Disease Pathophysiology Research Report
Target Disease - Disease Name: Atopic Dermatitis (AD) - MONDO ID: MONDO:0004994 - Category: Complex
Pathophysiology description (current understanding, 2023–2025 emphasis) Atopic dermatitis is a chronic, relapsing inflammatory dermatosis driven by the interplay of epidermal barrier dysfunction, type 2–skewed immunity, neuroimmune pruritus circuitry, and microbial/ environmental exposures. Barrier failure (filaggrin insufficiency, altered ceramide composition, and tight-junction defects) permits enhanced allergen/microbe ingress and promotes alarmin release, which activates dendritic cells and ILC2/Th2 axes. IL-4/IL-13 signaling amplifies inflammation and further downregulates barrier genes, establishing feed-forward loops. Pruritus is sustained by neuroimmune mediators—especially IL-31—signaling to TRP channel–bearing sensory afferents and, in chronic exposure, engaging a paradoxical neurogenic anti–type 2 brake via CGRP. JAK–STAT integrates many of these cytokine signals and is a validated therapeutic hub. Multi-omics studies reveal clinically relevant endotypes aligning cutaneous and blood transcriptomes with phenotypes and treatment trajectories. Therapeutically, targeting IL-4/IL-13 (dupilumab; IL-13 inhibitors) and JAK1/2 pathways improves disease activity and, in some studies, barrier function, supporting causal roles for these axes in AD. (katsarou2023theroleof pages 12-12, kamata2025mechanismsofitch pages 2-4, torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4, bai2025atopicdermatitisdiagnosis pages 25-26, zhakparov2026protectiveandsusceptibility pages 22-23)
Key concepts and definitions (with recent sources) - Epidermal barrier dysfunction: Tight junction (TJ) impairment (e.g., reduced claudin-1) and filaggrin deficiency increase permeability and trans-epidermal water loss, facilitating allergen and pathogen entry; Th2 cytokines suppress TJ proteins. Quote: “Impaired TJ barrier function and skin permeability in AD lesions is correlated with cldn-1 levels. Th2 inflammation inhibits the expression of cldn-1 and cldn-23” (Feb 2023, Journal of Clinical Medicine; URL: https://doi.org/10.3390/jcm12041538). (katsarou2023theroleof pages 12-12) - Type 2 cytokine axis: IL-4 and IL-13 orchestrate barrier disruption, dysbiosis, pruritus, and inflammation in AD. Narrative review emphasis: “IL-4 plays a critical role in skin barrier dysfunction, dysbiosis, pruritus, and inflammation” (Feb 2025, Dermatology and Therapy; URL: https://doi.org/10.1007/s13555-025-01352-y). (torres2025interleukin4andatopic pages 14-15) - Neuroimmune itch (IL-31 axis): IL-31 acts directly on pruritoceptors (IL31RA/OSMR) to induce itch and neurite outgrowth and is a central mediator of AD pruritus. Quote: “IL-31 directly induces pruritus… and selectively promotes nerve fiber extension in these neurons” (Jan 2025, Juntendo Medical Journal; URL: https://doi.org/10.14789/ejmj.jmj24-0036-r). (kamata2025mechanismsofitch pages 2-4) - Neurogenic restraint of type 2 inflammation: In chronic allergen exposure, IL-31 activation of sensory neurons can trigger CGRP release that suppresses Th2 responses, providing a mechanistic basis for paradoxical flares with anti–IL-31 receptor therapy. Quote: “IL-31… restrains cutaneous type 2 inflammation… IL-31 activation of IL31RA+ pruritoceptors triggers release of calcitonin gene-related protein (CGRP), which… inhibit[s] CD4+ T cell proliferation and reduce[s]… IL-13” (Oct 2023, Science Immunology; URL: https://doi.org/10.1126/sciimmunol.abi6887). (bai2025atopicdermatitisdiagnosis