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Type 2 inflammation
Type 2 inflammation
Type 2 inflammation
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Type 2 inflammation (or type 2 immunity) is a pattern of immune response. Its physiological function is to defend the body against helminths, but a dysregulation of the type 2 immune response has been implicated in the pathophysiology of several diseases.[1][2] Although it has traditionally been associated with tumor promotion, emerging evidence indicates a potential tumor-suppressive potential.[3]

Molecular biology

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IL-25, IL-33, and TSLP are alarmins released from damaged epithelial cells. These cytokines mediate the activation of type 2 T helper cells (Th2 cells), group 2 innate lymphoid cells (ILC2 cells), and dendritic cells. Th2 cells and ILC2 cells secrete IL-4, IL-5 and IL-13.[1][4]

IL-4 further drives CD4+ T cell differentiation towards the Th2 subtype and induces isotype switching to IgE in B cells. IL-4 and IL-13 stimulate trafficking of eosinophils to the site of inflammation, while IL-5 promotes both eosinophil trafficking and production.[2]

Dysregulation in human disease

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Type 2 inflammation has been implicated in several chronic diseases:

Persons with one type 2 inflammatory disease are more likely to have other diseases.[10]

Pharmacological targets

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Several medicines have been developed that target mediators of type 2 inflammation:[2]

References

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Type 2 inflammation

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Type 2 inflammation is an adaptive and innate immune response characterized by the activation of T helper 2 (Th2) cells and group 2 (ILC2s), leading to the production of signature cytokines such as interleukin-4 (IL-4), IL-5, and IL-13, which promote recruitment, (IgE) class switching, mucus hypersecretion, and tissue remodeling. This response evolved primarily to combat parasitic infections like helminths but becomes dysregulated in response to environmental allergens, pollutants, or epithelial barrier disruptions, resulting in chronic allergic and atopic conditions. In its pathological form, type 2 inflammation drives a range of diseases affecting the airways, , and , including , chronic rhinosinusitis with nasal polyps (CRSwNP), , and . These conditions affect hundreds of millions worldwide, with type 2 inflammation present in 50-100% of cases depending on the disease, contributing to symptoms like wheezing, nasal obstruction, and pruritus, as well as pathological changes such as through mechanisms involving mast cells, , and epithelial-derived alarmins (e.g., [TSLP], IL-25, IL-33). Key cellular players include , which infiltrate tissues under IL-5 influence to release pro-inflammatory mediators, and Th2 cells that amplify the response via IL-4-mediated B-cell activation. Therapeutic advancements have targeted this pathway with biologic agents, such as anti-IL-4/IL-13 monoclonal antibodies (e.g., , approved 2017 for and 2018 for ) and anti-IL-5 therapies (e.g., , with recent expansion to eosinophilic COPD in 2025), which reduce exacerbations and improve in moderate-to-severe cases. Emerging research highlights the role of epithelial barrier dysfunction and alterations in initiating type 2 responses, underscoring the need for multifaceted interventions beyond blockade. Overall, understanding type 2 inflammation has transformed the management of allergic diseases, shifting from broad to precision medicine.

Definition and Overview

Core Characteristics

Type 2 inflammation represents a coordinated adaptive pattern designed to combat multicellular parasites, such as helminths, through the of Th2 cells and type 2 (ILC2s), which drive recruitment, hyperplasia, and (IgE) production. This response facilitates the expulsion of large extracellular pathogens by promoting barrier immunity at mucosal surfaces, including the airways, gut, and . In contrast to Type 1 inflammation, which is predominantly mediated by Th1 cells and interferon-γ (IFN-γ) to target intracellular pathogens like viruses and , Type 2 inflammation emphasizes humoral and eosinophil-mediated mechanisms over cytotoxic responses. Similarly, it differs from Type 3 inflammation, driven by Th17 cells and interleukin-17 (IL-17) to recruit neutrophils against extracellular and fungi at epithelial barriers. These distinctions highlight Type 2 inflammation's specialized role in anti-helminth defense, avoiding the granulomatous or neutrophilic features seen in the other types. Key hallmarks of Type 2 inflammation in affected organs include mucus hypersecretion from expansion, smooth muscle hypertrophy leading to enhanced contractility, and chronic tissue remodeling such as subepithelial . The concept of this inflammatory paradigm was formalized in the 1980s through foundational studies on subsets in murine models of helminth infections and allergies, with the Th1/Th2 dichotomy first described in 1986. By the , research on allergic airway models further solidified its characteristics in human contexts.

