, pathological response results in allergy. Studies on immune pathogenesis of allergic disorders have improved our understanding of the role of altered synthesis of some cytokines (key mediators of allergic inflammation). Cytokines involved in the initiation and regulation of allergy are p roduced by epithelial cells, various subsets of leukocytes, innate lymphoid cells, and allergen-activated T helper cell clones. Analysis of the associations of the changes in immune reactivity and clinical manifestations has established pathogenic heterogeneity and identified asthma phenotypes and endotypes. These findings have provided a basis for more reasonable, successful, and personalized approach to biological anti-cytokine treatment for allergic disorders.
Keywords: allergy, cytokines, T helper cell clones, phenotype, asthma, anti-cytokine therapy.
For citation: Simbirtsev A.S. Cytokines and their role in immune pathogenesis of allergy. Russian Medical Inquiry. 2021;5(1):32–37. DOI: 10.32364/2587-6821-2021-5-1-32-37.
Background
Allergy is characterized by the inadequate hyperimmune response to one or several antigens with the properties of allergens and manifests with asthma, allergic rhinitis, atopic dermatitis, food allergy, anaphylaxis, and other conditions. The key factor of the immune pathogenesis of allergy is a specific variant of impaired synthesis of various cytokines, principal molecular mediators of the induction, development, and regulation of allergic inflammation. This is particularly true of cytokine synthesis by epithelial cells the first time they encounter allergens (at the initial stage of allergy) since subsequent events are determined by the spectrum of these mediators.
Synthesis of pro-allergic cytokines by epithelial cells
Following exposure to allergens, epithelial cells produce cytokines inducing inflammation, activating dendritic cells (DCs), and recruiting many types of leukocytes into the epithelial submucosal layer. The most important cytokines are thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 which determine a specific type of activation of DCs guiding the differentiation of allergen-activated T helper (Th) cells into Th2 and Th9. In addition, these three cytokines activate innate lymphoid cells type 2 (ILC2) resembling Th2 cells in cytokine production [1].
TSLP is a 17-kDa cytokine. In humans, major cells producing TSLP are epithelial cells of the skin, lungs, thymus, GI tract, endotheliocytes, neutrophils, macrophages, DCs, and mast cells. TSLP receptors are expressed in the thymus, liver, bone marrow, brain, and other organs. Human TSLP activates myeloid CD11c+ DCs but does not affect the functions of other antigen-presenting cells (APCs). The effects of TSLP on myeloid DCs include the activation of the expression of membrane molecules OX40L, CD40, CD80, and CD86 and the synthesis of chemokines CCL17 and CCL22. A common receptor for CCL17 and CCL22 (whose biological activity is to recruit Th2 cells) is CCR4. TSLP-activated human DCs prime CD4+ T cells to produce IL-4, IL-5, IL-5, and tumor necrosis factor (TNF) while IL-10 and IFN γ production is inhibited. TSLP may act directly on antigen-activated T cells thereby guiding their differentiation into Th2 cells and expression of the IL-4 gene (the mechanism of action of TSLP involves the activation of transcription factors JAK2 and STAT5) [2]. TSLP also induces the synthesis of pro-allergic cytokines by mast cells, basophils, ILC2, and some other cells. Recently, it was demonstrated that TSLP stimulates tissue sensory neurons and provokes itching (e.g., in atopic dermatitis) [3]. TSLP also induces the generation of T regulatory cells (Tregs) in the thymus and other tissues (e.g., intestinal submucosa) [4]. However, the role of this phenomenon in the regulation of allergic reactions remains unclear but is possibly associated with the autoregulation of excessive allergic inflammation.
Expression of TSLP is increased in many allergic diseases mediated by the activation of Th2 cells (e.g., atopic dermatitis and asthma) being correlated with the severity of clinical presentations of allergy [5]. Meanwhile, TSLP is involved in the regulation of various homeostatic functions including physiological differentiation of T cells in the thymus. This paradox has been explained after the discovery of two isoforms of TSLP: (1) the short isoform is constitutively expressed under the control of an individual promotor and regulates homeostatic functions in the thymus and GI tract; (2) the long isoform is expressed only in inflamed barrier tissues [6].