pages 25-26) - JAK–STAT as hub pathway: Many AD cytokines signal via JAKs; clinical efficacy of oral and topical JAK inhibitors supports centrality of this pathway (reviewed 2025). (urzua2025skinbarrierdysfunction pages 3-4) - Molecular endotypes: Integrated skin and blood transcriptomics uncover endotype–phenotype associations and clusters aligned with severity and trajectories, enabling personalized monitoring. (Oct 2023, Nature Communications; URL: https://doi.org/10.1038/s41467-023-41857-8). (bilinski2025antiinflammatorytherapiesfor pages 2-4)
1) Core Pathophysiology - Primary mechanisms - Barrier failure: FLG deficiency and TJ defects (e.g., CLDN1) lead to increased permeability; scratching worsens claudin-1 loss and barrier leak. Th2 cytokines (IL-4/IL-13) suppress claudins and barrier proteins, coupling immunity to barrier pathology (Feb 2023; URL above). (katsarou2023theroleof pages 12-12) - Epithelial alarmins: Barrier stress releases TSLP/IL-33/IL-25 from keratinocytes, priming DCs/ILC2/Th2; their role is integrated within itch reviews and type 2 discussions (2025; URLs below). (kamata2025mechanismsofitch pages 2-4, torres2025interleukin4andatopic pages 14-15) - Type 2 immunity: IL-4/IL-13 drive IgE class switching, eosinophilia, keratinocyte chemokine production, and barrier gene suppression. (torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4) - Neuroimmune itch: IL-31→IL31RA/OSMR on TRPV1/TRPA1+ small-diameter afferents; neuronal plasticity (hyperinnervation) correlates with itch; Sema3A↓ and NGF↑ alter epidermal innervation in AD (Jan 2025; URL below). (kamata2025mechanismsofitch pages 2-4) - Neurogenic restraint loop: IL-31–induced CGRP limits Th2 cell accumulation and IL-13 output in chronic allergen dermatitis (Oct 2023; URL below). (bai2025atopicdermatitisdiagnosis pages 25-26) - JAK–STAT integration: Many cytokines (IL-4/IL-13/IL-31/TSLP) signal through JAK1/2→STAT6/others; clinical responses to JAK inhibition reflect pathway centrality (Jun 2025; URL below). (urzua2025skinbarrierdysfunction pages 3-4) - Systems endotypes: Cross-tissue transcriptomics reveal modules linked to erythema vs papulation and longitudinal clusters tied to severity and treatment response; proteomic modules correlate with disease activity (Oct 2023; URL below). (bilinski2025antiinflammatorytherapiesfor pages 2-4)
IL-4/IL-13–STAT6 signaling; IL-31–neuronal TRP channels; alarmin (TSLP/IL-33/IL-25)–DC/ILC2 pathways; NF-κB and MAPK in keratinocytes; JAK–STAT (kamata2025mechanismsofitch pages 2-4, bai2025atopicdermatitisdiagnosis pages 25-26, torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4)
Affected cellular processes
2) Key Molecular Players (ontology-ready annotations) - Genes/Proteins (HGNC symbol) - FLG (filaggrin): epidermal barrier scaffold; loss-of-function predisposes to AD (HGNC: 3752). (katsarou2023theroleof pages 12-12) - CLDN1 (claudin-1): tight junction component; reduced in AD lesions; Th2 cytokine–sensitive (HGNC: 2031). (katsarou2023theroleof pages 12-12) - IL4, IL13: type 2 cytokines central to AD pathogenesis (HGNC: 6014, 5991). (torres2025interleukin4andatopic pages 14-15) - IL31, IL31RA, OSMR: pruritogenic pathway receptors on sensory neurons (HGNC: 20497, 21491, 8506). (kamata2025mechanismsofitch pages 2-4, bai2025atopicdermatitisdiagnosis pages 25-26) - TSLP, IL33, IL25/IL17E: epithelial alarmins initiating type 2 responses (HGNC: 30742, 5996, 5964). (kamata2025mechanismsofitch pages 2-4, torres2025interleukin4andatopic pages 14-15) - JAK1, JAK2; STAT6: JAK–STAT transducers in type 2 signaling (HGNC: 6190, 6192, 11366). (urzua2025skinbarrierdysfunction pages 3-4, torres2025interleukin4andatopic pages 14-15) - CALCA (CGRP): neuropeptide mediating IL-31 neurogenic restraint (HGNC: 1434). (bai2025atopicdermatitisdiagnosis pages 25-26) - TRPV1, TRPA1: neuronal ion channels mediating itch (HGNC: 12306, 132). (kamata2025mechanismsofitch pages 2-4)
