Clinical and Pathophysiological Tangles Between Allergy and Autoimmunity: Deconstructing an Old Dichotomic Paradigm

Abstract

Allergic and autoimmune disorders are characterised by dysregulation of the immune responses to otherwise inert environmental substances and autoantigens, leading to inflammation and tissue damage. Their incidence has constantly increased in the last decades, and their co-occurrence defies current standards in patient care. For years, allergy and autoimmunity have been considered opposite conditions, with IgE and Th2 lymphocytes cascade driving canonical allergic manifestations and Th1/Th17-related pathways accounting for autoimmunity. Conversely, growing evidence suggests that these conditions not only share some common inciting triggers but also are subtended by overlapping pathogenic pathways. Permissive genetic backgrounds, along with epithelial barrier damage and changes in the microbiome, are now appreciated as common risk factors for both allergy and autoimmunity. Eosinophils and mast cells, along with autoreactive IgE, are emerging players in triggering and sustaining autoimmunity, while pharmacological modulation of B cells and Th17 responses has provided novel clues to the pathophysiology of allergy. By combining clinical and therapeutic evidence with data from mechanistic studies, this review provides a state-of-the-art update on the complex interplay between allergy and autoimmunity, deconstructing old dichotomic paradigms and offering potential clues for future research.

Introduction

Definitions

For the purposes of this review, we will use the following definitions:

• Allergy as any “hypersensitivity reaction initiated by immunological mechanisms”, thus encompassing “classic” immediate-type reactions sustained by IgE responses and other types of immediate- and delayed-type hypersensitivity, in line with the guidelines of the World Allergy Organization/European Academy of Allergy and Clinical Immunology (WAO/EAACI) consensus definitions [1].

• Autoinflammatory diseases: conditions primarily caused by a defect or a dysregulation of the innate immune system [2, 3]

• Allergen: sensu stricto, a harmless substance that is capable of stimulating a type-I hypersensitivity reaction in atopic individuals through immunoglobulin E responses. In line with the above definition of allergy, any harmless exogenous trigger of a hypersensitivity reaction [1]

• Autoallergy: autoimmunity accompanying an atopic disease, with antigen-specific IgE that can activate the innate immune system [4, 5]

Epidemiological Background

Autoimmune disorders and allergy are chronic immune–mediated diseases characterised by inflammatory responses towards antigens: allergy results from an exaggerated immune response to foreign antigens (allergens), whereas autoimmune diseases are characterised by a pathological response to internal antigens (autoantigens). These two conditions share some similarities and also some differences and their relationship has been broadly discussed.

Allergic diseases constitute a broad set of pathophysiologically and clinically variegated conditions affecting a large share of the general population. Despite the chance of amelioration during adulthood, most of them have a profound impact on long-term prognosis, quality of life, and productivity with increased direct and indirect healthcare costs [6]. In fact, the severity of allergy symptoms can range from seasonal mucocutaneous manifestations and rhinitis to life-threatening anaphylaxis and severe asthma. In recent decades, there has been a significant increase in the incidence of allergic disorders, with prevalence reported in between 10 and 30% in developed nations [7–10]. For example, in 2021, an American survey reported that nearly one-third of adults aged 18 and over had a diagnosed seasonal allergy, eczema, or food allergy [11]. Seasonal allergy was the most common, with about one-quarter (25.7%) of adults being affected, followed by eczema (7.3%) and food allergy (6.2%) [11]. Moreover, it was recently estimated that asthma affects 2.4–4.3% of the global population [6]. Furthermore, although worldwide asthma mortality has significantly decreased over the past decades, it has been estimated that approximately 250,000 people die prematurely of asthma each year [12–14]. The increase in asthma survival may be attributed to the introduction of inhaled corticosteroids over the past 20–30 years [15]. Several risk factors may explain the high number of near-fatal or fatal asthma attacks: comorbidities such as systemic vasculitis, a history of severe asthma with previous near-fatal asthma attacks, inappropriate use of anti-asthmatic medications, and poor compliance [16–19]. The other possibly life-threatening situation is anaphylaxis: worldwide data are heterogeneous, but it has been estimated that 0.3–5% of the population will experience anaphylaxis [20, 21]. Fatal outcomes are quite rare, with a mortality rate of less than one death per million people per year [21]: drugs are usually the most commonly reported cause of fatal anaphylaxis, with an estimated rate of 0.05–0.51 per million people per year, followed by food-induced anaphylaxis (0.03–0.32) and venom-induced anaphylaxis (0.09–0.13) [22–24].

Similar to allergies, autoimmune diseases are a heterogeneous group of conditions with a wide variety of clinical manifestations. In addition, they share with allergy the preferential targeting of young women [25], along with common musculoskeletal and mucocutaneous manifestations [26, 27]. In parallel to the epidemiological trends observed in allergy, autoimmune diseases also showed an increase in incidence during the last decades [28, 29]. It has been reported that autoimmune diseases affect nearly 10% of the global population [30, 31]. However, the umbrella term of autoimmune diseases includes common conditions such as organ autoimmune diseases (for example autoimmune diabetes) as well as less frequent diseases, such as systemic autoimmune diseases (SAID). Within the SAID subgroup, rheumatoid arthritis (RA) is the most frequent (with a worldwide prevalence between 0.46 and 2%) [32, 33]. In contrast, other conditions, such as systemic lupus erythematosus (SLE) or systemic vasculitis have a lower prevalence and are frequently included among “rare diseases”, even if there is no single, widely accepted definition for rare diseases [34]. Despite recent advances in treatments and management, morbidity and mortality remain higher in patients with SAID than in age- and sex-matched controls [35, 36]. The causes of death may reflect disease-related irreversible organ damage, complications linked to chronic inflammation, and side effects of treatments. For instance, several SAID are linked to enhanced atherosclerosis due to the increased prevalence of traditional cardiovascular risk factors but also to disease-related risk factors, and consequently, higher cardiovascular morbidity and mortality rates [37].

In summary, both allergic and autoimmune diseases showed a recent rise in their incidence, with persistent higher prevalence in industrialised countries and a potential acceleration in the detection of new cases in developing countries, parallels advances in urbanization and industrialization [38]. This raises questions about what might explain their development. Several hypotheses have been formulated, even if the exact pathogenetic pathways still need to be completely understood.

The relevance of this topic is underlined by the presence of several interdisciplinary ongoing initiatives, as the European Network for IgE-Mediated Autoimmunity and Autoallergy (ENIGMA) consortium, a network created with the aim to evaluate and address several unmet needs in IgE-mediated autoimmunity and autoallergy [4].

From Old to Novel General Paradigms

Th1/Th2 Dichotomy

The Th1/Th2 paradigm has historically been the foundation to classify immune responses and their aberrations. This hypothesis was established in the late eighties following the discovery that helper T cells could be categorised by distinct cytokine signatures [39, 40]. Intracellular pathogens polarise CD4 + cells towards to the Th1 lineage with the production of interferons, TNF-β, and subsequent cytotoxic effector mechanisms such as macrophage activation and lysosome acidification and have a crucial role in the pathogenesis of autoimmune diseases [41, 42]. Conversely, extracellular pathogens promote differentiation into Th2 cells that lead to the release of IL-4, IL-5, and IL-13 and play major pathogenic roles in allergic diseases [42]. Moreover, specific cytokines produced by Th1 and Th2 cells exert reciprocal inhibitory effects, and this has provided support to the hypothesis that these disorders might be mutually exclusive [43]. However, in recent years, an increasing amount of evidence has emerged to support the limits of this paradigm: countless new helper T cell subsets have been described [44, 45]. Furthermore, the ability of T cells to switch from one functional phenotype to another and to redifferentiate in vivo and in vitro has been demonstrated [46, 47], and examples of beneficial mixed-type immune responses are available [48, 49].

Novel Hypotheses

A first clue towards a unified view of immune-mediated disorders came with the advent and subsequent development of the “hygiene hypothesis”. This principle was first proposed by Strachan in 1989 and it predicates that the occurrence of prenatal and childhood infections may reduce the incidence of allergic diseases. Therefore, the reduction of infectious pressure linked to modern lifestyle would diminish this protective role, leading to immune system dysregulation [50]. This hypothesis was initially described for atopic dermatitis then extended to other allergic diseases [51] and subsequently for some autoimmune diseases [52, 53]. More recently, the hygiene hypothesis was reformulated as the “old friends/microbiota hypothesis” by Rook [54]: the reduction of non-pathogenic commensal microorganisms might lead to poorer control over host inflammatory responses.

Another proposed hypothesis is the “barrier hypothesis”: several exogenous substances as allergens, cleaning products, microbes, and cigarette smoke can cause alterations of the epithelial barrier integrity, with transepithelial translocation of opportunistic microbes and microbial dysbiosis, possibly leading to a vicious circle promoting both inflammation and barrier damage [55]. In fact, the role of mucosal barrier dysfunction has been reported in both allergy and autoimmune diseases [56–58]: local epithelial barrier damage in the affected tissues is a hallmark of several chronic conditions such as asthma, atopic dermatitis, and allergic rhinitis. In patients with atopic dermatitis and several allergic diseases, gene mutations in filaggrin can be found impairing normal structure of the skin [59, 60]. Therefore, in patients with a genetic predisposition, early exposure to harmful substances may be relevant to the development of allergen sensitization. For several autoimmune conditions such as chronic arthritis and SLE, activation of pathogenic immune cells in mucosal tissues with damaged barriers and subsequent migration to the affected organ have been demonstrated [61–63]. In a mouse model of RA, this has been specifically observed for effector T cells migrating to affected joints [63].