IL-25 (IL-17E) is a member of the IL-17 family but is different in its biological properties fr om key members of this family (IL-17A and IL-17F) determining Th17 cell functions. IL-25 is synthesized by CD4+ Th2 cells, alveolar macrophages, eosinophils, basophils, mast cells, and many subtypes of epithelial cells. IL-25 interacts with a heterodimer receptor complex composed of two subunits (IL-17RA and IL-17RB) expressed on T cells, DCs, macrophages, eosinophils, and ILC2. IL-25 is constitutively expressed by epithelial cells of the skin and lungs. However, in allergy (asthma, polypoid rhinosinusitis, etc.), its production is significantly higher [7]. Allergens and helminths enhance IL-25 production in the mucosae of various organs. In allergy, IL-25 stimulates functional activity of Th2 cells, NK T cells, DCs, eosinophils, ILC2, fibroblasts, and endotheliocytes and induces Th2 response [8].
IL-33, a member of the IL-1 family, regulates allergic inflammation via the activation of several key types of effector cells including eosinophils, basophils, mast cells, ILC2, and Th2 cells expressing its specific membrane receptor ST2 (IL1RL1) to stimulate MyD88- and IRAK-associated intracellular signaling pathways [9]. IL-33 induces ILC2 and Th2 cells to produce IL-4, IL-5, and IL-13. In addition, IL-33 mobilizes ILC2 precursors fr om the bone marrow [10]. Despite the structural similarity of IL-33 and its receptors and IL-1 family members, this cytokine is lacking anti-inflammatory activity (which is typical of other members of this family) but selectively stimulates humoral immunity by enhancing the functions of basophils and eosinophils and the synthesis of Th2 cytokines and increasing plasma levels of immunoglobulins. IL-33 is produced by epithelial, endothelial, and other cells [11]. Full-size IL-33 is biologically active but its cleavage with neutrophil and mast cell proteases additionally increases IL-33 activity [12]. Many allergens are proteases and contribute to the increased activity of IL-33 [13]. IL-33 (as IL-5) seems to be of crucial importance for the functioning of eosinophils since peripheral blood eosinophil counts are reduced in patients with IL-3 gene mutation. Moreover, these patients do not develop asthma [14]. The role of IL-33 in protective responses is to activate anti-helminthic immunity while its role in pathological conditions is to enhance allergic manifestations. Human genome-wide association studies have demonstrated that IL-33 and IL1RL1 genes are associated with asthma and eosinophilic esophagitis morbidity while IL-33 levels are higher in patients with asthma, atopic dermatitis, and anaphylactic shock [15, 16].
Therefore, the role of TSLP, IL-2, and IL-33 is to induce Th2- and ILC2-mediated inflammatory reactions resulting in the activation of eosinophils, basophils, and mast cells and the synthesis of histamine and other low-molecular mediators of tissue inflammation (which normally has a protective function). These cytokines are not merely epithelial alarmins involved in the epithelial response to various substances and regeneration after injuries but also stimulate exactly allergic inflammation in barrier tissues. TSLP, IL-25, and IL-33 are similar in their ability to enhance allergic inflammation in tissues. However, these cytokines are characterized by different kinetics of expression after contact with allergens and presumably somewhat different functions at various stages of allergic inflammation depending on dosage, exposure time, and type of allergy [17].
Th cell cytokines and their role in the regulation of Th2 response
It is generally accepted in recent years that allergic diseases are mediated by the impairments of immune regulation associated with the increased imbalanced activation of allergic-specific Th2 clones. The allergic variant of the immune response is now referred to as type 2 immune response that provides humoral immunity and protection against helminths and other pathogens in physiological conditions and allergy in pathological conditions. Immune mechanisms of the development of type 2 response involve activation of Th2 cells and ILC2, production of IgE by B cells, accumulation and activation of eosinophils, basophils, and mast cells. These processes are associated with the increased synthesis of pro-allergic cytokines (or type 2 response cytokines) IL-4, IL-5, IL-9, and IL-13. Normally, stimulation of Th2 cells activates humoral immunity that is required for the protection against a myriad of pathogens. However, in allergy, this activation acquires the features of pathological inflammation.