Historical Context

The understanding of Type 2 inflammation traces its roots to early investigations into allergic disorders in the 19th and early 20th centuries. In 1873, Charles Harrison Blackley conducted pioneering experiments demonstrating that pollen exposure triggered hay fever symptoms, marking one of the first systematic links between environmental allergens and immediate reactions characteristic of Type 2 responses. Shortly thereafter, in 1879, identified as a distinct leukocyte population with affinity for acidic dyes, noting their accumulation in tissues during parasitic infections and allergic conditions, which laid foundational observations for the cellular hallmarks of Type 2 inflammation. These early studies, though not yet framed in modern immunological terms, highlighted the eosinophil-rich infiltrates and IgE-mediated responses central to atopic diseases. A pivotal shift occurred in the with the delineation of subsets, fundamentally reshaping the conceptualization of adaptive immunity. In 1986, Tim R. Mosmann and Robert L. Coffman described two distinct murine helper clones: Th1 cells producing interferon-gamma and promoting , and Th2 cells secreting interleukin-4 (IL-4) and IL-5, which drove humoral responses, activation, and IgE production associated with and helminth defense. This Th1/Th2 paradigm, later extended to humans, established Type 2 inflammation as a coordinated cytokine-driven process, linking it explicitly to allergic and parasitic contexts through IL-4's role in class switching to IgE. The 2000s and 2010s brought deeper insights into innate mechanisms and formalized the nomenclature. In 2005, IL-33 was identified as a novel alarmin cytokine of the IL-1 family, signaling through the ST2 receptor to induce Th2-associated cytokines like IL-4, IL-5, and IL-13, amplifying Type 2 responses in barrier tissues. Concurrently, the discovery of group 2 (ILC2s) in 2010 revealed an innate counterpart to Th2 cells, capable of rapid production of Type 2 cytokines in response to epithelial-derived signals such as IL-25 and IL-33, independent of adaptive immunity. These advances culminated around 2010 in the widespread adoption of "Type 2 inflammation" terminology within and anti-parasitic immunity literature, distinguishing it from Type 1 responses and emphasizing its role in helminth expulsion and allergic airway disease. In the 2020s, research has expanded Type 2 inflammation's scope beyond and to include regulatory functions in tissue and cancer. Studies have elucidated its contributions to fibrotic remodeling in organs like the and liver, where IL-13-driven extracellular matrix deposition promotes repair but can exacerbate chronic scarring. Notably, a 2025 analysis has highlighted Type 2 immunity's tumor-suppressive potential in certain contexts, such as through eosinophil-mediated and IL-4/IL-13 signaling that restrains tumor progression in early-stage malignancies, challenging prior views of it solely as pro-tumorigenic. These developments underscore the evolving recognition of Type 2 inflammation as a versatile axis balancing host defense, repair, and pathological dysregulation.

Physiological Roles

Defense Against Parasites

Type 2 inflammation represents an evolutionarily conserved adaptive response that protects hosts from large extracellular parasites, such as nematodes and trematodes, by deploying eosinophil-mediated toxicity and mucus hypersecretion to entrap and expel invaders. This mechanism likely arose as a specialized arm of the to counter the physical and biochemical challenges posed by macroparasites, which evade classical type 1 responses through , , and immunosuppressive secretions. In this context, type 2 cytokines orchestrate tissue remodeling and cellular recruitment to create an inhospitable environment for parasite survival and reproduction.30516-2) Central to this defense are key processes driven by type 2 cytokines, including IL-5-mediated , which promotes the recruitment, survival, and activation of at sites.02534-X/fulltext) Activated undergo , releasing cytotoxic granules containing major basic protein, which damages parasite tissues through membrane disruption and , thereby contributing to larval immobilization and killing. Complementing this, IL-13 induces goblet cell in mucosal epithelia, leading to excessive production that physically entraps worms and facilitates their expulsion via and smooth muscle contraction. These coordinated actions enhance barrier integrity and promote worm clearance without excessive host tissue destruction in acute infections. Illustrative examples include , where type 2 inflammation forms -rich granulomas around trapped parasite eggs in hepatic and intestinal tissues, sequestering antigens and limiting systemic dissemination while aiding egg excretion. In infections, such as those caused by , the type 2 response correlates with reduced worm burdens, as IL-13-driven and activity accelerate larval and adult expulsion from the gut, particularly in previously exposed hosts. Evidence from animal models underscores these roles; for instance, IL-4/IL-13 knockout mice exhibit severely impaired expulsion of the nematode Nippostrongylus brasiliensis, with delayed goblet cell hyperplasia and reduced eosinophil infiltration, resulting in prolonged intestinal parasitism compared to wild-type controls.80477-X) This deficiency highlights the non-redundant contributions of these cytokines to effective anti-helminth immunity.80477-X)

