T_H2-driven manifestations of inborn errors of immunity

Abstract

Monogenic lesions in pathways critical for effector functions responsible for immune surveillance, protection against autoinflammation, and appropriate responses to allergens and microorganisms underlie the pathophysiology of inborn errors of immunity (IEI). Variants in cytokine production, cytokine signaling, epithelial barrier function, antigen presentation, receptor signaling, and cellular processes and metabolism can drive autoimmunity, immunodeficiency, and/or allergic inflammation. Identification of these variants has improved our understanding of the role that many of these proteins play in skewing toward T_H2-related allergic inflammation. Early-onset or atypical atopic disease, often in conjunction with immunodeficiency and/or autoimmunity, should raise suspicion for an IEI. This becomes a diagnostic dilemma if the initial clinical presentation is solely allergic inflammation, especially when the prevalence of allergic diseases is becoming more common. Genetic sequencing is necessary for IEI diagnosis and is helpful for early recognition and implementation of targeted treatment, if available. Although genetic evaluation is not feasible for all patients with atopy, identifying atopic patients with molecular immune abnormalities may be helpful for diagnostic, therapeutic, and prognostic purposes. In this review, we focus on IEI associated with T_H2-driven allergic manifestations and classify them on the basis of the affected molecular pathways and predominant clinical manifestations.

Inborn errors of immunity (IEI) are diseases caused by variants in genes regulating immune system development and function. To date, there are more than 500 reported IEI, which may present with susceptibility to severe or recalcitrant infections, autoinflammation, autoimmune disease, lymphoproliferation, and allergic disease and other forms of type II inflammation.¹

T_H2 cells, which drive typical atopic diseases, are key elements of the type II immune response, which protects against helminth infection, stimulates tissue repair, neutralizes toxins and counteracts other forms of inflammation, and has other functions as well.² T_H2 cells can secrete IL-4, IL-5, IL-9, and IL-13, which recruit mast cells, eosinophils, and basophils and promote B-cell class switching to IgE.^3–7 Failure to properly regulate T_H2 cells and/or their downstream targets can lead to symptoms seen in clinical allergic and atopic diseases, such as IgE-mediated hypersensitivity and/or mast cell activation, allergic inflammation of the skin and mucosa, and interference with other forms of inflammation. Although, in general, immunologic markers of type II immunity such as elevated IgE, eosinophilia, and increased IL-4 and IL-13 are often associated with the clinical signs of atopy, such as allergic rhinitis, allergic asthma, and atopic dermatitis (AD), the clinical signs may not always correlate with laboratory abnormalities in IEI. Furthermore, there can be substantial variability in the type of type II immune-related phenotypes despite these abnormal laboratory values—such as AD without immediate hypersensitivity and vice versa.

Population data on the frequency of atopy in IEI are limited; however, estimates range from 10% to 28.8%, suggesting it may be more common than previously appreciated, with 5% to 25% of patients with IEI presenting initially with isolated complaints of atopy.⁸ Allergic diagnoses in the general population are becoming increasingly more common; nearly 1 in 3 adults and more than a quarter of children in the United States report having an allergic disease.^8,9 Consequently, IEI may go unrecognized if allergic manifestations, such as AD, are the predominant initial symptoms and may result in delays in diagnosis.¹⁰ Conversely, atopic manifestation may not be addressed in the context of an IEI if severe infections or inflammations are the main clinical focus. The pathway of a patient with an IEI to clinical attention therefore significantly colors current conceptions of the relationship between IEI and atopic disease.

Although primary immunodeficiency refers to host defense defects presenting predominantly with infection, and primary immune regulation disorder refers to impaired tolerance and inflammation control presenting predominantly with increased autoimmunity and/or autoinflammation, primary atopic disorders is a term used to describe monogenic disorders with prominent atopic manifestations.¹¹ Primary atopic disorders can include syndromes referred to previously as “hyper-IgE syndromes,” but also many other described disorders leading to this recent classification.¹¹ This review will focus on allergic manifestations of IEI in general, with a focus on primary atopic disorders. We will highlight patterns of allergic disease linked to disturbances of specific molecular pathways and provide examples of precision treatment targeting these T_H2-driven processes (Table I^12–148; Fig 1).

TABLE I.