Among cytokines characterizing type 2 immune response, IL-4 being the key inductor of naïve Th0 cells into Th2 is the most important one. The biological activity of IL-13 is largely similar to that of IL-4 in stimulating B cell and monocyte/macrophage functions. Meanwhile, in humans, IL-13 does not affect T cells at all since T cells do not express their receptors. The major producers of IL-4 are activated Th2 cells, ILC2, basophils, mast cells, and, to a lesser degree, cytotoxic T cells, γ and δ T cells, eosinophils, and some other cells. The signal for IL-4 gene expression in T cells is their activation via T cell receptors in the presence of polarizing signals of differentiation into Th2 cells provided by TSLP, IL-33, and IL-4. One of the key biological properties of IL-4 is its ability to activate the proliferation and functional activity of B cells after their activation with a specific antigen (allergen). IL-4 induces the production of specific subtypes of antibodies (IgE and IgG4) by activated B cells. The mechanism of action of IL-4 is associated with Ig heavy chain class switch from IgM to IgE or IgG4.
IL-4 together with IL-10 are commonly referred to as pro-inflammatory cytokines. This misconception is based on their ability to prevent activation of Th1 and production of TNF and IFN γ thereby attenuating their immunostimulating effect. In many cases, the biological activity of IL-4 is regarded given inter-regulating relations of Th clones since, in addition to the stimulation of humoral immunity and allergy, IL-4 is one of the major negative regulators of cellular immunity. This effect of IL-4 is realized via preventing Th1 cytokine-mediated immune reactions (e.g., by inhibiting T cell and NK cell activation under the effect of IL-2). However, this phenomenon is manifested only in changing the balance of Th clone activation. IL-4 per se is a classic pleiotropic pro-inflammatory and pro-allergic cytokine with a wide-spectrum biological activity covering many cell types involved in innate and acquired immunity. IL-4 stimulates the functions of T and B cells, promotes differentiation of monocytes into macrophages, activates differentiation of the precursors of eosinophils, basophils, and mast cells, stimulates their proliferation and expression of CD23, enhances the production of oxygen-derived radicals by neutrophils and proliferation of fibroblasts.
IL-5 is synthesized by antigen-activated CD4+ T cells (Th2), usually in parallel with IL-4, but the expression of these genes is regulated independently. IL-5 is the major growth and differentiation factor of eosinophils. In asthma, IL-5 provides the mobilization of eosinophils from the bone marrow and, in synergy with eotaxin, attracts these cells in lung tissue. However, an isolated increase in eosinophil count does not result in disease until other factors provoking their degranulation appear [18].
IL-9 also contributes to the development of status asthmaticus. This cytokine increases basophil count in lung tissue and initiates mucus hypersecretion by airway epithelium. IL-9 is a growth factor produced by Th cells after antigen encounter that enhances proliferation of mast cells and all subsets of T cells. IL-9 was long considered a Th2 cell product. However, a specific CD4+ Th cell clone (referred to as Th9 cells) was later recognized as a key producer of this cytokine. Th9 cells differentiate from Th0 cells under the effect of transforming growth factor β (TGF-β) and IL-4 or from Th2 cells which lose their property to produce transcription factor GATA-3 and cytokines (IL-4, IL-5, and IL-13). In asthma, an increase in both IL-9 levels in lavage and Th9/Th1 ratio was reported [19].
The current hypothesis of immune pathogenesis of allergy based on impaired activation of Th cells suggests that Th2 cells and Th9 cells are predominant cell subtypes in asthma while Th1-mediated response is inadequate. However, recent advances in exploring the functions of other Th cell clones (Тh17, Тh22, and Treg) have shaped a more complex pattern of allergic inflammation [20]. Thus, IFN γ (a Th1 cytokine) has a dual role in the immune pathogenesis of asthma, i.e., stimulation and inhibition of allergic inflammation depending on its phase and severity.
Th17 cells are also involved in the development of allergy through the production of IL-17 family cytokines that stimulate inflammation via activating the functions of various subtypes of leukocytes (mainly neutrophils) and recruiting many cell types into lung tissue due to the induction of chemokine synthesis. Activation of Th17 cells is associated with T2-low asthma characterized by the increase in neutrophil count rather than eosinophil count. The involvement of Th17 cells in the pathogenesis of allergy is supported by studies in patients with asthma. The levels of IL-17A and other cytokines in bronchial mucus and peripheral blood are higher in asthma being correlated with the severity of disease presentations [21].