Further developments are still ongoing to refine the definition of the determinants of loss of immune tolerance and chronicisation of aberrant allo- and auto-antigen sensitisation [64]. Despite significant achievements in terms of our understanding of these pathophysiological processes and our ability to deflect their course, autoimmune and allergic disorders still constitute a major cause of morbidity and clinical complexity for a large number of patients. In this review, we aim to provide a comprehensive summary of the most significant evidence supporting the existence of clinical and pathophysiological tangles linking allergy to autoimmunity and of current and potentially future strategies for innovative treatments tackling immune dysfunction in patients with both types of conditions.

Pathophysiological Insights

Allergy and autoimmunity rise from dysregulation of the immune system. Many molecular and cellular actors have been reported to participate in both allergic inflammation and autoimmune disorders (Fig. 1). Herein, we review the possible role and interactions between classic mediators of allergic reactions and autoimmune responses, cytokines, chemokines, endothelium, and cellular types potentially involved in both conditions.

Fig. 1.

Allergic and autoimmune disorders are the results of a complex interplay between innate and adaptative immune responses. In response to several favouring factors, such as allergen exposure, epithelial damage and/or altered epithelial barrier integrity or genetic susceptibility, innate and/or adaptative immunity may be activated. In this context, a core network of cellular and humoral innate immune mediators might be identified, which encompasses basophils/mast cells, eosinophils, neutrophils, macrophages, and a set of cascades of soluble molecules, including the complement system, the bradykinin system, and the coagulation cascade. Innate immune cells can be activated by epithelial-derived alarmins and inflammatory cytokines, such as IL-18, IL-25, and IL-33 or thymic stromal lymphopoietin (TSLP) and are able to mutually enhance their inflammatory activity through pro-inflammatory mediators, such as TNF-α, IL-8, IL-17, prostaglandins, and leukotrienes (blue arrows). Neutrophils directly kill target cells through phagocytosis and interact with other immune cells through release of pro-inflammatory cytokines and extracellular traps. Eosinophils promote allergic inflammation through degranulation and release of several mediators (such as major basic protein, MBP or eosinophilic peroxidase, EPO) contribute to antibody-dependent cell cytotoxicity and increase B-cell activity with the production of APRIL and IL-6 (yellow arrows). In addition, they are endowed with the ability to generate extracellular traps. Innate immune cells can contribute to the activation of the coagulation cascade through several mechanisms, such as the expression of tissue factor (TF) and the release of inflammatory mediators and digestive enzymes. Factors contributing to the activation of the coagulation cascade, in turn, are in part shared with the set of potential triggers of the bradykinin system and the complement system. These latter mediators are involved in tissue damage and further enhancement of innate immune cell activation. Depending on the type of stimulus and the environmental cytokine milieu, naive T lymphocytes differentiate into different subsets (grey bold arrows). T-cell differentiation follows antigen presentation by myeloid dendritic cells (mDC) along with B cells and other types of antigen-presenting cells, which, in turn, can be boosted by exposure to type I interferon. Polarisation into Th2, Th9, and Th22 cells promotes B cell–dependent humoral responses, including IgG and IgE production. IgG can cause tissue damage or dysfunction directly, through the activation of complement cascade or through the interaction with specific FcγRs (I, II, III) expressed on mast cells, basophils, macrophages, and neutrophils (green arrows), whereas IgE interacts with FcϵR located on mast cells and basophils and regulates cells differentiation, survival, and maturation (orange arrows), affecting both allergic and autoimmune mechanisms of inflammation. IL4 and IL13 play a crucial role in B cell–dependent responses. Type 2 innate lymphoid cells (ILC2), stimulated by epithelium-derived cytokines IL-25, IL-33, and TSLP, represent the main source of IL-13. IL-4 and IL-13, produced by ILC2, Th2, and Th22 cells, promote the maturation of B lymphocytes to plasma cells (brown arrows) and IgE isotype switching. Th2 cells also release IL-5 (light orange arrows), which is crucial for the recruitment and activation of eosinophils (as abovementioned). The right-hand side of the figure depicts cell-mediated responses orchestrated by Th1, Th17, and Th22 cells and dominated by the downstream biological activity of CD8 + T cells, natural killer (NK) cells, macrophages, and neutrophils. TNF-α (red arrows), interferon gamma (IFN-γ), and IL-17 (light pink arrows) are key inflammatory mediators in this context. Tissue-derived signals (black arrows), such as IL1-beta or IL-23, are able to trigger the release of IL-17 by macrophages, NK cells, and γδ-T lymphocytes along with ILC-3 (light pink arrows). When IL-1, IL-6, IL-23, and TGF-beta dominate the inflammatory environment, naive T cells develop (grey bold arrows) into Th17 cells, which also produce IL-17 promoting neutrophil and macrophage activation. In a similar way, ILC-1, stimulated by IL-12, release IFN-gamma, which can directly activate Th1 cells but also macrophages (dark pink arrows) and promote killing activity. TNF-alpha, released by Th1 and Th22 cells, promotes the killing activity of macrophages and NK cells along with cytotoxic T cells (red arrows). Upon stimulation by IL-6 and TNF-alpha, naive T cells preferentially polarise towards Th22 cells, which can secrete both IL-13 and IL-22, but also TNF-alpha but not IL-17 or IL-4. Finally, T reg cells limit inflammatory responses through the secretion of immunosuppressive cytokines such as TGF-β and IL-10, thus inhibiting CD4⁺ and CD8⁺ effector T cells, NK cells, and antigen-presenting cells. Independent of which pathway becomes preferentially activated, both allergic and autoimmune disorders lead to various degrees of inflammation, fibrosis, hypercoagulable state, vascular inflammation, tissue remodelling, ultimately ending in tissue damage and cell death (thick black arrows). APRIL, a proliferation-inducing ligand; Ba, basophil; ECP, eosinophilic cationic protein; EDN, eosinophil-derived neurotoxin; Eo, eosinophil; EPO, eosinophil peroxidase; IFN-I, interferon type I; ILC, innate lymphoid cell; mDC, myeloid dendritic cells; Mc, mast-cell; MΦ, macrophage; MBP, major basic protein; NK, natural killer cells; PGD2, prostaglandin; PRR, pattern recognition receptor; pDC, plasmacytoid dendritic cell; ROS, reactive oxygen species; TF, tissue factor; NETs, neutrophil extracellular traps

B-Cell Responses

Loss of Tolerance

Aberrant B-cell responses are implicated in a multitude of immune-mediated disorders ranging from immune-deficiency to allergy and autoimmunity. A key step in the development of autoimmunity is the breakdown of immune tolerance with proliferation of self-reactive B cells and production of high affinity autoantibodies [65]. Follicular helper T cells (Tfh, a distinct subset of CD4 + T lymphocytes expressing surface markers CXCR5, ICOS, and PD-1, cytokine IL-21, and transcription factor Bcl6) are pivotal for the generation of germinal centre reactions, follicular B cells’ maturation into antibody-secreting cells, and development of memory B cells [65–69]. Follicular regulatory T cells (Tfr) have been also identified as a specialised subset of T regulatory (Treg) cells, which can negatively regulate germinal centre responses [70]. These cells share phenotypic markers with conventional Treg cells and Tfh [65, 71, 72] and can be subclassified into circulating (CD4 + CXCR5 + Foxp3 + T cells) and resident (expressing CXCR5, ICOS, and PD-1) Tfr [65, 73, 74]. Tfh and Tfr cells count and functions are dysregulated in several autoimmune disease such as SLE, RA, primary Sjögren’s syndrome (SjS), and other rheumatic conditions contributing to pathogenic autoantibody production [66, 67, 69, 75–80]. Indeed, optimal control of proliferation and function of these cells is critical for regulating the humoral response against thymus-dependent antigens and to prevent self-reactivity [66]. In the germinal centres, Tfh operate a stringent selection on B cells to avoid the generation of self-reactive specificities, providing positive (e.g., CD40L signals) and negative selection signals (e.g., CD95/FAS signals or cytokines such as IL-21 and IL-4) [81–83]. This way, only selected B cells will join the bone marrow-homing plasma cells and memory B cells [81]. Receptor editing, clonal deletion, and anergy are other mechanisms contributing to the removal of self-reactive lymphocytes from the circulating repertoire [84]. Impaired central and peripheral tolerance to exogenous or self-antigens (that is autoantigens or allergens) is involved in pathogenic autoantibody production. According to a standard pathophysiological paradigm, IgE-mediated responses constitute the pathogenic hallmark of stricto sensu allergic responses, while other immunoglobulin classes are associated with autoimmunity. Specifically, IgE bound to innocent exogenous antigens (that is allergens) are known to activate basophils/mast cells to initiate immediate-type hypersensitivity reactions with downstream histamine and leukotriene release, along with later eosinophil recruitment at sites of stimulation. IgG, IgM, and IgA are usually regarded as major autoimmunity triggers by means of antigen neutralisation/activation, immune complex formation with complement activation (and eventual innate immune cell recruitment and tissue injury) or by activation of professional phagocytes leading to cell cytotoxicity. Novel evidence is progressively erasing the boundaries of the IgE vs. IgG, IgA, and IgM dichotomy, paving the way to more complex pathophysiological models.