Selected IEI associated with T_H2-related phenotypes

Defect	Genes	Distinguishing phenotypic patterns	Insight/precision medicine/questions
Epithelial barrier disruption12–32	DSG1, CDSN, DSP, SPINK5, FLG, COL7A1	Severe dermatitis	Mechanism of positive IVIG effect for some? IL-4/IL-13R blockade improves skin immunity and inflammation
Attenuated antigen receptor signaling: actin cytoskeleton defects35–47	WAS, WIPF1, ARPC1B, DOCK8, NCKAP1L, CARMIL2	Viral skin infection Atopy and autoimmunity variable	Dupilumab treatment improves viral skin infection Protection from mast cell–related symptoms in WAS
Attenuated antigen receptor signaling: CBM complex mutations48–50	CARD11, CARD14, MALT1	Viral skin infection/eczema herpeticum Atopy and autoimmunity variable	NF-κB vs mTORC1 vs mTORC2 in driving TH2 phenotypes Lack of association of NF-κB–related IEI with TH2 phenotypes
Tolerance defects: enhanced PI3K/mTOR (APDS, IPEX)51–63,125	PIK3CD, PIK3R1, FOXP3	Mixed inflammation Variable phenotype	PI3K/mTOR inhibition for TH2 phenotypes?
Omenn phenotype64–69	Numerous SCID-related genes	Marked eosinophilia, erythroderma, IgE elevation Lack of antigen-specific allergy	Leaky oligoclonal T-cell role in TH2-like phenotype?
Cytokine and cytokine signaling—diminished IL-6/STAT3 signaling70–83,126,127	STAT3, IL6ST, IL6R ZNF341, IL6R, PGM3	Elevated IgE, poor inflammatory response, relative protection from IgE-mediated severe allergic disease, fungal disease Rash at birth (STAT3 DN)	Increased IL-4R expression–responsiveness to dupilumab AD but lack of significant hypersensitivity in STAT3 DN
Cytokine and cytokine signaling—increased JAK1/STAT5B/STAT684–102	JAK1 GOF, STAT5B, STAT6	Urticaria, failure to thrive, marked eosinophilia (JAK1/STAT5B) with eosinophilic GI disease, pan TH2-allergic/atopic phenotypes (STAT6)	Response of TH2-related phenotypes to JAK inhibition, dupilumab Extent of non-TH2 comorbidities in STAT5/STAT6 GOF?
Cytokine and cytokine signaling—TGF-β signaling100,101	TGFβR1, TGFβR2, ERBIN	Eosinophilic gut disease, overlap with STAT3 DN pathway	Increased IL-4R expression–responsiveness to dupilumab
Cytokine and cytokine signaling—decreased IFN-γ production/signaling and counterregulation102–107,109,110,112–114	IFNGR1, IFNGR2, IL12RB, IKZF1 GOF, TBX21	Elevated IgE, eosinophilia	Use of biologics to improve TH1 skewing/IFN-γ signaling through IL-4 inhibition?
Mast cell degranulation142–148	KIT, PLCG2, ADGRE2, KARS	Lifelong urticaria, increased anaphylaxis risk	Distinguish from mast cell extrinsic causes of allergic phenotypes

ARPC1B, Actin-related protein 2/3 complex subunit 1B; CARD14, caspase recruitment domain family, member 14; CARMIL2, capping protein regulator and myosin 1 linker 2; CBM, CARD11-BCL10-MALT1; DSG1, desmoglein 1; DSP, desmoplakin; GI, gastrointestinal; IFNGR1/2, IFN-γ receptor 1/2; IVIG, intravenous immunoglobulin; NCKAP1L, NCK-associated protein 1 like; ZNF341, zinc finger protein 341.

FIG 1.

Outline of pathways implicated in genetic disorders of the immune system associated with atopic disease. Red backgrounds indicate genes/gene products with causal variants associated with increased function, and yellow backgrounds indicate decreased function. Mix of 2 suggests that both GOF and LOF can cause atopy. CBM, CARD11-BCL10-MALT1; IFNGR1/2, IFN-γ receptor 1/2; TCR, T-cell receptor.