Certainly, there are several levels of control over the excessive activation of inflammation to protect self-tissues from damage both in response to pathogens and the development of allergic reactions. Immunoregulatory and immunosuppressive cytokines (including TGF-β, IL-10, IL-27, IL-35, and IL-37) are responsible for this control [22]. They are mainly produced by Tregs and, in part, Th2 cells as well as some other cells. The role of immunoregulatory cytokines is to maintain the balance during the development of allergic reactions and to lim it their pathological effects resulting in tissue damage and severe clinical manifestations. The disruption of this balance is a possible cause of allergy.
Therefore, different Th clones contribute to the development of allergy. However, the principal mediators of the induction and further progression of allergic inflammation in tissues are Th2 cells. Two major factors promote differentiation into Th2 cells: (1) the nature of antigen belonging to allergens (molecules with diverse structure but similar in inducing allergy) and (2) genetic traits of a person.
The role of innate lymphoid cells type 2 (ILC2) in the regulation of allergic reactions
ILC2 belonging to the innate immune system are one of the major participants of allergic reactions in various organs. There is a strong focus on these cells as analogs or peculiar doppelgangers of Th2 cells producing IL-4, IL-5, IL-9, IL-13, and amphiregulin in response to TSLP, IL25, and IL-33 [23–25]. This is the reason why the term "type 2 immune response" (previously referred to as Th2 response) was adopted. Additional subpopulations of ILC2 are distinguished based on their response to IL-25 and IL-33. Resting cells (natural ILC2/nILC2) respond to IL-33 while inflammatory ILC2 (iILC2) respond to IL-25 [26]. In addition, a specific ILC2 population produces IL-10 [27]. In normal conditions, these cells possibly lim it the excessive synthesis of pro-inflammatory cytokines in response to parasites.
ILC2 are involved in the immune pathogenesis of allergic rhinitis. A myriad of these cells is found in nasal polyps. Their number increases in the peripheral blood, and these cells appear in the nasal mucosa in allergic rhinitis. Meanwhile, successful allergen-specific immunotherapy reduces ILC2 counts [28, 29]. Anti-cytokine treatment using anti-IL-5 monoclonal antibodies provides a good therapeutic effect in polypoid rhinosinusitis [30]. ILC2 are important components of asthma pathogenesis. In asthma, increased ILC2 count in the peripheral blood, activation of ILC2 in lung tissue, and extensive production of cytokines typical for type 2 immune response are reported [31]. In particular, ILC2 produce IL-13 that stimulates the migration of activated DCs in drainage lymph nodes to induce Th2 cell differentiation [32]. In asthma, allergen encounter dramatically increases the levels and activation of ILC2 producing IL-5 and IL-13 [33]. ILC2 and IL-33 levels in the bronchoalveolar lavage correlate with asthma severity [34].
Asthma phenotyping is a way to personalize therapy
Asthma is a chronic immune-mediated inflammatory disease of the respiratory tract manifested by airway hypersensitivity, mucus hypersecretion, and progressive bronchial obstruction. Asthma results from allergic inflammation that involves eosinophils, basophils, mast cells, neutrophils, and various subtypes of T and B cells [35]. Previously, asthma was considered an allergic disorder associated with Th2-like inflammation and the production of IL4, IL-5, IL-9, and IL-13 (type 2 inflammation) that normally provide mucosal protection of barrier tissues. Asthma is currently classified into phenotypes and endotypes as reported by A.D. Ado and G.B. Fedoseev as early as in the 1970s.
According to the GINA-2019, asthma is now regarded as a heterogeneous condition. The most common phenotypes are allergic asthma, non-allergic asthma, adult-onset asthma, asthma with fixed airflow obstruction, and obese asthma. In general, asthma is classified into two large phenotypes: (1) type 2 (or T2-high) asthma is characterized by type 2 inflammation and occurs in 50-70% of patients, and (2) non-T2 (or T2-low) asthma.