Tissue Homeostasis and Repair

Type 2 inflammation contributes to tissue homeostasis by supporting epithelial barrier integrity, particularly in response to injury. Group 2 innate lymphoid cells (ILC2s), activated by alarmins such as IL-33 released from damaged epithelium, produce IL-13, which promotes epithelial cell proliferation and regeneration. For instance, IL-13 enhances the self-renewal of LGR5+ stem cells in the intestinal crypts, facilitating barrier repair post-injury. Additionally, ILC2-derived amphiregulin, an epidermal growth factor-like molecule, strengthens epithelial barriers by upregulating tight junction proteins such as claudin-1 and promoting mucin production, thereby restoring integrity in the lungs and gut after viral or mechanical damage. These actions collectively maintain epithelial function without invoking chronic inflammatory pathways. In , type 2 inflammation aids acute tissue repair through -derived mediators that modulate activity. Eosinophils release transforming growth factor-β (TGF-β), which stimulates proliferation and deposition essential for formation during the proliferative phase of healing. This process supports controlled remodeling in and wounds, preventing excessive scarring in non-pathological settings, as evidenced by eosinophil infiltration in burn injuries where TGF-β promotes epithelial migration and development. Studies in wound models demonstrate that disruption of type 2 signaling impairs this response; for example, IL-4Rα-deficient mice exhibit delayed epithelialization and reduced wound closure rates compared to wild-type controls, highlighting the receptor's role in coordinating myeloid cell-dependent repair. Type 2 inflammation also influences metabolic via IL-4-mediated regulation of function. IL-4 inhibits by suppressing accumulation and promoting in adipocytes, thereby enhancing expenditure and glucose utilization. This occurs through activation of pathways like the futile triacylglyceride cycle, which supports and insulin sensitivity, linking type 2 cytokines to systemic balance in .

Molecular and Cellular Mechanisms

Alarmins and Initiation

Type 2 inflammation is initiated by alarmins, a group of epithelial-derived cytokines that act as early danger signals in response to tissue stress or damage. These include interleukin-25 (IL-25), interleukin-33 (IL-33), and (TSLP), which are rapidly released from barrier tissues such as the airway or skin upon exposure to environmental insults. Unlike classical cytokines stored in granules, alarmins like IL-33 originate from the nucleus and are actively transcribed or passively released during cell injury, functioning as part of the IL-1 family to bridge innate and adaptive immunity. IL-25, also known as IL-17E, was identified in 2001 as a Th2-promoting produced by Th2 cells and epithelial cells, capable of inducing IL-4, IL-5, and IL-13 expression . It is released from stressed epithelial cells and acts primarily on tuft cells and type 2 (ILC2s) to amplify type 2 responses, though its role is more prominent in gastrointestinal contexts compared to airways. IL-33, discovered in 2005 as a ligand for the ST2 receptor (previously an associated with Th2 responses), is a nuclear alarmin that, upon release, binds to ST2 on ILC2s and Th2 cells, triggering rapid production of type 2 such as IL-5 and IL-13 to orchestrate recruitment and production. TSLP, an IL-7-like , complements these by activating dendritic cells to prime naive T cells toward a Th2 , enhancing allergen-specific IgE production and sustaining . Environmental triggers, such as allergens and pollutants, initiate alarmin release by compromising epithelial integrity. For instance, proteases from (e.g., ragweed or ) or cleave tight junctions like PAR-2 and E-cadherin, allowing passive leakage of nuclear IL-33 and active secretion of TSLP and IL-25 from damaged cells. This protease-driven mechanism activates the ripoptosome complex in epithelial cells, amplifying alarmin production and linking environmental exposure directly to type 2 immune activation. Downstream, these alarmins converge to drive networks that propagate the response.

Key Cytokines and Pathways

Type 2 inflammation is primarily driven by a triad of cytokines—interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13)—which orchestrate immune responses characterized by activation, IgE production, and tissue remodeling. IL-4 plays a pivotal role in Th2 cell differentiation and B cell IgE class switching by activating the transcription factor STAT6, thereby promoting allergic sensitization and . IL-5 specifically supports survival, maturation, and recruitment through binding to the IL-5 receptor α chain (IL-5Rα), contributing to infiltration in affected tissues. IL-13, closely related to IL-4, induces hypersecretion, airway hyperresponsiveness, and via the shared type II receptor complex comprising IL-4Rα and IL-13Rα1. These cytokines signal predominantly through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, where IL-4 and IL-13 bind their receptors to activate JAK1/JAK3 or JAK2/TYK2, leading to phosphorylation and nuclear translocation of STAT6. Phosphorylated STAT6 then induces expression of the Th2 master regulator GATA3, amplifying transcription of type 2 genes and consolidating Th2 polarization. Additional pathways, such as Notch signaling, facilitate Th2 cell differentiation by interacting with cues to promote IL-4 production during helminth infections and allergic responses. , a , further supports Th2 polarization by regulating functions that drive IL-4-dependent T cell responses. IL-4 and IL-13 exhibit functional redundancy due to their shared utilization of the IL-4Rα subunit in receptor complexes, allowing overlapping effects on epithelial cells and fibroblasts despite distinct primary receptors.00842-9/fulltext) This redundancy is evident in their concerted promotion of and deposition in type 2-driven pathologies. Receptor binding affinity is quantified by the KdK_d, defined as Kd=[IL−4][IL−4Rα][IL−4⋅IL−4Rα],K_d = \frac{[IL-4][IL-4R\alpha]}{[IL-4 \cdot IL-4R\alpha]}, where typical values for IL-4 binding to IL-4Rα range from 20 to 300 pM, reflecting high-affinity interactions essential for efficient signaling. Alarmins like IL-33 can upstream initiate these cascades by priming epithelial responses, but the effector phase relies on IL-4, IL-5, and IL-13 amplification. In clinical models of , enzyme-linked immunosorbent assay () measurements of these cytokines in (BAL) fluid provide insights into severity.