ALLERGIC MANIFESTATIONS OF IEI AND UNIQUE PATHWAY-SPECIFIC PATTERNS OF DISEASE

Atopy in conjunction with other forms of inflammation, autoimmunity, or significant infection raises suspicion for underlying immune dysregulation. Elevated IgE in the context of recurrent pneumonia and staphylococcal infection and abscess was originally described in patients also referred to as having Job syndrome as the hyper-IgE syndrome. The initial description ultimately was found to be due to signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) variants; however, many other syndromes with a range of inheritance patterns associated with IgE elevation have been described with and without infection, with and without abscess formation, and with or without connective tissue or other immune and nonimmune comorbidities. Even the presence of IgE elevation itself can vary within any of these disorders. As such, it is important to classify IEI associated with T_H2 and/or type II abnormalities by the pathways, genes, and presentations affected, instead of lumping them all together under a “hyper-IgE syndrome” umbrella.

Because of T_H2 skewing, many conditions associated with excessive IgE production often have comorbid elevated eosinophilia. There are more than 30 IEI with associated eosinophilia as part of their clinical phenotype.¹¹⁹ Eosinophil counts higher than the upper limit of normal were present in almost 1 in 5 patients with IEI on the United States Immunodeficiency Network (USID-NET) registry,¹⁰⁶ most notably in diseases such as STAT3 DN, Omenn syndrome, dedicator of cytokinesis 8 (DOCK8) deficiency, Wiskott-Aldrich syndrome (WAS), and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX).¹²⁰ Sustained and severe neonatal hypereosinophilia has been reported in somatic heterozygous gain-of-function (GOF) variants in STAT5B^84,85,121 and Janus kinase 1 (JAK1) GOF.⁸⁶ Eosinophilic gastrointestinal diseases (EGIDs) have also been reported in IEI, including Comel-Netherton syndrome, STAT3 DN, ERBB2-interacting protein (ERBIN) deficiency, Loeys-Dietz syndrome (LDS), IPEX, DOCK8 deficiency, CARD11 (caspase recruitment domain family, member 11) DN, STAT6 GOF, and others. Recent data from USIDNET reported that EGID was seen more frequently in patients with common variable immunodeficiency (CVID), chronic granulomatous disease (CGD), hyper-IgE syndrome (including STAT3 DN and phosphoglucomutase 3 [PGM3] deficiency), and autoimmune lymphoproliferative syndrome (ALPS),¹²² although this was a retrospective study dependent on centers’ reports and subject to ascertainment bias.

Monogenic autoinflammatory disorders, which are most commonly associated with IL-1, TNF, interferons, and/or IL-6 mediated inflammation, and thus not intuitively expected to have T_H2 skewing, nonetheless display a range of T_H2-related clinical phenotypes and T_H2 cytokine production profiles. For instance, patients with adenosine deaminase 2 (ADA2) deficiency have autoinflammation and vasculitis associated with excessive TNF-α activity, and, as might be expected, serum IgE and eosinophils are significantly reduced compared with levels in the general population. However, cryopyrin-associated periodic syndromes due to nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 GOF variants leading to excessive IL-1β secretion are associated with marked eosinophilia and multiple clinical allergy diagnoses.¹²³ The reasons for the diverging type II phenotypes in autoinflammatory diseases remain to be fully understood, but their study may ultimately offer insight into the interaction between autoinflammatory and atopic pathophysiology, even in contexts outside IEI.

Diseases associated with tolerance defects, the so-called regulatory T (Treg)-opathies, may include T_H2-related symptoms as well. Food allergy can be an early or initial manifestation of IPEX syndrome or IPEX-like diseases. In a study,⁵¹ 12% of patients with IPEX syndrome or IPEX-like diseases were initially diagnosed with food allergy, and only 15% of these patients were correctly diagnosed with IPEX at the time of presentation to medical care.

Patients with asthma are reported to have a higher prevalence of CVID compared with patients without asthma.¹²⁴ Whether this signifies an expansion of the atopic phenotype or whether CVID is a predisposing factor for asthma is not clear, especially because asthma has both type II and non–type II endotypes. The association of asthma with CVID is interesting in light of CVID having the highest prevalence in the USIDNET report previously mentioned.¹⁰⁶ Various monogenic etiologies encompassed under the diagnosis of CVID may provide opportunities to understand the underlying mechanism of atopy in these patients. For instance, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PI3KCD) GOF variants have been found as disease-causing in some patients originally carrying the CVID diagnosis and have been associated with atopic disease.¹²⁵

It is noteworthy that there are IEI that are associated with relative protection from some forms of allergic disease. As examples, patients with STAT3 DN and WAS are relatively protected from severe IgE-mediated immediate hypersensitivity, partly because of defects in mast cell degranulation.^126–131 In addition, GATA2 deficiency markedly impairs mast cell function and patients have lower rates of clinical allergy.¹³²