Histamine (CHEBI:18295): mast-cell mediator contributing to pruritus (review synthesis). (torres2025interleukin4andatopic pages 14-15)
Cell types (CL terms)
Keratinocyte (CL:0000312); Langerhans cell (CL:0000475); Dendritic cell (CL:0000451); ILC2 (CL:0001065); Th2 cell (CL:0000910); Sensory neuron (CL:0000101). (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12, torres2025interleukin4andatopic pages 14-15)
Anatomical locations (UBERON)
Epidermis (UBERON:0001003); Dermis (UBERON:0002067); Skin nerve endings (UBERON:0001825). (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12)
Drugs/biologics (mechanism-linked)
3) Biological Processes (GO) disrupted - Keratinocyte differentiation (GO:0030216); Cornified envelope assembly (GO:0070268) (FLG-related). (katsarou2023theroleof pages 12-12) - Tight junction organization (GO:0034330) (CLDN1-related). (katsarou2023theroleof pages 12-12) - Cytokine-mediated signaling pathway (GO:0019221) via JAK–STAT (GO:0007259). (urzua2025skinbarrierdysfunction pages 3-4, torres2025interleukin4andatopic pages 14-15) - Immune response–Th2 cell differentiation (GO:0042092); ILC2 activation (GO:0001773). (torres2025interleukin4andatopic pages 14-15) - Sensory perception of itch (GO:0036231); Neuron projection development (GO:0031175) (IL-31–induced neurite extension). (kamata2025mechanismsofitch pages 2-4) - Neurogenic inflammation (GO:0050729) via CGRP signaling impacting T cells. (bai2025atopicdermatitisdiagnosis pages 25-26)
4) Cellular Components (GO-CC) - Cornified envelope (GO:0001533); Keratin filament (GO:0045095). (katsarou2023theroleof pages 12-12) - Tight junction (GO:0005923). (katsarou2023theroleof pages 12-12) - Plasma membrane of pruritoceptors (GO:0005886) housing TRPV1/TRPA1 and IL31RA/OSMR. (kamata2025mechanismsofitch pages 2-4) - Extracellular space (GO:0005615) for cytokines and neuropeptides (IL-4/IL-13/IL-31, CGRP). (torres2025interleukin4andatopic pages 14-15, bai2025atopicdermatitisdiagnosis pages 25-26)
5) Disease Progression (sequence of events) - Initiation: Genetic predisposition (e.g., FLG variants) and environmental insults disrupt the barrier and elevate skin pH; TJ/FLG insufficiency increases permeability. (katsarou2023theroleof pages 12-12) - Epithelial alarm: Keratinocytes release alarmins (TSLP, IL-33, IL-25), activating DCs/ILC2 and priming Th2 responses. (kamata2025mechanismsofitch pages 2-4, torres2025interleukin4andatopic pages 14-15) - Amplification: IL-4/IL-13 from Th2/ILC2 downregulate barrier genes (e.g., FLG, CLDN1), recruit inflammatory cells, and perpetuate itch–scratch cycles; JAK–STAT transduces these signals. (torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4) - Pruritus circuitry: IL-31 directly activates IL31RA/OSMR+ TRPV1/TRPA1 neurons, enhances nerve fiber density, and drives chronic itch behavior. (kamata2025mechanismsofitch pages 2-4) - Chronic modulation: With repeated allergen exposure, IL-31–induced CGRP imposes a neurogenic restraint on tissue Th2 inflammation—an adaptive feedback that may be perturbed by anti-IL31RA therapies. (bai2025atopicdermatitisdiagnosis pages 25-26) - Endotypic divergence: Cross-tissue transcriptomic modules align with clinical phenotypes and severity clusters and can inform treatment monitoring/response. (bilinski2025antiinflammatorytherapiesfor pages 2-4)