Aberrant IgG Responses in Allergy

IgG from patients with atopic dermatitis are involved in the activation of peripheral and thymic lymphocytes [85–88]. To this regard, an interesting article by Rodrigues de Sousa et al. [87] showed that these antibodies can stimulate the neonatal thymic maturation of Th22 and cutaneous lymphocyte–associated antigen-positive CD4 + T cells through direct idiotypic interactions of IgG with thymic T cells. The same research group showed that IgG from patients with atopic dermatitis modulate intrathymic nonatopic γδT cells and their production of IL-17 and IL-22, and demonstrates epigenetic implications mediated by miRNAs [87].

Despite being best known as markers of effective desensitisation to or inborn protection from allergens [89, 90], IgG, IgM and IgA may also promote non-classical allergic responses, including anaphylaxis [91]. In fact, human mast cells are able to bind and respond to IgG and IgG-based immune complexes through FcγRI and FcγRII [92, 93]. The extent of neutrophil activation after engagement by allergen-reactive IgG is also correlated to anaphylaxis severity [94]. FcγR-independent activation of pathways conventionally attributed to a Th2 profile may also occur during IgG/basophil interactions and account for the antagonising effect of intravenous immunoglobulins (IVIG) on autoimmune phenomena [95]. Conversely, IgG-induced activation of the complement system can further contribute to non-IgE-mediated hypersensitivity reactions thanks to the expression of anaphylotoxin receptors on myeloid and endothelial cells [96]. In turn, dysregulated complement activation might be enhanced by coexistence of aberrations in bradykinin system regulation and can contribute to atypical complications of hypersensitivity reactions such as thromboembolic events [97]. In the setting of chronic spontaneous urticaria (CSU), IgG autoantibodies against IgE or high affinity Fc epsilon receptor I (FcεRI) favour basophil and mast cell degranulation [98, 99]. In CSU, this mechanism is referred to as type II autoimmunity, in contrast to IgE-mediated type I autoallergic responses.

Aberrant IgE Responses in Autoimmunity

Besides exogenous antigens, IgE are in fact also able to bind to self-antigens and contribute to the long-term maintenance of inflammation in autoimmune and allergic disorders [5, 100]. Autoreactive IgE in CSU are an excellent example of a common ground between some autoimmune disease and allergy. IgE autoantibodies targeting thyroid antigens such as thyroid peroxidase (TPO), and able induce basophil degranulation, have been described in patients with CSU [101–103]. In addition, in vitro experiments show that TPO induces basophil activation (measured as CD203c expression) in blood samples of patients with aspirin intolerance associated with urticaria and [102] with CSU [104], suggesting a direct role of anti-TPO IgE to in effector cells.

Extensive clinical overlap between SLE and IgE-related manifestations (see below) provides a strong clue to the existence of significant similarities between mechanisms of allo- and auto-reactive hypersensitivity. Indeed, allergy and SLE share some pathophysiological mechanisms, such as B-cell hyperactivity and the production of different types of immunoglobulins [105, 106]. In the 1980s, Diumenjo et al. [107] postulated that this was due to a higher level of hypersensitivity to exogenous antigens through cytotropic autoantibodies or through anaphylactoid products of complement activation. A few years later, Gruber et al. [108] found anti-IgE autoantibodies (IgM‒anti-IgE and IgG‒anti-IgE) in a significant number of patients with SLE and hypothesised that they might contribute to the pathogenesis of the vascular and joint lesions characterising this disease. In vitro studies have demonstrated that the capacity of activated pDCs to maintain Treg cell homeostasis is reduced by IgE-cross linking. Hereby, the use of anti-IgE therapy seems to be able to re-establishes pDCs function. Specifically, pretreatment of pDCs with omalizumab restores the capacity of pDCs to support the differentiation of CD4 + Foxp3 + Tregs. Conversely, anti-double-stranded DNA-specific IgE antibodies affect pDC release of interferon alpha (IFN-α), a key cytokine in SLE pathophysiology and a major target for therapeutic intervention [100, 108, 109]. More generally, consolidated evidence suggests that IgE may play a role in immune complex disease, promoting the release of vasoactive mediators from basophils and mast cells, which in turn facilitate the deposit of immune complexes in the glomeruli through increased vascular permeability [110]. Taken together, these findings might support further development of anti-IgE treatments in patients with systemic autoimmune diseases [111].

B-Cell Repertoire Landscape in Autoimmune and Allergic Disorders

In a recent study, Bashford-Rogers et al. analysed the B-cell repertoire of a heterogeneous set of immune-mediated diseases. They found that patients with SLE share with those with eosinophilic granulomatosis with polyangiitis (EGPA), a preferential isotype switch to IgE (while also retaining similarities with Crohn’s disease, Behçet’s disease, and IgA-vasculitis in terms of expansion of the IgA repertoire) and an expansion of Ig hypervariable regions, facilitating loss of tolerance [112]. Interestingly, the same authors also showed that EGPA, SLE, and Crohn’s disease also share the tendency to generate subpopulations of (allo/autoreactive) B cells characterised by disproportionate clonal expansion along with extensive diversification of the clonal progeny within the same population. These features might account for treatment resistance and progressive antigen/allergen spreading, as observed in these disorders [112].

Eosinophils, Basophils, and Mast Cells Beyond Allergy: Role in Autoimmunity

Eosinophils are pivotal cells in multiple pathological conditions, while they also participate in physiological processes, such as metabolism, tissue remodeling, microbiome regulation, and infection control. Eosinophil-mediated inflammation is involved in both allergic and autoimmune disease [113–116] and constitutes the core pathogenetic feature of EGPA [117], eosinophilic esophagitis [118], and other hypereosinophilic syndromes [119]. Consistent with this, clinical evidence shows that eosinophilia is a hallmark of or can transiently be observed in a multitude of immune-mediated disorders (see below). Eosinophils participate in organ damage through their capability to interact with both innate and adaptive immunity [120]. Indeed, eosinophils act through a large plethora of molecular mechanisms including degranulation, antibody-dependent cytotoxicity, modulation of adaptive response through antigen presentation, and promotion of B-cell activity [121–123]. In addition, eosinophils exhibit strong cytotoxic properties mediated by granule proteins. Among eosinophilic-derived mediators, the most relevant are (a) major basic protein (MBP), which can interfere with membrane permeability; (b) eosinophilic cationic protein (ECP), a ribonuclease; and (c) eosinophil peroxidase (EPO), which is involved in the production of reactive oxygen species (ROS) [121]. Through these broad biological activities, eosinophils are key mediators of tissue damage by means of tissue inflammation, fibrosis, vasculitis, and thrombosis [121–123]. In particular, there is convincing evidence supporting the procoagulant effects of eosinophils. In fact, eosinophils express tissue factor and procoagulant phospholipids and can activate factor XII, promoting thrombin genesis via the intrinsic pathway [124, 125]. In addition, eosinophils can contribute to platelet activation through MBP-enriched eosinophil extracellular DNA traps, further promoting thrombophilia [126, 127]. The surface expression of adhesion molecules on activated cells is possibly the dominant molecular mechanism involved in platelet-eosinophils interaction [128]. These cells can be activated through an eosinophil β1-integrin activation–dependent process and are capable of moving into the lung through a platelet P-selectin–mediated mechanism in animal models of allergic airways inflammation [129–131].

Basophils play a crucial role in allergic responses and hypersensitivity reactions; however, emerging evidence suggests that their role could be more complex in the whole immune network [132]. As an example, basophils participate in propagating certain autoimmune diseases [133]. Charles et al. [134] demonstrated that basophils and a Th2 environment could promote lupus nephritis. In mice lacking Lyn (a tyrosine kinase that negatively regulates B-cell activation), the authors found that hyperactive B-cells generate autoreactive IgE and IgE immune complexes, which, in turn, activate basophils through FcεRI (a high-affinity receptor for IgE antibodies) and drive their homing to secondary lymphoid organs [134]. By promoting Th2 differentiation through local release of IL4 and other mediators, basophils consolidate autoreactive B-cell differentiation and survival along with the release of autoantibodies. Eventually, Lyn-deficient mice develop lupus nephritis, a condition characterised by extensive deposition of immune complexes in the glomeruli [134]. Dependence of basophil-mediated accumulation of Tfh in secondary lymphoid organs on IL-4 and PD-L1 was further shown by Tchen et al. [78]. More recent evidence shows that constitutive basophil deficiency prevented pristane-induced lupus-like disease development by limiting autoantibody titers and renal damages [135]. In patients with SLE, autoreactive IgE levels have been related to increased activated basophil (CD203c +) counts, enhanced expression of markers of increased basophil migration abilities (CD62L, PTGDR-2, and CXCR4), and basopenia due to basophil accumulation in secondary lymphoid organs [136–139].