PATHWAY-SPECIFIC IMPAIRMENTS ASSOCIATED WITH IEI

Enhanced numbers and activity of allergic effector cells and/or loss of genes that contribute to the regulation of these T_H2 pathways result in pathologic allergic disease and inflammation.^11,119,133 Severe combined immunodeficiencies (SCIDs) were some of the first known IEI presenting with atopic manifestations, such as eczematous dermatitis. Although complete SCID with absent T cells hinders the ability to mount an allergic response, hypomorphic variants allow for sufficient development of allergy effector cells despite otherwise compromised T-cell immunity against infection.¹³⁴ The higher prevalence of severe clinical atopic disease in patients with IFN-γ receptor defects supports the notion that IFN-γsignaling may normally suppress T_H2 responses via counterregulation of T_H2 immunity pathways such as T-cell differentiation from naive T cells into T_H2 cells or B-cell class switching to IgE.¹⁰⁷ The following sections will highlight specific pathways whose derangements are associated with allergic inflammation (Fig 1).

Epithelial barrier disruption and risk for AD and skin infection

The integrity of the skin barrier is crucial to the prevention of allergic diseases. The link between atopy and an impaired skin barrier is not fully understood; however, activation of antigen-presenting cells by penetrating allergens, enhanced inflammation by resident microorganisms, allergic sensitization to Staphylococcus superantigens, and transepithelial water loss may all contribute to an environment more conducive to an allergic phenotype.¹¹ Furthermore, T_H2 inflammation appears to impair antimicrobial peptide production and activity, predisposing skin to infection and altered commensals.^135,136 Monogenic disorders that primarily lead to disruption of the integrity of the skin barrier have been associated with inflammatory skin diseases, most notably atopic inflammation. Loss-of-function (LOF) variants in FLG, the gene encoding filaggrin, which is responsible for organization and crosslinking of keratin filaments, lead to severe eczematous dermatitis. Genome-wide association studies reveal a central role for rare and common FLG variants in the overall risk for AD.¹² Although FLG is not expressed in the lower airways, LOF variants in FLG have been significantly associated with the development of asthma in children, which may be due to allergen sensitization in those children with AD.¹³

Desmosomes are junctional protein complexes that protect skin integrity by resisting mechanical forces. Pathogenic variants in genes that encode desmosomal junctional protein complex components corneodesmosin, desmoplakin, and desmoglein 1 are also associated with severe type II skin inflammation,^14–16 and loss of corneodesmosome serine protease inhibitor of Kazal type 5 (SPINK5) leads to severe ichthyosis, erythroderma, bamboo hair, elevated IgE, and atopy.¹⁷ Although infants with AD are more likely to develop food allergies, data from infants with variants in SPINK5 and FLG have demonstrated a significant association with food allergy that is independent of AD status.^18,19 DN and biallelic LOF variants in COL7A1, a collagen protein critical for dermal-epidermal basement membrane barrier function, typically lead to an epidermolysis bullosa phenotype characterized by skin blistering, but immune and inflammatory comorbidities including IgA nephropathy, significant itch, eosinophilic infiltrate, and T_H2 cytokine production.²⁰ There is some degree of phenotypic-genotypic correlation that has been observed in dystrophic epidermolysis bullosa whereby DN missense variants are generally associated with milder clinical disease. Dupilumab blockade of the shared receptor subunit for IL-4 and IL-13 (IL-4Rα) has proven effective for atopic manifestations associated with pathogenic variants in SPINK5^21–26 and COL7A1.^20,27,28 Immunoglobulin replacement therapy is another treatment for skin lesions of Comel-Netherton syndrome (SPINK5), with some reports of significant improvement.^29–31 The mechanism by which this improvement occurs is unknown; however, earlier literature highlighted improvement in AD symptoms in patients with severe disease.³²

Abnormal antigen receptor signaling

Activation of T and B cells and propagation of signaling are dependent on a multitude of mediators for proper transcriptional regulation of effector function, migration, proliferation, and adhesion. Defects in genes involved in this process are highly associated with atopy and are detailed herein.

Impaired actin skeleton assembly.