Primary Immune Cells Involved

Type 2 inflammation is orchestrated primarily by a network of adaptive and innate immune cells that coordinate cytokine production, recruitment, and effector functions to drive the response. Central to this process are T helper 2 (Th2) cells and group 2 (ILC2s), which serve as key initiators and amplifiers. Th2 cells, a subset of + T cells, differentiate from naive T cells under the influence of the transcription factor GATA3 and produce signature including IL-4, IL-5, and IL-13 to promote B cell class switching, eosinophil survival, and production. ILC2s act as the innate counterparts to Th2 cells, enabling a rapid response through early secretion of IL-5 and IL-13 upon activation by alarmins such as IL-33, thereby bridging innate and adaptive immunity without requiring antigen-specific priming. Eosinophils function as major effector cells in Type 2 inflammation, recruited to tissues via the eotaxin and its receptor CCR3, where they release cytotoxic granule proteins such as major basic protein (MBP) and (EPO) to target parasites and modulate inflammation. In peripheral blood, normal counts are typically below 500 cells/μL, but elevations exceeding 5% of total leukocytes indicate active Type 2 inflammation, as observed in conditions like . Mast cells and contribute to the acute phase of Type 2 responses through IgE-dependent mechanisms. Mast cells, resident in tissues, undergo upon IgE cross-linking with FcεRI, releasing preformed mediators like and proteases that promote and smooth muscle contraction. , circulating granulocytes, serve as an early source of IL-4 during acute inflammation and similarly degranulate to release and cytokines upon IgE activation, enhancing Th2 differentiation and recruitment.

Pathophysiology and Dysregulation

Mechanisms of Aberrant Activation

In type 2 inflammation, aberrant occurs when physiological responses fail to resolve, leading to chronicity through dysregulated immune suppression, self-perpetuating signaling, and sustained initiation cues. This dysregulation transforms an adaptive response into a pathological state, characterized by persistent and Th2 cell activity without effective counter-regulation. Key mechanisms include impairments in and alterations in pro-resolving pathways, which collectively prolong inflammation in tissues such as the airways and mucosa. One major persistence factor is the impairment of regulatory T cells (Tregs), which normally suppress type 2 responses via secretion of anti-inflammatory s like interleukin-10 (IL-10) and transforming growth factor-β (TGF-β). In chronic settings, Tregs exhibit functional defects, reducing their ability to inhibit Th2 production and recruitment, thereby allowing unchecked IL-4 and IL-13 signaling. This Treg dysfunction is evident in allergic airway diseases, where diminished IL-10/TGF-β activity correlates with exacerbated Th2-mediated inflammation. Additionally, epigenetic modifications, such as enhanced and DNA hypomethylation at the GATA3 promoter, stabilize GATA3 expression in Th2 cells and innate lymphoid cells type 2 (ILC2s), promoting sustained transcription of type 2 s like IL-5 and IL-13. These changes lock cells into a pro-inflammatory state, resisting resolution signals and contributing to long-term immune memory in type 2-high environments. Feedback loops further entrench chronicity, exemplified by IL-13 induction of 15-lipoxygenase (ALOX15) in airway epithelial cells and macrophages, which generates lipid mediators that amplify type 2 responses. ALOX15 catalyzes the production of 15-hydroxyeicosatetraenoic acid (15-HETE), which promotes hypersecretion and airway remodeling. This loop is prominent in , a type 2-high condition, where elevated ALOX15 expression correlates with persistent inflammation. Separately, cysteinyl s such as E4 (LTE4), produced via the 5-lipoxygenase pathway in and mast cells, act on the cysteinyl leukotriene receptor 2 (CysLT2R) on Th2 cells and ILC2s, promoting further IL-13 release and forming a vicious cycle of activation and tissue damage. Barrier dysfunction in epithelial tissues also drives aberrant activation by enabling chronic release of alarmins such as IL-33 and (TSLP) from damaged cells. Defective epithelial junctions, often due to protease activity from allergens or pollutants, compromise barrier integrity, leading to ongoing alarmin exposure that continuously stimulates to produce IL-5 and IL-13. This sustained ILC2 activation bypasses initial triggers, maintaining and mucus hypersecretion independently of external stimuli. In type 2 inflammatory contexts, such as , this epithelial-immune crosstalk perpetuates a low-grade inflammatory state resistant to natural resolution. Failure of resolution mechanisms compounds these issues, particularly through reduced production of pro-resolving mediators like lipoxin A4 (LXA4). In type 2-high states, diminished LXA4 levels—derived from the transcellular metabolism of by 5- and 15-lipoxygenases—impair the clearance of and the restoration of epithelial integrity. LXA4 normally acts via its receptor ALX/FPR2 to suppress IL-13 signaling and promote Treg function, but its deficiency in severe airways correlates with prolonged and impaired tissue repair. This reduction shifts the eicosanoid balance toward pro-inflammatory leukotrienes, hindering the transition from to .