Mast cells produce a multitude of inflammatory mediators, such as tryptases, chymases, cytokines, prostaglandins, and leukotrienes, which have a modulating effect on both innate and adaptive immunity [140, 141]. The role of mast cells through the release of histamine and other mediators in response to IgE-FcεRI stimulation is well characterised in allergy [142]. Mast cells may also participate in autoimmunity, as suggested by the identification of these cells in the target tissue of patients with some autoimmune disorders [143]. For example, mast cells count and their mediator levels are found to be increased in the inflamed synovium in RA [144–146]. In addition, in bullous pemphigoid, mast cells are increased in the lesional skin, and their mediators have been found to be elevated in blister fluid [147, 148]. In patients with spondylarthritis, mast cells are significantly increased, being an important source of IL17, a pivotal mediator of inflammation in this condition [149]. In salivary glands of SjS, mast cells are increased and contribute fibrosis through the production of extracellular matrix proteins via TGFβ [150] and stimulating fibroblast chemotaxis in CCR7-positive cells through the release of CCL19 and CCL21 chemokine [151]. Finally, mast cells are increased in both the skin and esophagus of systemic sclerosis patients, where they express an inflammatory gene signature [152, 153]. In contrast to human studies, results from mouse models of autoimmune diseases with mast cell deficiency have shown conflicting results [143]. Some authors observed that KIT-dependent mast cell–deficient mice are protected from some autoimmune diseases (e.g., multiple sclerosis, RA, and autoimmune skin–blistering diseases), while more recent studies conducted on a new generation of KIT-independent mast cell–deficient strains did not show substantial participation of mast cells to autoimmunity [143]. This discrepancy in results is possibly due to the high heterogeneity and complexity of human autoimmune diseases, which is difficult to replicate in mice models. Therefore, further studies are required to elucidate the role of mast cells in autoimmunity.

Cytokines and Chemokines as a Potential Bridge Between Allergy and Autoimmunity

High serum levels of several cytokines have been correlated with both SAID and allergic conditions [109]. For example, in CSU, both type 1 and type 2 cytokines can be involved in the pathogenesis [109]. Grieco et al. [109] reported that patients with CSU display higher levels of IL-6 and IFN-α as compared to controls. Interestingly, these cytokines levels decreased after treatment with the anti-IgE monoclonal antibody omalizumab, followed by remission of CSU [109]. IFN-α and IL-6 are proinflammatory cytokines that are strongly related to autoimmunity. Most studies have emphasised a crucial role of IFN-α and other type I interferons in the pathogenesis of SLE and of a broader set of disorders termed interferonopathies [154]. Recent clinical trials with a type I interferon receptor antagonist have further proved the validity of this principle [155]. Nonetheless, an abnormal IFN-γ-related gene expression signature has also been found in SLE, especially in the initial and active stages of the disease, suggesting an active role of this cytokine in SLE pathogenesis [156]. Abnormal IFN-γ expression has also been found to correlate with the extent of tissue inflammation in other autoimmune diseases such as systemic sclerosis and SjS [157] and constitutes a key pathogenic driver of systemic inflammation in hemophagocytic lymphohistiocytosis, a life-threatening complication of multiple autoimmune disorders [158]. Mechanistically, IFN-γ affects the maturation and differentiation of dendritic cells and modulates their antigen processing and presentation abilities. Furthermore, it regulates CD8 + T-cell proliferation after antigen exposure [159] and promotes B-cell proliferation following primary antigen exposure [160, 161]. IFN-γ expression has historically been intended as a marker of allergic responses that are resolving or that are being effectively regulated [162]. For example, in patients with β-lactam-induced hypersensitivity serum IFN-γ is significantly lower than in healthy controls [163]. Furthermore, peripheral blood mononuclear cells of healthy subjects show detectable IFN-γ release in vitro after challenging with beta-lactam, despite no clinical evidence of immediate or delayed-type hypersensitivity [164]. Normal to reduced IFN-γ responsiveness has also been found in subjects with atopy [165], apparently supporting the notion that IFN-γ has no role in allergic responses. Nonetheless, evidence from other studies challenges this contention. A recent article by Yin et al. demonstrated that IFN-γ (and IL-17A) levels were higher in the saliva of children with food allergies compared to controls [161]. These results were in line with findings from other cohorts showing increased IFN-γ secretion, accumulation of IFN-γ-secreting cells, and a high expression level of IFN-γ mRNA in the duodenum of children with delayed-type cow’s milk allergy [166, 167]. High IFN-γ is also a well-known hallmark of inflamed skin in patients with atopic dermatitis [168]. Taken together, these data suggest that similar to its potential role in propagating tissue damage in autoimmunity, IFN-γ release might participate in local inflammation in a multitude of allergic disorders.

Dysregulation of the IL-6 axis is known to be involved in several autoimmune disorders such as RA, idiopathic juvenile arthritis, autoimmune epilepsy, and neuromyelitis optica spectrum disorder [169]. Of note, IL-6 induces Tfh expansion and differentiation, which is critical for the generation of high affinity IgE producing B cells, and germinal centre Tfh-dependent autoantibody producing B cells [80, 170]. IL-6 promotes CD4 + T cell differentiation into proinflammatory Th17. Conversely, it prompts a reduction in TGF-β-induced CD4 + differentiation into Treg cells, thus leading to dysregulation of the Th17/Treg balance and eventually loss of immune tolerance, inflammation, and autoimmunity [169, 171]. In addition, IL-6 promotes the differentiation of CD8 + T cells into cytolytic T cells [169, 172], participates in the differentiation of B cells into plasmacells [169, 172], and promotes angiogenesis and vascular permeability, including TNF-α-driven responses [173, 174].

TNF-α is a potent proinflammatory cytokine that exerts multiple pathogenic and homeostatic actions. This cytokine has indeed been implicated in many inflammatory conditions, and its inhibition is a cornerstone of the treat to target therapy of many systemic autoimmune diseases [175–177]. A study by Jimènez-Morales et al. [178] provided evidence in support of TNF-α as a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and SLE. Specifically, the authors found significant differences in the TNF-α−308A allele frequency between patients and healthy controls. TNF-α is involved in many aspects of airway pathology in bronchial asthma [179]: (i) it promotes the release of several cytokines, chemokines adhesion molecules, and mucins supporting chronic inflammation and airway hyperreactivity; (ii) it enhances the adhesion of activated eosinophils to epithelial cells; and (iii) it stimulates neutrophil chemotaxis [180]. This evidence may also explain the effectiveness of TNF-α in a small subset of patients with severe asthma with and a prominent TNF-α [180]. Both protein and mRNA levels have been found to increase in the airways of patients with mild perennial atopic asthma [181, 182]. In addition, the administration of inhaled recombinant TNF-α to normal subjects leads to airway neutrophilia, hyperresponsiveness, and bronchoconstriction [183]. The mechanisms behind these effects are not fully elucidated. However, they are possibly mediated by the effects of TNF-α on airway smooth muscle [184], histamine and cytokine release from human mast cells [185, 186], recruitment of neutrophils and eosinophils [187], activation of T-cells [188], cytotoxic effect of eosinophils and endothelial cells [189], and increased epithelial and endothelial expression of adhesion molecules [190]. Together, these actions participate in the development of bronchial hyperresponsiveness, steroid resistance, and airway remodelling. Moreover, an elevated expression of IFN-γ and T1 chemokines (e.g., CXCL9 and CXCL10) can be identified in the airways of a subset of patients with severe asthma with reduced Th2 response poorly responsive to corticosteroid therapy [191–193].

Besides TNF-α, CCL5 has also been suggested to play a role in asthmatic T1 inflammation [174]. In fact, murine studies have shown evidence of severe asthma amelioration with both the inhibition of CXCL9/CXCL10 (acting through C-X-C chemokine receptor 3 (CXCR3)) and of CCL5 (acting through CCR5) along with their downstream effects on lung T cells [194]. Furthermore, CCL5 has been suggested to play a role as a potential bridge between T1 and T2 inflammation [174], since its levels were reported to be increased in BAL of allergic asthmatic patients [195], and its receptor CCR5 was found on Th1 cells at sites of inflammation in autoimmune diseases [196, 197]

IL-17 is an inflammatory cytokine that induces the production of granulocyte colony-stimulating factor (G-CSF) and chemokines such as CXCL1 and CXCL2, which are involved in the pathogenesis of several autoimmune diseases (e.g., RA, psoriatic arthritis, and multiple sclerosis) [198]. T helper cells producing IL-17 characterise the synovial tissue of patients with RA [199]. IL17 stimulates RANKL expression on osteoblasts in the joints, which promotes osteoclastogenesis from monocytes. The osteoclasts, in turn, are involved in bone and joint destruction observed in inflammatory arthritis [200, 201]. In addition, Th17 cells contribute to the onset of psoriasis through the production of IL-17 and IL-22, which stimulates keratinocyte proliferation and acanthosis through the activation of STAT3 and the expression of CXCL1 and CXCL8 [202, 203]. However, IL17-driven inflammation also likely plays a role in chronic lung inflammation observed in bronchial asthma [204]. In particular, the expression and production of IL-17A and IL-17F are enhanced in asthma as increased levels of these cytokines have been observed in the patients’ sputum, serum, bronchial, and nasal biopsies [204–209]. IL-17A appears to mainly act on structural cells of the airway mucosa and indirectly induces corticoid-resistant airway neutrophilia. Indeed, the levels of airway neutrophilia in asthmatic patients correlate with IL-17A expression [210–212], although neutrophils do not express IL-17RC, which is required for the signalling of this cytokine [213]. In addition, in vitro stimulation of endothelial cells, fibroblasts, bronchial epithelial cells, airway smooth muscle cells with IL-17A prompts the production and release of powerful neutrophils attractors (i.e., CXCL1, CXCL5, and CXCL8), neutrophils growth factors (i.e., GM-CSF and G-CSF), and of proinflammatory cytokines (IL-1, IL-6, IL-11, and TNF) creating a favourable microenvironment for neutrophil infiltration [205, 206, 213–215]. As reported, IL-17F is capable of inducing similar effects since it stimulates the release of IL-1, IL-6, CXCL1, CXCL5, and CXCL8 in endothelial and bronchial epithelial cells [216, 217]. Moreover, in mice models, both IL17A and IL17F induce prominent airway neutrophilia [218, 219]. Besides the induction of neutrophil inflammation, IL-17 cytokines participate in asthma pathogenesis, also inducing the expression of mucin genes MUC5AC and MUC5B in bronchial epithelial cells in vitro [220] and promoting the expression of profibrotic factors such as transforming growth factor TGF, IL-11, and IL-6 contributing to airway remodelling [205, 221]. Finally, of note, there is a two-way relationship between Th17 and Th2 response since these two pathways seem to regulate each other and sometimes act synergically [204]. Indeed, IL-17A has been shown to enhance IL-13-induced signal transducer and activator of transcription 6 (STAT6), thus enhancing IL-13 activity in vitro experiments, and the simultaneous induction of IL-13 and IL-17A led to pronounced airway hyperresponsiveness in a mouse model of experimental asthma [222].