T-cell migration and effector functions are dependent on actin polymerization and rearrangement of the cytoskeleton. LOF variants in the genes linked to this process have been associated with disorders of severe infections, autoimmunity, and neoplastic disease, as well as variably penetrant eczematous dermatitis and other forms of allergy. These include WAS due to LOF WAS protein, and LOF variants in WAS protein–interacting protein (encoded by WIP), actin-related protein 2/3 complex subunit 1B (encoded by ARPC1B), hematopoietic protein-1 (HEM-1) (encoded by NCKAP1L [NCK-associated protein 1 like]), and DOCK8.^33–42 Abnormal actin dynamics and overlapping clinical phenotypes also feature prominently in patients with LOF in RLTPR encoding capping protein regulator and myosin 1 linker 2, which is important for CD28-mediated signaling.^43–45 The drivers of allergic inflammation in these disorders may include Treg-cell dysfunction and loss of tolerance.¹¹ The extensive viral skin infections frequently seen in DOCK8 deficiency are thought to be, in part, due to the inability of the DOCK8-deficient natural killer and T lymphocytes to migrate normally through the skin matrix, leading to lymphocyte destruction^42,46 and subsequent environment conducive to allergic inflammation.⁴⁷

CARD11-BCL10-MALT1-opathies.

The CARD11-BCL10-MALT1 (caspase recruitment domain family, member 11–B-cell chronic lymphocytic leukemia/lymphoma 10–mucosa-associated lymphoid tissue lymphoma translocation gene 1) complex is a key bridge between antigen receptor/coreceptor stimulation and activation of transcription factors necessary for regulatory and inflammatory responses, such as mediators involved in the nuclear factor-κB (NF-κB) pathway.⁴⁸ Bacterial respiratory and viral skin infections as well as autoimmunity are prominent manifestations of DN variants in CARD11. These incompletely penetrant hypomorphic variants are associated with variable interference of NF-κB signaling, allowing some effector function that can be skewed to T_H2 response with strong atopic phenotype.^48–50 Although these rare variants that negatively affect CARD11-BCL10-MALT1 component function lead to rare IEI, common, noncoding, regulatory variants that associate with decreased expression of MALT1 and CARD11 are associated with increased allergy risk, highlighting the central importance of this pathway in regulating allergic disease.⁴⁸

Activated PI3K delta syndrome.

Activated PI3K delta syndrome (APDS) is characterized by humoral immune deficiency, abnormal EBV immunity, autoimmunity, and susceptibility to lymphoproliferative phenotypes including lymphoma. It results from GOF variants in PIK3CD and PIK3R1, resulting in excessive signaling through the PI3K/AKT/mTORC1/mTORC2 pathways. Multiple atopic phenotypes including peripheral and symptomatic tissue eosinophilia (eg, EGID), allergy, eczema, and elevated IgE are also seen in APDS.^52,53 Although impaired mTORC1 may be associated with the allergic disease seen in CARD11-associated atopy with dominant interference of NF-κB signaling, there is excessive mTORC1 activity in APDS, which can explain the autoimmune/T_H1/T_H17 phenotypes. How the T_H2 phenotypes emerge may potentially be explained by excess mTORC2 activity, which has been shown to drive T_H2 responses and impair Treg-cell function.^54–56 Rapamycin, an mTORC1/mTORC2 inhibitor, has been used successfully in APDS and other primary immune regulation disorders by inhibiting effector T cells while improving the function of Treg cells.^57–59 PI3K inhibition in the form of leniolisib, a small molecule inhibitor of PI3K, is highly effective in treating the clinical phenotypes of APDS,¹²⁵ and PI3K inhibition has shown significant promise in several models of allergic inflammation.^60–63 These observations raise the possibility of rapamycin and leniolisib as precision therapies for type II–associated inflammation.

Omenn syndrome.

Hypomorphic LOF variants in genes regulating T-cell receptor rearrangement or development, which lead to SCIDs—such as LIG4, DCLRE1C, RAG1 and RAG2, ADA, IL7RA, CDH7, and IL2RG—can result in Omenn syndrome with the onset of erythroderma and eczematous dermatitis, hypereosinophilia, increased IgE levels, histiocytic and lymphocytic infiltrate, as well as hepatosplenomegaly and lymphadenopathy.^64–67 Hypomorphic, “leaky,” variants lead to oligoclonal expansion of T cells, which is not allergen-specific in neither clinical nor laboratory-based testing. Although not fully understood, leaky SCID phenotypes lead to a T_H2-like phenotype potentially because of a combination of lymphopenia-driven proliferation, oligoclonal T-cell receptor repertoire, and thymic abnormalities that affect tolerance.⁶⁸ This phenotype can manifest as early as the first few weeks of life.⁶⁷ Microbial drivers of the inflammatory process tend to occur more often in infants with less impacted gene product levels and/or function.⁶⁸ Frequently, management requires significant immune suppression before the curative hematopoietic stem cell transplantation.⁶⁹ Immunomodulators such as cyclosporine and tacrolimus are often needed to manage immune dysregulation while waiting for transplant.