Genetic and Environmental Contributors

Genetic factors play a significant role in predisposing individuals to dysregulation of Type 2 inflammation, particularly through polymorphisms that enhance signaling in key pathways. The I50V variant (rs1801275) in the IL4RA gene, which encodes the alpha chain, increases receptor signaling and STAT6 activation, thereby amplifying Th2 responses and elevating risk for atopic conditions such as . Similarly, mutations in ADAM33, a disintegrin and involved in remodeling, are associated with airway hyperresponsiveness and structural changes in the lungs, independent of overt inflammation, as identified in early positional cloning studies of susceptibility loci. Genome-wide association studies (GWAS) from the 2010s have further highlighted loci near IL33 and TSLP; for instance, variants at the IL33 locus on chromosome 9p24 enhance IL-33 expression, promoting alarmin-driven Type 2 immunity in epithelial cells, while TSLP variants on chromosome 5q22 influence production, exacerbating allergic sensitization in multiple ancestries. Environmental exposures, especially during early life, modulate the risk of Type 2 inflammation by shaping immune development and . Living on a in childhood, often termed the "farm effect," confers protection against and through increased exposure to diverse microbes, such as those in unpasteurized milk and animal , which foster regulatory T-cell responses and reduce Th2 skewing. In contrast, urban , including particulate matter and , promotes and epithelial damage, leading to heightened alarmin release and Type 2 production, thereby increasing susceptibility in genetically prone individuals. The gut exerts a profound influence on Type 2 inflammation via the , which posits that reduced microbial diversity in modern environments impairs . characterized by low abundance of species skews the toward Th2 dominance by diminishing short-chain production and regulatory T-cell induction, as demonstrated in models of and . This concept originated from epidemiological observations linking larger household sizes—and thus greater early infection exposure—to lower hay fever incidence, suggesting that diminished microbial challenges in hygienic settings drive allergic predisposition. Gene-environment interactions further amplify risk; for example, loss-of-function mutations in the filaggrin (FLG) gene compromise skin barrier integrity, allowing penetration that triggers the atopic march from to respiratory allergies in polluted or -rich environments.

Associated Diseases

Allergic and Atopic Conditions

Type 2 inflammation underlies the of several classic allergic and atopic conditions, where dysregulated immune responses lead to chronic symptoms driven by Th2 cytokines such as IL-4, IL-5, and IL-13. In these diseases, epithelial barrier dysfunction and exposure trigger the release of alarmins, promoting recruitment, IgE production, and activation, which perpetuate . Asthma, particularly the type 2-high subset, exemplifies this process, affecting approximately 50% of patients with mild to moderate disease and characterized by eosinophilic airway inflammation. This endotype features recurrent symptoms including wheezing, , and , often exacerbated by allergens, with associated declines in forced expiratory volume in 1 second (FEV1) during attacks. , recruited by IL-5, infiltrate the airways, contributing to hypersecretion and . Atopic dermatitis involves skin barrier defects exacerbated by type 2 inflammation, where IL-4 and IL-13 disrupt expression and promote Th2-skewed responses, leading to chronic and skin thickening. These cytokines drive neurogenic through activation and induce lichenification via collagen production, resulting in thickened, inflamed skin lesions. Disease severity is commonly assessed using the SCORAD index, which evaluates extent, intensity, and subjective symptoms like pruritus. Allergic rhinitis manifests as nasal inflammation with type 2 cytokine-driven in the , causing symptoms such as sneezing, , and congestion following exposure. IL-5 enhances survival and recruitment, while IL-4 and IL-13 amplify IgE-mediated , contributing to early- and late-phase responses. The classification categorizes it by duration (intermittent or persistent) and severity (mild or moderate/severe), based on symptom impact on daily activities and . The atopic march describes the sequential progression of type 2 inflammatory diseases, often starting with in infancy and advancing to and in childhood. Cohort studies from the indicate that children with atopic dermatitis face a 20-30% risk of developing asthma by age 6, with early-onset eczema increasing the odds through persistent Th2 sensitization and barrier impairment. This trajectory is supported by longitudinal data showing heightened IgE levels as a marker of progression risk.