6) Phenotypic Manifestations (clinical; HP terms) - Pruritus (HP:0000989) driven by IL-31–TRP pathways and hyperinnervation; quote above. (kamata2025mechanismsofitch pages 2-4) - Eczema/erythematous scaly dermatitis (HP:0000988) from Th2-driven skin inflammation and barrier leak. (torres2025interleukin4andatopic pages 14-15, katsarou2023theroleof pages 12-12) - Xerosis (HP:0000958) from barrier lipid/protein deficits. (katsarou2023theroleof pages 12-12) - Lichenification (HP:0000984) in chronic disease, aligned with distinct transcriptomic modules. (bilinski2025antiinflammatorytherapiesfor pages 2-4)
Recent developments and latest research (2023–2025; with URLs/dates) - IL-31 neuroimmune restraint of Th2 inflammation (Science Immunology, Oct 2023): Demonstrated that IL-31–responsive pruritoceptors release CGRP to limit cutaneous type 2 programs in chronic HDM dermatitis; mechanistic insight into paradoxical flares on anti-IL31RA therapy. URL: https://doi.org/10.1126/sciimmunol.abi6887. (bai2025atopicdermatitisdiagnosis pages 25-26) - Systems endotyping (Nature Communications, Oct 2023): Cross-tissue transcriptomics linked detailed skin phenotypes (erythema vs papulation) with distinct immune signatures and identified blood transcriptome clusters tracking severity and treatment history, enabling personalized monitoring. URL: https://doi.org/10.1038/s41467-023-41857-8. (bilinski2025antiinflammatorytherapiesfor pages 2-4) - Tight-junction barrier in AD (J Clin Med, Feb 2023): Systematic review highlighting claudin-1 reduction, Th2 suppression of claudins, and scratching-induced claudin-1 decreases as central to barrier pathophysiology. URL: https://doi.org/10.3390/jcm12041538. (katsarou2023theroleof pages 12-12) - Itch mechanisms synthesis (Juntendo Med J, Jan 2025): Integrated view of Th2/alarmin–neuronal crosstalk, IL-31 receptor expression on pruritoceptors, and hyperinnervation mechanisms (Sema3A↓, NGF↑). URL: https://doi.org/10.14789/ejmj.jmj24-0036-r. (kamata2025mechanismsofitch pages 2-4) - IL-4 centrality and therapeutic implications (Dermatology and Therapy, Feb 2025): Review underscoring IL-4/IL-13 as nexus for barrier, dysbiosis, itch, and inflammation; contextualizes dupilumab and IL-13 inhibitors. URL: https://doi.org/10.1007/s13555-025-01352-y. (torres2025interleukin4andatopic pages 14-15) - Barrier, immunity, and targeted therapy integration (Cureus, Jun 2025): Review summarizing evidence for IL-13 blockade improving barrier function and rapid efficacy of JAK inhibitors; notes emerging microbiome-directed approaches. URL: https://doi.org/10.7759/cureus.86937. (urzua2025skinbarrierdysfunction pages 3-4)
Current applications and real-world implementations - IL-4/IL-13 pathway blockade - Dupilumab (anti–IL-4Rα) is a standard of care for moderate–severe AD; reviews document early and sustained improvements in systemic and cutaneous immune abnormalities, consistent with interruption of the type 2 axis (reviewed 2025; URL above). (torres2025interleukin4andatopic pages 14-15) - IL-13–selective monoclonals (tralokinumab, lebrikizumab) have demonstrated efficacy in phase III trials and are integrated in recent therapeutic reviews (2025 summary; mechanism detailed in 2025 narrative review). (torres2025interleukin4andatopic pages 14-15) - JAK inhibitors - Oral JAK1-selective agents (e.g., upadacitinib) and JAK1/2 (baricitinib) and topical ruxolitinib cream show rapid pruritus and lesion improvement consistent with broad cytokine signal interruption (2025 review synthesis). (urzua2025skinbarrierdysfunction pages 3-4) - Monitoring and personalization - Multi-omic endotyping and cross-tissue modules are being developed for patient stratification and longitudinal monitoring, aligning skin phenotypes and blood modules with severity and response (Oct 2023). (bilinski2025antiinflammatorytherapiesfor pages 2-4)