Disruption of cytokine and cytokine signaling

Effective immune regulation depends on intercellular signaling initiated by cytokines and chemokines. Disrupted cellular processes involving cytokine receptors and downstream signaling molecules have been found to be associated with allergic inflammation.

Impaired IL-6 receptor/IL-6 signal transducer/STAT3/zinc finger protein 341 signaling.

STAT3 is downstream of the IL-6 receptor (IL-6R) and the cytokine coreceptor GP130, and DN variants in STAT3 lead to an IEI characterized by eczematous dermatitis and markedly elevated IgE, as well as recurrent infections including reactivation of latent viruses (eg, varicella-zoster virus and EBV), connective tissue, dental, skeletal, and vascular abnormalities reflecting the ubiquitous expression of STAT3 in a multitude of tissues, and varied cytokines and chemokines that use this pathway.⁷⁰ Additional disorders with a similar phenotype but varying nonimmunologic features along this pathway including LOF variants in IL-6 signal transducer (IL6ST), which encodes GP130, IL6R, and biallelic variants in STAT3’s promoter zinc finger protein 341.^71–73 IL-6R deficiency is limited to atopic manifestations, reduced inflammatory responses, and recurrent skin and lung infections, whereas patients with IL6ST DN variants frequently develop severe destructive lung disease with pneumatoceles and bronchiectasis, frequently associated with Aspergillus infection or allergic bronchopulmonary aspergillosis.^72–75 STAT3 DN leads to enhanced expression of IL-4R, likely explaining the success in treating atopic phenotypes with dupilumab in these patients.⁷⁶

PGM3 deficiency due to biallelic hypomorphic variants in PGM3 can lead to profound allergic disease with severe AD, food allergy, asthma, EGIDs, allergic rhinitis, allergic bronchopulmonary aspergillosis, and food-protein–induced enteropathy syndrome.^77–80 Infectious, inflammatory, and musculoskeletal and neurodevelopmental comorbidities are also present. PGM3 is critical for normal glycosylation, and the abnormal N-glycan pattern on the surface of lymphocytes can be detected via flow cytometry particularly in naive T cells.⁸⁰ The process by which abnormal glycosylation contributes to allergic inflammation is yet to be elucidated; however, decreased N-glycosylation of GP130 in PGM3 deficiency has been observed, resulting in poor surface expression, which may explain some of the phenotypic overlap with IL6ST deficiency.⁸¹

Of note, although many clinical aspects of STAT3 GOF such as significant autoimmunity and lymphoproliferation are distinctly different than STAT3 DN, as expected, patients with STAT3 GOF have a predisposition to developing eczematous dermatitis,⁸² although they do not appear to have classical IgE-mediated disease. JAK inhibitors have been shown to be effective for the treatment of atopic manifestations in STAT3 GOF by blocking downstream cytokine-induced JAK activation.⁸³

JAK1, STAT5, and STAT6 GOF.

Germline and/or somatic GOF variants in JAK1 or in STAT5B, which is directly downstream of JAK1,^84–86 can lead to profound urticaria or eczematous dermatitis, autoimmunity, failure to thrive, and marked eosinophilia. Heterozygous GOF variants in STAT6, which is also downstream of JAK1 and propagates signal via IL-4 and IL-13 receptors,⁸⁷ have recently been described in cohorts of patients with severe allergic disease.^88–93 Patients with STAT6 GOF develop the full spectrum of atopic disorders including early-onset severe AD, EGIDs, asthma, eosinophilia, elevated IgE, IgE-mediated food allergies, and anaphylaxis.⁹³ Functional studies revealed sustained STAT6 phosphorylation resulting in T_H2 skewing. Clinical response to dupilumab has been seen, as expected given the role of STAT6 in IL-4 and IL-13 signaling.⁸⁸