Chronic Respiratory and Skin Disorders

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a subtype of chronic rhinosinusitis characterized by the presence of nasal polyps and persistent of the sinonasal mucosa, often driven by type 2 immune responses. In Western populations, CRSwNP predominantly exhibits a type 2 inflammatory endotype, with elevated expression of cytokines such as IL-5, which promotes recruitment and polyp formation in approximately 80% of cases. This IL-5-driven contributes to tissue remodeling and polyp persistence, distinguishing it from non-type 2 forms more common in Asian cohorts. Disease severity is commonly assessed using the Lund-Kennedy endoscopic scoring system, which evaluates polyp size, , discharge, and other mucosal changes on a scale that correlates with symptom burden and treatment response. CRSwNP affects about 1% to 4% of adults worldwide, with higher in urban and elderly populations. Eosinophilic esophagitis (EoE) represents a chronic, immune-mediated esophageal disorder involving type 2 inflammation, leading to accumulation and esophageal dysfunction. Diagnosis requires symptoms of esophageal dysfunction, such as and food impaction, alongside esophageal of at least 15 per high-power field on , after confirming nonresponsiveness to (PPI) therapy to exclude PPI-responsive esophageal . Type 2 cytokines like IL-4, IL-5, and IL-13 orchestrate this eosinophilic infiltration, often triggered by environmental allergens or food antigens, resulting in and stricture formation if untreated. The incidence of EoE has risen markedly since the establishment of diagnostic criteria in the 1990s, increasing from approximately 0.01 per 100,000 in 1995 to over 3 per 100,000 by 2019 and approximately 34 per 100,000 patient-years by 2023, reflecting improved recognition and potential environmental factors. Subsets of (IPF) exhibit type 2 inflammatory signatures, highlighting an overlap with chronic type 2-driven pathologies despite IPF's primary association with type 1 and fibrotic responses. In particular, elevated IL-13 expression in IPF lung tissue correlates with disease progression in certain patient subsets, promoting alveolar epithelial dysfunction and deposition through activation of type 2 (ILC2s) and fibroblasts. Studies from 2018 demonstrated that IL-13 signaling exacerbates fibrosis in allergen- and TGF-α-induced models, suggesting therapeutic potential in targeting this pathway for type 2-high IPF variants, however, clinical trials with IL-13 inhibitors, such as SAR156597, have not demonstrated efficacy in slowing lung function decline. This dysregulation may stem from aberrant activation of type 2 pathways in response to epithelial injury, as detailed in broader discussions.

Emerging Associations (Fibrosis and Cancer)

Type 2 inflammation contributes to fibrotic diseases through synergistic interactions and cellular mechanisms that promote deposition. Interleukin-13 (IL-13) collaborates with transforming growth factor-β (TGF-β) to drive organ , as IL-13 selectively induces TGF-β1 expression and activation in s and stellate cells, leading to excessive production. In schistosomiasis-associated liver , IL-13 acts as the dominant pro-fibrotic , stimulating hepatic stellate cells to produce TGF-β and via signaling through the IL-13 receptor α2. Similarly, in (IPF), IL-13 exacerbates lung by enhancing TGF-β-mediated differentiation and matrix synthesis, with preclinical models showing that IL-13 blockade attenuates bleomycin-induced accumulation. M2-polarized macrophages further amplify this process by upregulating arginase-1, which depletes L-arginine to favor synthesis and deposition; in hepatic models, arginase-1 expression in M2 macrophages directly correlates with increased fibrotic and tissue remodeling. In oncological contexts, Type 2 inflammation displays a dual role, both promoting and suppressing tumor progression. Classically, IL-4 fosters tumor by inducing (VEGF) expression in endothelial cells and tumor-associated macrophages, thereby enhancing vascularization and supporting cancer cell proliferation in solid tumors. Conversely, recent evidence underscores protective effects, particularly through eosinophil-mediated cytotoxicity. A 2025 study in revealed that tumor-infiltrating exhibit direct anti-tumor activity via granule protein release and , correlating with improved patient survival and reduced in the . Post-COVID-19 observations highlight Type 2 's involvement in fibrotic sequelae. In , persistent Type 2 signatures, including IL-13 elevation, drive by activating fibroblasts and promoting TGF-β-dependent collagen deposition, as documented in studies from 2022–2024 analyzing post-viral tissue. during the acute phase of is a marker of severe and poor , often preceding fibrotic complications, while recovery post-acutely predicts reduced risk of persistent . Additionally, in obesity-related , IL-33 released from stromal cells elicits Type 2 responses that mitigate metabolic dysfunction; 2010s research showed that IL-33 administration in obese mouse models reduces adiposity, attenuates adipose , and improves insulin sensitivity by expanding regulatory T cells and in fat depots.