IL-4 promotes naïve T cell differentiation into Th2 cells [223, 224], which further produce inflammatory cytokines (i.e., IL-4, IL-13, IL-5, and IL-9). These, in turn, stimulate mast cells and eosinophils recruitment along with B cell maturation and Ig switching towards the IgE isotype, thus sustaining both allergic and autoimmune diseases [225, 226]. In atopic dermatitis, IL-4 together with IL-13- and IL-31-related pathways is considered a pathogenic hallmark. Specifically, IL-4 contributes to the epidermal barrier impairment (i.e., filaggrin and loricrin downregulation) and stimulates Th2 differentiation [225]. Similar mechanisms may have a role in SLE. In a lupus nephritis model, Charles et al. [134] demonstrated the crucial role of IL-4 (along with IL-13) in maintaining B-cell differentiation, survival, and production of autoantibodies. In addition, IL-4 and STAT6 gene polymorphisms were found to be associated with SLE [227–229].

Bradykinin and Autoimmunity

Both autoimmune and lymphoproliferative disease have been associated with a particular form of recurrent angioedema mediated by bradykinin (i.e., angioedema with acquired deficiency of C1 inhibitor; AAE-C1-INH) [230]. This condition is frequently overlooked and difficult to identify since it may resemble more common allergic diseases [231, 232]. C1-INH belongs to the superfamily of serine protease inhibitors and inhibits components of the fibrinolytic, clotting, and kinin pathways, which, when activated, cause an increase in blood bradykinin that, in turn, induces capillary leakage [233, 234]. Indeed, bradykinin is a powerful vascular mediator that may induce an increase in vascular permeability, causing swelling of the skin and gastrointestinal tract [235], respiratory airways [236], and urinary and genital tracts [237]. C1-INH may be inactivated by autoantibodies (i.e., anti-C1-INH autoantibodies) detected in approximately 74% of AAE patients [238]. In these patients, IgG class, IgM class, simultaneously IgG and IgM classes, and/or C1-INH–antiC1INHAb complexes may be detectable [239]. This autoantibody production has been observed in patients with concomitant autoimmune (e.g., SLE, antiphospholipid syndrome, immune-mediated cytopenia, SjS) and hematologic conditions (e.g., monoclonal gammopathy of uncertain significance (MGUS), non‐Hodgkin lymphomas) [230, 239] and is sustained by B cell proliferation, frequently with clonal characteristics leading to the expansion of anti-C1-INH autoreactive clones [239–241]. The link between C1-INH-AAE and autoimmune diseases may appear quite straightforward, but the connection between MGUS and lymphomas may look less intuitive. Some authors suggested that lymphoma cells are capable of depleting C1-INH or causing its consumption through C1 activation. For example, evidence comes from in vitro tests by Hauptmann et al. [242], showing that abnormalities of the complement system were caused by neoplastic lymphocytic cells. In addition, in the same study, splenectomy led to the correction of complement components and C1-INH levels in patients with C1-INH-AAE and lymphosarcoma. Similar evidence suggesting that neoplastic lymphatic tissue may cause C1-INH consumption has been provided by Caldwell et al. [243]. However, more recent studies in larger population groups are needed to confirm this hypothesis.

Shared Genetic Variants in Allergy and Autoimmunity

Allergy and autoimmunity may be considered two effects of a dysregulated immune system. In this view, several authors, through the years, have evaluated the shared and different genetic components of allergic and autoimmune diseases. Certain loci have been associated with allergic diseases only (e.g., MIIP, CXCR4, SCML4, CYP1B1, ICOS, LINC00824), while others to both allergic and autoimmune conditions (e.g., PRDM2, G3BP1, HBS1l, POU2AF1) [244, 245]. In particular, Shirai et al. [245] performed a multi-trait and cross-population genome-wide association study (GWAS) meta-analysis of three autoimmune diseases (i.e., RA, Graves’ disease, type 1 diabetes) and three allergic diseases (i.e., atopic dermatitis, asthma, and pollinosis), and integrated research from the Biobank Japan and UK biobank (including 105,721 cases and 433,663 controls) for SLE and psoriasis. Consequently, through the multi-trait GWAS meta-analysis, the authors identified four loci shared between the six autoimmune and allergic diseases, two of which were confirmed also for SLE and psoriasis [245]. Finally, an enrichment analysis of biological pathways and cell types was performed, revealing that Treg and natural killer cells were significantly enriched in allergic diseases, suggesting the involvement of both innate and adaptive immune systems. In addition, the allergic diseases were involved in various cytokine signals, including type 1 interferon [245]. Another research article by Kreiner et al. [246] showed that allergy and autoimmunity share susceptibility loci, genetic pathways, and genomic regulatory sites, thus suggesting shared disease mechanisms. In addition, Mendelian randomization analyses using GWAS [247] showed that atopic dermatitis increases the risk of some autoimmune conditions (RA, type 1 diabetes, and alopecia areata). Recent additional clues about potential genes acting as master regulators of allergy and autoimmunity have been provided by Gonzalez-Figueroa et al. [64]. In an elegant murine study, the authors showed that mice lacking follicular regulatory T cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centres and developed autoantibodies against histones and tissue-specific self-antigens. Another series of experiments showed that these mice produced increased levels of IgE and IgG1 upon immunization [64]. Neuritin is indeed a protein capable of reducing the differentiation of germinal centre B cells into plasmacells, impairing IgE class switching, downregulating BLIMP-1 (a transcription factor driving the differentiation of B cells into plasmacells), and upregulating BCL6 (which is expressed on follicular regulatory B cells) [64], thus suppressing IgE-mediated allergy and B-cell-driven autoimmunity.

Clinical Data

An oversimplistic clinical/pathophysiological approach would restrict the occurrence of allergic manifestations to Th2-biased disorders, and autoimmunity to conditions characterised by prominent activation of the Th1–Th17 axis. This section will explore the limitations of this classification by discussing epidemiological and clinical evidence of overlapping phenotypes among these two extremes and the less defined set of diseases with mixed-type T helper responses. Despite growing pathophysiological evidence suggesting the existence of shared mechanisms for the induction and maintenance of inflammation among allergic and autoimmune disorders, clinical data are still limited to date. In particular, very little is known about the distinctive characteristics of allergic patients within the broad clinical spectrum of concomitant autoimmune disorders, while knowledge gaps regarding the impact of autoimmunity in the course of allergic disorders are also far from being filled. Epidemiologically, growing evidence from nationwide studies suggests that the onset of allergy in early life constitutes a major risk factor for autoimmunity later on [248–250]. These data are also consistent with the old notions that allergic manifestations along with autoimmunity are frequently coexisting and early evident in patients with inborn errors of immunity [251].

Autoimmune Disorders with Th2-prominent Mechanisms

Th2-polarised immune responses are associated with IgE production and eosinophilia, which constitute the hallmark of atopy [113]. As anticipated, excessive IgE responses also characterise atopic dermatitis and are associated with defective (epithelial) barrier function, a shared pathogenic hallmark with multiple other Th2-biased disorders [250]. Extreme Th2 polarisation is observed in hypereosinophilic syndromes (HES) [252] including idiopathic HES, eosinophilic esophagitis, and conditions traditionally classified as autoimmune, such as EGPA. Furthermore, the spectrum of disorders characterised by Th2-polarisation also extends to other autoimmune diseases such as IgG4-related disease (IgG4RD).