Improvements in AD, urticaria, autoimmunity and eosinophilia, and even food allergy, growth, and quality of life have been described with targeted inhibition of JAK1/2 in patients with JAK1 and STAT5B GOF.^86,94,95 The food allergy response raises the possibility that JAK inhibition could be a potential therapy for IgE-mediated food allergy, and in fact JAK inhibitors are being trialed for the treatment of food allergy (NCT05069831). Oral and topical JAK inhibitors are now approved for the treatment of AD.⁹⁶ For AD, JAK inhibitors have been demonstrated to be better than dupilumab in a network analysis of AD treatments⁹⁷; however, the side effect profile must be considered when long-term therapy is planned. Insights from the use of these agents in IEI could help establish recommended therapies for specific defects (eg, dupilumab vs JAK inhibitors for JAK/STAT GOF^{83,88,95,98,99}) to optimize risks and benefit considerations.

TGF-β pathway and atopy with connective tissue features.

An autosomal-dominant disorder called LDS secondary to TGF-β, TGFβR1, and TGFβR2 LOF variants predisposes to the development of AD, asthma, food allergy, and EGIDs. Although the exact mechanism by which this occurs is unknown, in vivo, these patients have increased T_H2 cytokine–producing lymphocytes, leading to elevated IgE and eosinophils.¹⁰⁰ Like STAT3 DN, LOF variants in TGF-β–related genes result in connective tissue abnormalities. A link between the 2 pathways involves the protein ERBIN (ERBB2IP), which complexes with STAT3 and limits nuclear localization of SMAD2/3. Disrupted STAT3 signaling or decreased lymphocytic ERBIN expression can lead to increased IL-4Rα expression.⁷⁶ ERBIN deficiency shares features of elevated IgE, EGID, and connective tissue abnormalities with STAT3 DN and LDS. As expected, IL-4Rα blockade was effective in an otherwise treatment-resistant ERBIN patient with eosinophilic esophagitis.¹⁰¹

IFN-γ pathway.

Rare genetic variants in IFN-γ receptor pathway genes are enriched in patients with AD with the specific phenotype of having comorbid eczema herpeticum, associated with enhanced T_H2 immunity, and suppressed production of antimicrobial peptides.^102–105 This of course raises the question as to whether the susceptibility to viral skin infection is due to loss of IFN-γ–related host defense or rather enhanced T_H2 cytokine production from loss of T_H2 counterregulation from the T_H1/IFN-γ pathway. Patients with rare and common LOF variants in IFN-γ receptor 1 are enriched for significant T_H2 laboratory phenotypes, although they tend not to be enriched for overt allergic and atopic clinical phenotypes.^{102,104,106–111} Deficiency of T-bet (encoded by TBX21), the master transcription factor for T_H1 cells, which is up-regulated by IFN-γ, has been reported in 1 patient with susceptibility to mycobacterial infection. The patient also had eosinophilia and T_H2 cytokine–driven airway disease.^112–114

IKZF1 is a transcriptional repressor of IFN-γ, and patients with IKZF1 GOF variants can develop impaired IFN-γ expression, significant allergic disease, eosinophilia, and increased IL-4 expression, in addition to autoimmunity, lymphoproliferation, and other immune dysregulations. This is in contrast to patients with IKZF1 LOF in whom atopy was not a feature and eosinopenia has been noted. It is tantalizing that immunomodulatory amide drugs such as lenalidomide cause activation of T_H1 cells by inducing proteasomal degradation of IKAROS family proteins leading to increased IFN-γ production, and treatment of patient T cells with lenalidomide improves IFN-γ expression while diminishing excess IL-4 production.¹¹⁴

A good representation of the interplay between T_H1/T_H2 immunity is illustrated by the use of anti–IL-4 blockade. Dupilumab has shown efficacy in reducing the risk of eczema herpeticum in patients with severe AD because of increased type I immune response against herpes simplex virus type 1.^115–118 Dupilumab treatment also has been reported to enhance T_H1 host defense in a patient with refractory disseminated coccidioidomycosis,¹³⁷ and various allergic fungal disorders have been successfully treated with dupilumab.^138–140

Symptoms of mast cell dysregulation

Consideration of symptoms of mast cell degranulation in the context of IEI focuses on typical IgE-mediated activation as seen in many of the disorders described herein: autoimmune urticaria as comorbid immune dysregulation, such as autoimmune polyendocrinopathy and ectodermal dysplasia syndrome¹⁴¹; lesions that cause mast cell intrinsic abnormalities, such as cold urticaria seen in PLCG2-associated antibody deficiency and immune dysregulation (PLAID); or vibratory urticaria caused by LOF variants in adhesion G protein–coupled receptor E2 (ADGRE2).¹⁴²