From the immunological viewpoint, this division is based on the level of activation of mainly Th2 cells and ILC2 and the production of their cytokines. T2-high asthma with a high level of T2 activation is more common in patients with allergic asthma and is characterized by eosinophilic inflammation, eosinophilia, increased lavage and blood levels of IL-4, IL-5, and IL-13, high mast cell count, and increased expression of periostin in lung tissue. The most relevant biomarkers of this phenotype are increased plasma levels of IgE, eosinophil count in the bronchoalveolar lavage and peripheral blood, and fractional exhaled nitric oxide (FeNO) in breath [36]. In T2-low asthma, the production of IL-4, IL-5, and IL-13 is not as high. Neutrophilic or polygranulocytic inflammation presumably associated with Th1 and Th17 cell activation is typical of T2-low asthma. In addition, asthma is divided into subtypes based on the age of onset, body mass index, smoking, plasma IgE levels, etc. [36, 37].
Since cytokines are the principal mediators of allergic inflammation, there are attempts to address the balance between endogenic cytokines in allergy using anti-cytokine biologics. Several anti-cytokine biologics (preparations of monoclonal antibodies/mAbs) are currently approved for asthma, e.g., dupilumab (mAb against the IL-4/IL-13 receptor alpha subunit), mepolizumab and reslizumab (mAbs against IL-5), and benralizumab (mAb against the IL-5 receptor alpha subunit). Biological therapy with mAbs improves asthma control and reduces the severity of clinical presentations and steroid dependence [36, 38]. Studies on anti-cytokine therapy against cytokines stimulating neutrophilic granulocytes (IL-8, IL-17, IL-23), anti-inflammatory cytokines (TNF, IL-6, IL-1), cytokines regulating early steps of allergic inflammation (TSLP, IL-25, IL-33), etc. in asthma currently undergo [38].
mAbs against Th2 cytokines failed to demonstrate the desired efficacy at the first stages of clinical trials. A new wave of interest in anti-cytokines for asthma using mAbs against Th2 and Th9 cytokines has emerged as a result of the recognition of the heterogeneity of this disease and a widespread classification of asthma into phenotypes. Most treatment approaches to asthma using anti-cytokines are designed for T2-high asthma since this phenotype is characterized by more clear treatment response criteria, i.e., levels of biomarkers (eosinophils, IL-4, IL-5, IL-13). Polygranulocytic inflammation in T2-low asthma is hard to assess. These patients better respond to bronchodilators and steroids while currently available therapies against Th2 cytokines are less effective [37].
Asthma classification by phenotypes and endotypes significantly improved treatment outcomes using mAbs against Th2 cytokines. Thus, mAbs against Il-4 are ineffective in asthma in general but clinically effective in eosinophilic asthma and patients with inhaled steroid withdrawal. This therapy reduces IgE levels, eosinophil entry into the lung, inflammation, and lung remodeling. mAbs against IL-13 are also ineffective in asthma in general and effective only in patients with high levels of IL-13 in lavage. mAbs against IL-5 (reslizumab) and its receptor (benralizumab) reduce eosinophilia without any clinical efficacy in asthma in general but are effective in frequent exacerbations and increased eosinophil counts in the airways. mAbs against IL-9 are moderately effective in asthma in general and more effective in exercise-induced bronchoconstriction [39].
Conclusions
The analysis of treatment outcomes given asthma classification by phenotypes demonstrates a much higher efficacy of anti-cytokine biologics. Blocking endogenic Th2 and Th9 cytokines provides a therapeutic effect in asthma. When prescribing anti-cytokines, asthma should be classified by phenotypes and endotypes as this provides clear perspectives to switch to fully personalized asthma treatment.
About the author:
Andrey S. Simbirtsev — Doct. of Sci. (Med.), Professor, Corresponding member of RAS, chief researcher, State Research Institute of Especially Purified Bioproducts; 7, Pudozhskaya str., St. Petersburg, 197110, Russian Federation; ORCID iD 0000-0001-6779-7761.
Contact information: Andrey S. Simbirtsev, e-mail: a.s.simbirtsev@hpb.spb.ru. Financial Disclosure: author has no any financial or property interest in any material or method mentioned. There is no conflict of interests. Received 03.06.2020, revised 01.07.2020, accepted 20.07.2020.
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