Diagnosis and Biomarkers

Clinical Assessment Methods

Clinical assessment of Type 2 inflammation begins with a detailed patient history and to identify and suggestive clinical features. Screening for involves inquiring about personal or family history of allergic conditions such as , , , or food allergies, which are common in Type 2-dominant diseases. may reveal signs like wheezing on in , nasal polyps visible via anterior rhinoscopy in chronic rhinosinusitis with nasal polyps (CRSwNP), or eczematous skin lesions in . These findings help stratify patients for further evaluation, as Type 2 inflammation often presents with recurrent allergic symptoms triggered by environmental exposures. Functional tests provide objective measures of airway involvement and allergen sensitization. Spirometry is a cornerstone for assessing asthma, where a reduced forced expiratory volume in 1 second to forced vital capacity ratio (FEV1/FVC < 0.7) indicates airflow obstruction, supporting a diagnosis of Type 2-high asthma when combined with clinical history. Skin prick testing evaluates IgE-mediated sensitization to common aeroallergens or food allergens, with a positive wheal response (≥3 mm induration) confirming atopy relevant to Type 2 pathways in conditions like allergic asthma or rhinitis. These tests guide phenotyping without relying on invasive procedures initially. Imaging and endoscopic evaluations are employed for structural assessment in specific Type 2-associated disorders. Computed tomography (CT) of the sinuses is recommended for CRSwNP, revealing mucosal thickening, polypoid changes, or opacification in the to confirm disease extent and rule out complications. For eosinophilic esophagitis (EoE), upper with esophageal is essential, identifying endoscopic features such as rings, furrows, or exudates, followed by histopathological confirmation of eosinophilic infiltration. Guidelines from the Global Initiative for Asthma (GINA) 2025 emphasize Type 2 phenotyping during clinical assessment to tailor management, recommending integration of , , and testing alongside biomarkers such as blood (≥300 cells/μL) and fractional exhaled (FeNO) for precise identification of eosinophilic or allergic subtypes. This approach ensures comprehensive evaluation across Type 2 inflammation manifestations.

Specific Biomarkers

Specific biomarkers for Type 2 inflammation primarily include measures of eosinophil activation, (IgE) levels, and production in blood and exhaled air, which help identify eosinophil-driven immune responses characteristic of this pathway. Blood counts exceeding 300 cells/μL are a key indicator of Type 2 inflammation, particularly in , as they correlate with increased risk of exacerbations and responsiveness to therapy. Total serum IgE levels above 100 IU/mL further support the diagnosis of allergic Type 2 processes, reflecting B-cell activation and allergen-specific responses in conditions like atopic . Fractional exhaled (FeNO) levels greater than 50 ppb indicate eosinophilic airway inflammation driven by IL-13 signaling, providing a non-invasive measure of epithelial-derived Type 2 activity. In tissue samples, eosinophil cationic protein (ECP) detected in induced sputum serves as a direct marker of eosinophil degranulation and airway inflammation in Type 2-dominant diseases. Elevated ECP levels reflect granular protein release from activated eosinophils, which contribute to tissue damage and mucus hypersecretion. Serum periostin, measured via enzyme-linked immunosorbent assay (ELISA) with a cutoff of approximately 25 ng/mL, acts as a surrogate for IL-13 activity, as it is upregulated in response to this cytokine and associates with persistent eosinophilia in the airways. These biomarkers collectively guide clinical decision-making, as Type 2-high profiles in —defined by elevated , IgE, or FeNO—predict favorable responses to biologics targeting IL-5 or IL-4/IL-13 pathways, as demonstrated in the SIRIUS study for . Post-2020 advancements in multiplex assays, such as parallel reaction monitoring for and , enable simultaneous profiling of multiple Type 2 markers in serum or plasma, supporting precision approaches to stratify patients for targeted therapies.