EGPA is a systemic immune-mediated disease characterised by eosinophilic inflammation and (micro)vascular morbidity. Similar to other disorders of the same pathophysiological group, EGPA can be associated with vasculitic involvement of the skin (with purpura as the leading sign), peripheral and cranial nerves, upper and lower airways and, less frequently, of the kidneys and the gastrointestinal tract. These manifestations are usually associated with the detection of positive anti-neutrophil cytoplasmic antibodies (ANCA), while eosinophilic infiltration of the lung, ear-nose-throat district, heart, and peripheral nerves is usually clustered among ANCA-negative subjects [253, 254]. Endothelial activation in the context of small-vessel inflammation and eosinophil-related triggering of the coagulation cascade through tissue factor concur to an enhanced thrombotic risk in patients with EGPA [255]. Of note, disproportionate thrombophilia constitutes a common trait of a large spectrum of disorders sharing eosinophilia and activation of hypersensitivity reaction-like pathways such as parasitic disorders and uncontrolled asthma [256]. Asthma constitutes a pivotal criterion for the diagnosis of EGPA. Notably, severe asthma accounts for only 5% of the total asthma cases but can be found in more than 40% of EGPA cases at diagnosis [257]. In line with the Th2-biased pathophysiology of the disease [258], EGPA-associated asthma is usually an eosinophilic asthma with good response to anti-eosinophil targeted treatments (see also the next section about treatments) [259, 260]. Allergic sensitisation might trigger or coexist with eosinophilia in patients with eosinophilic asthma, but limited data are available about the impact of allergy in patients with EGPA. Recent studies suggest that atopy could have a prevalence of 20–30% in patients with EGPA [261, 262]. These figures might approach 50% of patients with EGPA by including other forms of allergy [263]. Intriguingly, pharmacological inhibition of the Th2 axis may reveal underlying Th1–Th17 dysregulation at least in the setting of some EGPA manifestations [264].

IgG4RD constitutes another example of a Th2-biased systemic autoimmune disorder with complex clinical and pathophysiological features. IgG4RD is a rare non-neoplastic mass-forming disease characterised by IgG4-secreting plasma-cells infiltrating tissues and by storiform fibrosis [265]. Substitution of functional tissue with this fibroinflammatory infiltrate leads to acute [266] or chronic organ dysfunction and significant morbidity [267, 268]. Although virtually any organ can be affected by the disease [269], four recurrent main clinical patterns have been described in the literature: group 1 includes patients with prominent involvement of the hepatobiliary tract and of the pancreas; group 2 refers to subjects with retroperitoneal fibrosis or aortitis; group 3 is characterised by limited head-neck manifestations; group 4 includes patients with prominent exocrinopathy and other multi-organ manifestations [270]. Elevated IgE and eosinophilia along with high IgG4 levels constitute frequent traits of patients with IgG4RD [271–273]. Nonetheless, atopy reportedly affects just 30% of patients with IgG4RD, suggesting that the Th2-skewed haematological and serological profile of IgG4RD might be independent of the development of clinically significant hypersensitivity manifestations [274, 275]. Drug allergy is also frequently reported in patients with IgG4RD and can account for up to 60% of allergic manifestations [153]. Limited data are instead available about asthma in IgG4RD, although EGPA/IgG4RD overlap syndromes have been described [276]. Nonetheless, scattered evidence of potential, though controversial, efficacy of Th2-targeted treatments adapted from asthma has been reported in the setting of IgG4RD [277].

Th1/Th17-biased Immune-mediated Disorders

Multiple “classical” autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases, psoriasis, and RA have been associated with aberrant Th1–Th17 responses [278]. Dysregulated activation of the Th1–Th17 axis is also a prominent feature of granulomatosis with polyangiitis and microscopic polyangiitis, which constitute the non-eosinophilic counterparts of EGPA in the setting of ANCA-associated vasculitis [279–282]. In a similar way, psoriasis shares common pathophysiological features with otherwise unrelated dermatological conditions. For example, defective maintenance of skin integrity might favour autoantigen sensitisation in psoriasis similar to the autoallergic responses observed in atopic dermatitis, besides triggering disease exacerbations through Koebner’s phenomenon [283]. Diverging immune profiles with prominent Th1/Th17 responses characterise psoriasis in contrast with atopic dermatitis or other disorders and affect treatment responsiveness. Nonetheless, atopic dermatitis constitutes a major risk factor (along with allergic rhinitis and asthma) for the coexistence of psoriasis at population level [248].

Evidence of hypersensitivity manifestations as part of the overall clinical phenotype is also growingly appreciated, along with eosinophilia [284], in patients with RA and connective tissue disorders [285–287]. Nonetheless, conflicting data can also be found in the literature, possibly due to discrepancies in methodologies among studies [105, 288, 289]. RA is a relatively common autoimmune disorder with prominent involvement of the synovial membranes and characterised by the development of a symmetric, additive chronic polyarthritis preferentially affecting small joints. Extra-articular manifestations and disease- or treatment-related complications are, however, not uncommon and may affect patient quality of life and, potentially, survival [290, 291]. Kronzer et al. analysed a cohort of > 1000 patients with RA (175 of whom with recent-onset disease) from a biobank repository and compared their self-reported clinical characteristics to a heterogeneous group of controls without RA from the same repository [292]. Allergy prevalence was very high in both the study (64%) and the control group (58%) in comparison to average data from the general population [11, 293]. After adjusting for potential confounders, the authors found a significant association between RA and comorbid allergy. Food allergy accounted for about one sixth of allergy cases and showed the strongest association with RA [292]. Olsson and collaborators also calculated a relatively high prevalence of allergy in their case–control study but found no statistical difference when comparing RA cases to controls in terms of eczema and allergic rhinitis, with a trend towards a protective effect of RA towards atopic manifestations [294]. Although Olsson et al. also found no significant differences in at least some allergen-specific IgE among patients with RA and controls, in both the studies by Kronzer and Olsson, allergy diagnosis was generally self-reported and not physician-validated. This might constitute a significant limitation, introduce a potential bias due to overestimation of some types of hypersensitivity reactions, such as those related to food [295] and account for inconsistencies among studies. Complementary to this evidence, nationwide population studies based on International Classification of Disease (ICD) codes suggest that patients with a history of allergy might be more likely to eventually develop RA along with other autoimmune disorders [249, 296]. Consistent with retrospective cohort studies, nationwide registries also indicate a potential additional association between RA and asthma [249, 292, 297].

Mixed-type Immune-mediated Disorders

As anticipated, CSU constitutes a paradigm disorder at the crossroads between allergy and autoimmunity. CSU manifests with recurrent spontaneous wheals for more than 6 weeks [298, 299] and affects a large share of the general population [300–302]. CSU may be due to a wide variety of underlying conditions, including autoimmune diseases [298]. Currently, two main CSU subtypes have been identified [299]. Type I CSU, also called autoallergic CSU, is due to the production of IgE antibodies targeting autoantigens. Type II CSU is characterised by “classical” autoimmunity and can be further dichotomised into two distinct subtypes. In particular, type IIb CSU mediated by IgG autoantibodies to IgE or its high-affinity receptor FcεRI (IgE-anti-FcεRI) which can target and activate mast cells [299, 172, 173], while type IIa reactions involve cytolytic destruction of targeted cells and are beyond the scope of this review. Type I and II mechanisms are not mutually exclusive and can coexist at least in a fraction of subjects with CSU, although type I is considered markedly more common than type IIb [299]. Interestingly, both mechanisms are associated to a substantially identical clinical presentation [299, 303], but may diverge in terms of treatment outcomes. Consequently, CSU treatment remains a challenge for many patients. In these difficult-to-treat endotypes, targeting pathways conventionally attributed to autoimmune disorders, including the JAK-STAT and the IL-17/IL-23 axis, is a growingly appreciated therapeutic strategy [304].

A disproportionately high risk of developing autoimmunity has also been reported by population studies analysing potential relationships among allergic disorders and SLE. SLE is a multi-organ disease belonging to the wider group of connective tissue disorders (which also encompasses SjS, systemic sclerosis, inflammatory myopathies, and a multitude of overlap syndromes). It is characterised by multi-organ inflammation and derangement of multiple aspects of the physiological innate and adaptive immune function. Genetic and environmental factors concur to cause functional defects in the clearance of cell death debris and cell nuclear components, leading to misdirected anti-viral-like inflammatory responses and downstream development of pathogenic autoantibodies and impaired pathogen responses. Clinically, SLE is most frequently characterised by mucocutaneous and musculoskeletal manifestations and might associate with renal, neuropsychiatric, cardiopulmonary, gastrointestinal, ophthalmic, and constitutional manifestations along with alterations in blood cell counts and evidence of autoantibody production and complement consumption. Interestingly, evidence from population studies seem to indicate that accrual of distinct types of atopic manifestations has an incremental impact on the risk of developing SLE [296, 305, 306]. Anecdotal cases of eosinophil count imbalances have also been reported [307]. Multiple cohort studies report data consistent with nationwide registries [105, 250, 308] and suggest a specific association of SLE with drug allergy [308, 309] in contrast to RA [292, 310]. Among drugs, antibiotics are reported as the preferential allergic culprits in patients with SLE [311, 312], possibly suggesting a concurrent role of acute infections in promoting the loss of immunological tolerance towards innocent exogenous stimuli, besides autoantigens. Mechanistically, higher total IgE levels can be detected in patients with SLE in association with a higher prevalence of “classic” allergy [250] but fail to segregate with specific autoimmune manifestations. Nonetheless, evidence of anti-dsDNA-IgE with nephritogenic potential has been reported in SLE [100] and is consistent with the encouraging (though small-sized) efficacy signal of pilot clinical trials with IgE-depleting agents [313]. Conversely, conventional mechanisms of SLE-related tissue inflammation such as autoreactive IgG have been claimed to account for the substantial clinical overlap between SLE and non-classic hypersensitivity responses, such as CSU [314, 315].