ADGRE2 encodes the receptor EGF-like module-containing mucin-like hormone receptor–like 2. Dissociation of a subunit of the receptor leading to mast cell degranulation occurs when physical forces such as vibration are applied.¹⁴² Subphysiologic temperatures can trigger spontaneous degranulation of mast cells in heterozygous genomic deletions in PLAID; cold urticaria, granulomatous skin disease, humoral deficiency, and autoimmunity are hallmarks of the disease.¹⁴³ The mechanism of autoimmune urticaria in autoimmune polyendocrinopathy and ectodermal dysplasia syndrome remains not elucidated. However, some case reports showed positive FCεRI antibodies, which perhaps suggests autoantibody-induced mast cell degradation.¹⁴¹

The KIT receptor is necessary for appropriate mast cell differentiation, survival, and chemotaxis, and KIT signaling enhances mast cell degranulation. Somatic and rare germline GOF variants leading to constitutive activation of the tyrosine kinase KIT can cause episodic increase in mast cell mediator release, manifesting as symptoms of recurrent urticaria, flushing, wheezing, and severe anaphylaxis.¹⁴⁴ Enhanced transcriptional activity of genes involved in anaphylaxis was also identified in an individual with a KARS missense variant who had severe anaphylaxis in response to paper wasp venom.¹⁴⁵

Acute urticaria is common in childhood and triggered spontaneously or in response to food, viral infections, and medications, but it is largely self-limited.¹⁴⁶ Recurrent urticaria beginning in infancy is potentially an early sign of IEI. Infants with somatic STAT5B GOF variants initially present with recurrent urticaria, but later develop AD, eosinophilia, and food allergy.⁸⁴ Early-onset cold urticarias are present in cryopyrin-associated periodic syndrome and PLAID; they differ, however, in that evaporative cooling triggers lesions in PLAID. Urticaria in response to vibration would raise suspicion for familial vibratory urticaria associated with ADGRE2.^147,148

Conclusions

T_H2-driven allergic inflammation is a prominent feature of many IEI, and a broad spectrum of multiple atopic conditions may be present because of the dysregulation of host immunity. Allergic disease may be the initial presentation of several of these disorders, and with the rise in polygenic allergic disease, this may prove to be a diagnostic challenge for providers. Suspicion for IEI should occur when atopic conditions cooccur with autoimmunity and/or infection susceptibility. Timely identification of monogenic variants in IEI through genetic sequencing is crucial for optimal management, and targeted therapies for genetic lesions may also improve concurrent allergic inflammation. Future work that better characterizes allergic disease in the context of specific clinical or laboratory findings and development of algorithms that inform which patients with allergy should undergo genetic testing for IEI are needed.

Abbreviations used

AD

Atopic dermatitis

ADGRE2

Adhesion G protein–coupled receptor E2

APDS

Activated PI3K delta syndrome

BCL10

B-cell chronic lymphocytic leukemia/lymphoma 10

CARD11

Caspase recruitment domain family, member 11

CVID

Common variable immunodeficiency

DN

Dominant-negative

DOCK8

Dedicator of cytokinesis 8

EGID

Eosinophilic gastrointestinal disease

ERBIN

ERBB2-interacting protein

FLG

Filaggrin

GOF

Gain of function

IEI

Inborn errors of immunity

IL-6R

IL-6 receptor

IL6ST

IL-6 signal transducer

IPEX

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked

JAK

Janus kinase

LDS

Loeys-Dietz syndrome

LOF

Loss of function

MALT1

Mucosa-associated lymphoid tissue lymphoma translocation gene 1

NF-κB

Nuclear factor-κB

PGM3

Phosphoglucomutase 3

PI3K

Phosphoinositide 3-kinase

PLAID

PLCG2-associated antibody deficiency and immune dysregulation

SCID

Severe combined immunodeficiency

SPINK5

Serine protease inhibitor of Kazal type 5

STAT

Signal transducer and activator of transcription

Treg

Regulatory T

USIDNET

United States Immunodeficiency Network

WAS

Wiskott-Aldrich syndrome

WIP

WASP-interacting protein