Therapeutic Approaches

Established Pharmacological Targets

Established pharmacological targets for Type 2 inflammation primarily focus on biologics and small-molecule inhibitors that block key cytokines, immunoglobulins, and signaling pathways involved in and allergic responses. These agents have been approved by regulatory authorities like the FDA for conditions such as severe and , where Type 2 inflammation drives pathology. Approval timelines and efficacy data stem from large-scale phase III trials demonstrating reductions in exacerbations, improvements in lung function, and symptom control. Dupilumab, a that inhibits signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13) by binding the IL-4 receptor alpha subunit, received FDA approval in March 2017 for moderate-to-severe in adults and adolescents aged 12 years and older, and in October 2018 for add-on maintenance treatment of moderate-to-severe with an or oral dependence in patients aged 12 years and older. In September 2024, it was approved as an add-on maintenance treatment for adults with (COPD) with type 2 inflammation, and in June 2025 for in adults. The recommended adult dosing is an initial subcutaneous (SC) dose of 600 mg followed by 300 mg every other week. In the phase III LIBERTY ASTHMA QUEST trial (n=1902 patients with uncontrolled moderate-to-severe ), dupilumab reduced the annualized rate of severe exacerbations by 47.7% compared to placebo (rate ratio 0.53; 95% CI, 0.45-0.63) and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) by 320 mL at week 12 (least-squares mean difference; 95% CI, 240-400 mL). Mepolizumab, an anti-IL-5 that prevents maturation and activation, was approved by the FDA in November 2015 for add-on maintenance treatment of severe with an in adults and adolescents aged 12 years and older. In 2025, its indication was expanded to include add-on treatment of COPD with type 2 inflammation in adults. It is administered as 100 mg SC every 4 weeks. In the phase III MENSA trial (n=576 patients), reduced the rate of exacerbations by 47% to 50% versus over 32 weeks, with greater benefits in patients with baseline blood ≥300 cells/μL. Benralizumab, an afucosylated anti-IL-5 receptor alpha that induces depletion via antibody-dependent cell-mediated cytotoxicity, received FDA approval in November 2017 for the same indication in patients aged 12 years and older. Dosing is 30 mg SC every 4 weeks for the first three doses, followed by every 8 weeks. In the phase III SIROCCO and CALIMA trials (pooled n=2339 patients with severe uncontrolled ), benralizumab reduced annualized exacerbation rates by 28% to 51% versus , with near-complete blood depletion observed within 24 hours of the first dose and sustained for up to 60 weeks. Omalizumab, a recombinant humanized anti-IgE that binds free IgE to prevent its interaction with high-affinity receptors on mast cells and , was approved by the FDA in June 2003 for moderate-to-severe persistent allergic inadequately controlled with inhaled corticosteroids in patients aged 6 years and older. Dosing ranges from 75 to 375 mg SC every 2 or 4 weeks, determined by baseline serum total IgE levels (30-700 IU/mL) and body weight. In pivotal phase III trials (e.g., n=1071 patients), reduced exacerbations by 25% to 60% compared to over 16 to 28 weeks, with the greatest reductions in patients with high baseline IgE and perennial allergen sensitivity. Other established agents include tezepelumab, an anti-thymic stromal lymphopoietin (TSLP) approved by the FDA in December 2021 for add-on maintenance treatment of severe in adults and adolescents aged 12 years and older, regardless of . It is dosed at 210 mg SC every 4 weeks and targets an upstream epithelial-derived in Type 2 inflammation. In the phase III (n=1061 patients), tezepelumab reduced annualized severe rates by 56% versus over 52 weeks (rate ratio 0.44; 95% CI, 0.35-0.56), with consistent benefits across low- and high- subgroups. antagonists, such as , a inhibitor approved by the FDA in February 1998 for prophylaxis and chronic treatment of in adults and children aged 12 months and older, represent an earlier oral small-molecule option. Administered as 10 mg orally once daily in adults, montelukast modestly reduces exacerbations and improves symptoms in mild-to-moderate persistent , with phase III trials showing approximately 30% to 40% reductions in daytime symptoms and rescue medication use versus over 12 weeks.

Emerging and Investigational Therapies

, a that selectively targets interleukin-13 (IL-13) without affecting IL-4 signaling, received FDA approval in September 2024 for the treatment of moderate-to-severe in adults and adolescents aged 12 years and older weighing at least 40 kg. Clinical trials demonstrated its efficacy in reducing and through specific blockade of the IL-13 pathway, a key driver of type 2 inflammation. Nemolizumab, an anti-IL-31 receptor A , was approved by the FDA in 2024 for moderate-to-severe and , addressing as a prominent symptom of type 2 inflammation. By inhibiting IL-31 signaling, it reduces pruritus and associated skin inflammation without broadly suppressing other cytokines. Lirentelimab, an agonist of SIGLEC-8 on and mast cells, reached phase II development for eosinophil-driven type 2 conditions but was discontinued in 2024 following underwhelming efficacy results in trials for and related disorders. Rocat inlimab, an anti-OX40 ligand antibody that modulates T-cell activation in type 2 responses, is in phase III trials for moderate-to-severe , with 2024 top-line data showing sustained efficacy in reducing during long-term extension studies. This approach targets upstream T-cell costimulation to achieve broader inhibition. For linked to type 2 , anti-TWEAK antibodies have demonstrated preclinical promise in reducing renal and pulmonary fibrotic progression by blocking TWEAK/Fn14-mediated pathways. Depemokimab, an ultra-long-acting anti-IL-5 designed for six-month dosing intervals, showed positive results in phase III trials in 2024, reducing severe exacerbations by up to 50% in patients with type 2 inflammation. The FDA accepted applications for review in March 2025 for add-on maintenance treatment of severe with type 2 inflammation and chronic rhinosinusitis with nasal polyps in adults. Gene and cell therapies remain in early stages; preclinical studies have explored CRISPR-based of the to disrupt type 2 signaling, though no emerged by 2025. Similarly, ILC2-targeted cellular therapies, including adoptive transfers, are under investigation for modulating innate lymphoid cell-driven , with early 2025 trials focusing on in allergic models.01347-8) Combination strategies, such as paired with anti-IL-33 agents like itepekimab, are being evaluated in ongoing trials to enhance type 2 blockade, with 2023 phase II data suggesting additive effects on exacerbation reduction in and COPD. Key challenges include biomarker-based patient stratification to predict responders, as variability in IL-4, IL-13, and levels complicates therapy selection. Future outlooks emphasize multi-cytokine inhibitors and fibrosis-specific agents to address unmet needs in chronic type 2 diseases post-2025.

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