Data suggesting a role for allergy as part of a broader dysimmune phenotype have also been acquired in the setting of SjS [316–319], another connective tissue disorder characterised by autoimmune exocrinopathy often developing secondary to other immune-mediated conditions. Multiple studies consistently show a disproportionately high prevalence of immediate-type drug allergy in patients with primary SjS (even in comparison with other immune-mediated disorders, such as RA), especially in case of positive anti-Ro antibodies [316, 317]. Similar to SLE, most allergic patients with SjS become sensitised to antibiotics [317]. Most recent studies also suggest a potential association among SjS and delayed-type hypersensitivity reactions to environmental antigens, including metals [317, 319], while conflicting evidence is reported with regard to food allergy [316, 317].

Treating Allergy and Autoimmune Diseases: From Conventional Drugs to Innovative Therapies

From a therapeutic perspective, the abovementioned standard classification into Th1–Th17- vs. Th2- vs. mixed type-driven disorders has been mirrored by the use of Th1–Th17-inhibitors in autoimmunity and Th2 modulators in allergy. Novel evidence suggests that a molecule originally developed to treat allergic conditions may indeed also be effective in tackling autoimmune pathogenic events and vice versa.

Non-targeted Therapies

Corticosteroids still constitute the mainstay of treatment for a broad set of allergic and autoimmune diseases [320]. Their efficacy in both conditions, owing to their anti-inflammatory and immunosuppressive effects, relies on several molecular mechanisms, most notably inhibition of the activity of NF-kB, a crucial transcriptional factor for several molecules involved in the inflammatory response [321, 322].

Thanks to their pharmacokinetic and pharmacodynamic features, they could be used, according to the guidelines, both as therapy for acute manifestations (e.g., CSU, asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, SLE, systemic vasculitis, RA) and as maintenance therapy (e.g., asthma, chronic rhinosinusitis with nasal polyps, systemic vasculitis, RA, SLE) [298, 320, 323–325].

Conventional immunosuppressants have historically had limited applications in the treatment of allergic disorders. Due to its peculiar pathophysiological background (see above), CSU represents a notable exception to this rule. The majority of case series reported in scientific literature belongs to the pre-omalizumab era or refers to patients non-responsive to it. The rationale for using immunosuppressive agents in CSU stems from the fact that autoimmunity plays a significant role in pathogenesis of this allergic condition, as previously mentioned [326]. Recently, a network meta-analysis analysing data from seven randomised clinical trials (410 patients) has compared the efficacy and safety of some immunosuppressive agents for CSU among which cyclosporine A, methotrexate, and azathioprine. The results pointed out that cyclosporine A resulted in greater improvements of CSU expressed by change in UAS7 [327]. According to these findings, the latest treatment guidelines developed by the European Academy of Allergy and Clinical Immunology and the World Allergy Organization (EAACI⁄GA2LEN⁄EDF⁄WAO) recommend that patients with no or partial response to anti-H1 agents should be started on or switched to cyclosporine A [298]. Conventional immunosuppressants have also been historically used for the treatment of severe asthma before the advent of targeted biological agents [328]. Curiously, translational data obtained from the use of these latter drugs in asthma paved the way to a multitude of applications in other allergic and autoimmune disorders. IVIG are part of the potential conventional armamentarium available to combat autoimmunity and are able to interact with surface bound IgE expressed on basophils, mediating in this way anti-inflammatory effects and promoting Th2 response [95].

Conversely, the potential role of classic anti-allergic immune modulators has only minimally been explored in the setting of autoimmune disorders [329–333]. Recently, a case series has been published about four patients with SLE and refractory skin lesions successfully treated with montelukast, a Cys-leukotriene (LT) antagonist. This therapeutic strategy is based on the fact that neutrophils and macrophages of cutaneous lupus produce prostaglandins and LT, which promote tissue damage [329].

Th1/Th17-targeted Therapies 

Cytokines involved in Th1/Th17 pathway like IL-6, TNF-α, and IL-17 exert potent inflammatory effects; thus, their inhibition is a well-established strategy for treating autoimmune systemic conditions [334, 335].

TNF-α

TNF-α has been involved in many aspects of the airway pathology in asthma, as described above, especially in severe and refractory asthma.

Therefore, in the last few years, TNF-α inhibitors have been identified as potential new treatments in asthma and have been tested in several clinical studies. The results have been analysed in a recent systematic review and meta-analysis, investigating the efficacy and safety of anti-TNF-α as a supplementary therapy for patients with asthma. Data from four trials (three etanercept and one golimumab) and 489 patients has been collected and the results highlight that, although treatment with anti TNF appears to improve asthma control in several cases, there is limited evidence that it improves lung function and reduces exacerbations [336]. Some years ago, also infliximab, another anti-TNF-a neutralizing antibody, was also used in patients with asthma. The results were controversial: infliximab improved only some lung function measures, and the trial failed to reach definite conclusions about the efficacy of infliximab in mild-to-moderate asthma [337].

Taken together, these findings suggest that TNF inhibitors may not be sufficient to fully control the disease in all patients. Further clinical data are needed in order to identify which kind of patients could benefit from this therapy [338].

IL-6

IL-6 blockade has an established role in the control of multiple autoimmune and autoinflammatory conditions, including RA, adult-onset Still’s disease, and post-chimeric antigen receptor T-cell cytokine release syndrome [334]. Furthermore, due to the role of IL-6 in asthma, and the evidence of high IL-6 levels in serum, sputum, and bronchoalveolar lavage fluid of asthmatic patients, inhibition of IL-6 has also been proposed as a potential anti-cytokine asthma therapy. In literature, two cases of severe paediatric asthma treated with tocilizumab (a humanised monoclonal antibody targeting IL-6R) as an additional therapy have been reported. Both patients showed good response to therapy without any adverse effects; however, peripheral eosinophilia in these patients was not impacted [339]. In another study of allergic mild asthma, tocilizumab failed to prevent bronchoconstriction caused by allergens [340].

Further studies are needed to determine if blocking IL-6 in severe asthma could provide a significant therapeutic effect; blocking a single cytokine, however important its role in its inflammatory cascade may not be sufficient for all patients. It has been proposed that pharmacological inhibition of TNF-α and IL-6 combined in acute allergic asthma may reduce the severity of inflammatory responses in the lungs more effectively than inhibition of these two cytokines separately, as it blocks multiple pathogenic mechanisms in parallel, but infectious risks should be monitored continuously [340]. The same drug has been reported to improve the eczema area and severity index in a small group of patients with atopic dermatitis, although an increased incidence of bacterial skin infections has also been reported [341].

IL-12/23-IL-17 Axis

Drugs targeting IL-12/23-IL-17 axis are already approved for the treatment of several rheumatic autoimmune conditions like psoriatic arthritis and ankylosing spondylitis [342–345], besides showing promising results in other autoimmune settings such as SLE [335, 346]. Evidence of a role of IL-12/23-IL-17 in CSU and asthma is also quite consolidated, supporting a potential role of anti-IL-23 and anti-IL-17 monoclonal antibodies to treat these conditions. Secukinumab, an anti-IL-17A mAb, and tildrakizumab, an anti-IL-23 mAb, have been tested in small groups of omalizumab- and ciclosporin-refractory urticaria, with good results [347, 348]. Ustekinumab, a monoclonal antibody that targets IL-12 and IL-23, has been used in the past, with success, in small series of patients with asthma and in atopic dermatitis, as an adjuvant therapy [349, 350]. Given the broad role that IL-12/IL-23 plays in chronic immune-mediated diseases, there is a possibility that these drugs may be used in the future to treat allergic diseases as well.

Th2-targeted Therapies

Inhibition of Th2 pathway could be achieved by drugs interacting with key cytokines for eosinophils and basophils functions, as well as with inhibitors of IgE.

IL-5

Targeting IL-5 has long been regarded as a key strategy to tackle eosinophil-driven disorders. Accordingly, multiple therapeutic agents targeting IL-5 have progressively been developed for eosinophilic asthma. Mepolizumab, a humanised monoclonal antibody directly targeting IL-5 was the first molecule in this specific pharmacological class. Following its successful use in asthma, mepolizumab has also been trialled in EGPA. In the MIRRA trial, the use of mepolizumab lead to significantly more accrued weeks of remission and a higher percentage of participants in remission at both week 36 and week 48 than placebo [259]. Recently, a post hoc analysis of the MIRRA trial has shown that mepolizumab is associated with clinical benefits in patients with and without a vasculitic phenotype, suggesting that eosinophils are implicated also in vasculitic process [351]. Accordingly, the drug has also become part of the standard of care for the disease and has been included in the European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) guidelines for the treatment of ANCA vasculitis [352].

More recently, new molecules have enriched the landscape of anti-eosinophilic drugs, including benralizumab. Benralizumab is a humanised monoclonal antibody which acts through dual mechanism: on one side it binds the chain alpha of IL5-R, inhibiting the signal transduction, and, on the other side, it induces an antibody-dependent cell-mediated cytotoxicity of eosinophils largely mediated by NK cells. Thus, through these very effective mechanisms, it induces a more rapid and powerful sustained depletion of eosinophils in both blood and tissue, and it has been approved as add-on maintenance treatment of patients with eosinophilic severe asthma [353]. Recently, benralizumab has been recently tested for the treatment of EGPA in a head-to-head phase 3 trial, showing to be non-inferior to mepolizumab in EGPA. This result offers new evidence that targeting IL-5 is a successful approach for the treatment of EGPA [354]. Anti-IL-5 drugs have been tested in another eosinophil-associated disorder: eosinophilic esophagitis. The evidence regarding the effectiveness of both mepolizumab and benralizumab in patients with eosinophilic esophagitis is conflicting. Data from clinical trials demonstrated histological improvements that did not reflect a significant amelioration in clinical symptoms. In clinical trials, histological improvements were observed but not accompanied by a significant improvement in clinical symptoms. Based on these data, it appears that eosinophils are not the primary mediator of these conditions, but rather other molecules that must be considered as well. Therefore, anti-IL-5 therapies have not been approved for this condition [355].

IL-4 and IL-13

IL-4 and IL-13 are other cytokines involved in promotion of Th2 responses, and dupilumab is a monoclonal antibody that inhibits IL-4 and IL-13 signalling approved for the treatment of asthma, chronic rhinosinusitis, and atopic dermatitis. On several occasions, dupilumab has been given to IgG4-RD patients with asthma and polyposis with good results: dupilumab was able to reduce serum IgG4 levels, the volume of swollen submandibular glands, and daily dose of GCs [356]. Studies with larger number of patients together with a deeper knowledge of IgG4RD pathogenesis could be necessary to establish the exact role of this drug.

TSLP

Thymic stromal lymphopoietin (TLSP) is a pleiotropic cytokine secreted by a wide variety of cells like lung and intestinal epithelial cells, keratinocytes, fibroblasts, dendritic cells, mast cells, and other immune cells, whose release is enhanced by several signals (e.g., inflammatory cytokines, allergens, infection, mechanical injury, cigarette). It plays a role in initiating both the innate and the acquired immune responses inducing activation of dendritic cell and group 2 innate lymphoid cells (ILC2), upregulating basophil functions and inducing eosinophils, mast cells and basophils hematopoiesis [357]. A human monoclonal antibody that inhibits TSLP, tezepelumab has been approved for the treatment of uncontrolled asthma, irrespective of T2 endotype. More recently, a successful use of tezepelumab in two patients with severe refractory EPGA-related asthma has also been reported [358]. Currently, a phase 2b trial for tezepelumab is underway: the NCT06230354 trial will evaluate the efficacy of tezepelumab in patients with active non-severe EGPA compared to placebo. An additional trial involving tezepelumab is currently in progress, which is evaluating its efficacy and safety in adults and adolescents with eosinophilic esophagitis (NCT05583227) and recently, it has been demonstrated that TSLP increases the number of circulating and esophageal-derived CD4 memory T cells [359]. Mechanistically, TSLP blockade might have therapeutic potential in other immune-mediated disorders, including cyroglobulinemic vasculitis and IgG4RD [360, 361].

IgE

Class E immunoglobulins are the canonical trigger of classical allergic responses. Therefore, IgE neutralisation constitutes an established strategy for the treatment of allergic diseases. First-generation agents encompass monoclonal antibodies such as omalizumab, a cornerstone treatment of atopic asthma refractory to step 1–4 Global INitiative for Asthma recommendations [362]. Ligelizumab, is a novel monoclonal antibody binding IgE with higher affinity than omalizumab [363]. More advanced pharmaceutical strategies include the use of IgE-neutralising nanobodies. These nanomolecules are endowed with smaller binding sites and are able to bind free IgE, to dissociate pre-complexed IgE from their high affinity interaction with receptors on mast cells, basophils and dendritic cells, assuring maximal therapeutic efficacy [364]. Similar to omalizumab, novel anti-IgE agents are expected to restore the ability of pDCs to generate FOXP3 + Tregs, supporting a broader use of anti-IgE treatments in Treg-defective diseases [363]. Indeed, based on these principles, on the discovery of potential pathogenic bonds between IFN-α- and IgE-related pathways, along with evidence of autoreactive anti-DNA IgE and dysregulated basophil activation in SLE, clinical trials have been designed to test the potential clinical efficacy of IgE silencing in this disorder [108, 109]. The STOP LUPUS trial was designed to this purpose and included 15 subjects with moderately active SLE who were treated with omalizumab. It demonstrated that omalizumab administered 300 mg monthly was not only well tolerated, but also able to improve disease activity score at week 16 and 32. Despite the promising results of this pilot study, no other trial has been conducted until now to validate the results in a larger population [313].

While asthma-derived anti-IL-5 agents have shown efficacy for the treatment of EGPA, IgE inhibition does not seem to tackle the pathogenesis of the disease and omalizumab could be considered as maintenance therapy of EGPA only in patients without severe forms and mainly in patients with good control of extrapulmonary but not of asthma symptoms [365].

 Therapies Targeting Common Leukocyte Signalling Pathways

Janus Kinase and Tyrosine Kinase Inhibitors

The approach of targeting a single cytokine or cytokine receptor does not always have durable effects. Therefore, targeting signalling pathways shared by multiple cytokine receptors with small molecules represents an innovative and effective approach. Janus kinases (JAKs), including JAK1, JAK2, JAK3, and TYK2, are key targets for several immune-mediated and inflammatory diseases, being associated with receptors of T cell and of type I/II cytokines [366]. Due to this feature, JAK-inhibitors, largely used for the treatment of inflammatory disease like rheumatoid and psoriatic arthritis and inflammatory bowel diseases, are gaining great relevance also for the treatment of Th2-related conditions. More robust data have been acquired with the use of upadacitinib (a JAK-inhibitor with higher selectivity for JAK1 than JAK2) in atopic dermatitis. The results of Measure Up 1 and Measure Up 2 demonstrated that upadacitinb was rapidly effective and superior to placebo in tackling disease activity, itch and ameliorating impact on quality of life in patients with atopic dermatitis paving the way to drug approval by regulatory agencies [367]. Therefore, the available indications for upadacitinb have been extended, beyond rheumatic conditions, to atopic dermatitis.

Another possible future approach will also be targeting kinases. Bruton’s tyrosine kinase is a tyrosine kinase expressed in cells of the innate and adaptive immune system, and preferentially associated with the B-cell receptor (BCR) signalling. Moreover, BTK is also an effector for signalling through the IgE receptor FcεRI. This dual feature provides a strong rationale for the use of BTK inhibitors in the treatment of allergies as well as autoimmune diseases. In particular, remibrutinib, a selective oral BTK inhibitor has recently demonstrated its efficacy in patients with CSU and in patients with SjS. In this latter setting, remibrutinib prompted a reduction in disease activity scores and improved the salivary flow [368, 369]. Several BTKi are under examination for their use in atopic dermatitis, chronic urticaria, anaphylaxis, asthma, and food allergy but also in SLE, RA, and IgG4RD. Simultaneous dual development of BTKi for allergic and autoimmune diseases is a growingly appreciated strategy. For example, branebrutinib, is now under evaluation for atopic dermatitis, RA, SLE, and SjS (NCT04186871, NCT05014438).

Rilzabrutinib, a highly selective BTKi with prolonged and reversible target occupancy, is under evaluation for IgG4RD, asthma, and atopic dermatitis [274].

Chimeric Antigen Receptor (CAR)-T Cell Therapies

CAR-T therapeutic strategies have first been developed for the treatment of haematological cancers and exploit the effectiveness and selectivity of T-cell responses towards their antigenic target [370]. Most CAR-T cells are cytotoxic T cells, while Treg cells engineered with specific antigens constitute a novel frontier in cell therapy research [371]. In recent years, some pilot trials using cytotoxic CAR-T cells have been performed in patients with autoimmune diseases such as SLE. These studies showed that patients with refractory disease having failed multiple therapy lines might achieve a very long-term corticosteroid-free remission [372]. Research on the use of CAR-Treg is currently ongoing. Recently, it has been suggested that CAR-T cells could be used also in asthma patients. In a mouse model, researchers developed CAR-T cells that could recognize and kill eosinophils expressing IL-5, mimicking the action of benralizumab. Furthermore, these CAR-T cells were engineered to release an IL-4 cytokine mutein which binds IL-4Rα, thereby blocking IL-4 and IL-13 signal transduction pathways, simulating the mechanism of action of dupilumab [373]. It is fascinating to project the potential benefits of these treatments in patients with refractory asthma and/or allergy.

Summary and Conclusions

Allergic and autoimmune disorders share common genetic determinants and pathophysiological features, including dysregulated activation of innate immunity and aberrant processing of innocent endogenous or exogenous antigens by cellular and humoral adaptive immunity. Rather than constituting opposite poles in the spectrum of mechanisms of local and systemic inflammation, allergy and autoimmunity might synergise to sustain acute and chronic immune–mediated tissue injury. While this concept has detrimental implications at a clinical level, where coexistence of autoimmune and allergic manifestations might occur at a disproportionately high frequency, it also offers unprecedented opportunities in terms of therapeutics. In fact, a growing amount of data supports the efficacy of selective and/or broad-spectrum tackling of core mechanisms of pan-immune dysregulation as a promising strategy to tailor more accurate treatments on the specific needs of patients living with allergic and autoimmune diseases.

Author Contribution

All authors participated in the design of the study and in critically revising the final draft of the manuscript. G.A.R., C.C., M.F., I.M. searched the literature and drafted the manuscript. S.L. contributed to the manuscript revision and to the design of the Figure accompanying the text. G.A.R. prepared the Figure accompanying the text. All authors read and approved the final manuscript.

Funding

Financial support for open access publishing and use of graphic editing software was provided by MED MAPS srl, Via Rossini 10 20062 Cassano d’Adda MI P.IVA: 12818150968. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval

Not applicable.

Competing Interests

The authors declare no competing interests.