Expert opinions and analysis - “IL-4 plays a critical role in skin barrier dysfunction, dysbiosis, pruritus, and inflammation” (Dermatology and Therapy, Feb 2025), anchoring IL-4/IL-13 as prime nodes for disease modification. URL: https://doi.org/10.1007/s13555-025-01352-y. (torres2025interleukin4andatopic pages 14-15) - “Impaired TJ barrier function and skin permeability in AD lesions is correlated with cldn-1 levels. Th2 inflammation inhibits the expression of cldn-1 and cldn-23… Scratching has also been reported to decrease cldn-1” (J Clin Med, Feb 2023), highlighting actionable barrier–immune feedbacks. URL: https://doi.org/10.3390/jcm12041538. (katsarou2023theroleof pages 12-12) - “IL-31 directly induces pruritus… and selectively promotes nerve fiber extension” (Juntendo Med J, Jan 2025), connecting cytokine signaling to neuronal remodeling. URL: https://doi.org/10.14789/ejmj.jmj24-0036-r. (kamata2025mechanismsofitch pages 2-4) - “IL-31… restrains cutaneous type 2 inflammation… [via] CGRP” (Science Immunology, Oct 2023), reframing IL-31 as both pruritogen and neuroimmune modulator. URL: https://doi.org/10.1126/sciimmunol.abi6887. (bai2025atopicdermatitisdiagnosis pages 25-26)
Relevant statistics and data from recent studies - Endotypic clustering: Integrated analysis of 115 AD patients and 14 controls identified skin–blood modules linking specific clinical features (erythema vs papulation) and longitudinal blood clusters aligned with severity and treatment history (Nature Communications, Oct 2023; details in article). URL: https://doi.org/10.1038/s41467-023-41857-8. (bilinski2025antiinflammatorytherapiesfor pages 2-4) - Barrier correlates: Systematic review collating >50 studies concluded that decreased claudin-1 associates with increased permeability and susceptibility to infection/allergen penetration; Th2 cytokines reduce claudin expression; scratching lowers claudin-1 (Feb 2023). URL: https://doi.org/10.3390/jcm12041538. (katsarou2023theroleof pages 12-12) - Neuroimmune plasticity: Clinical-pathobiological observations summarized in 2025 review include reduced Sema3A and increased NGF correlating with increased intraepidermal nerve density across AD states (Jan 2025). URL: https://doi.org/10.14789/ejmj.jmj24-0036-r. (kamata2025mechanismsofitch pages 2-4)
Evidence items (with PMIDs/DOIs/URLs) - Fassett MS et al. IL-31–dependent neurogenic inflammation restrains cutaneous type 2 immune response in allergic dermatitis. Science Immunology. Oct 2023. DOI: 10.1126/sciimmunol.abi6887; URL: https://doi.org/10.1126/sciimmunol.abi6887. Key quote and mechanism above. (bai2025atopicdermatitisdiagnosis pages 25-26) - Kamata Y et al. Mechanisms of Itch in Atopic Dermatitis. Juntendo Medical Journal. Jan 2025. DOI: 10.14789/ejmj.jmj24-0036-r; URL: https://doi.org/10.14789/ejmj.jmj24-0036-r. Key quote on IL-31 neurite extension; neuronal receptor expression. (kamata2025mechanismsofitch pages 2-4) - Katsarou S et al. The Role of Tight Junctions in Atopic Dermatitis: A Systematic Review. J Clin Med. Feb 2023. DOI: 10.3390/jcm12041538; URL: https://doi.org/10.3390/jcm12041538. Key quote on claudins/Th2 inhibition. (katsarou2023theroleof pages 12-12) - Torres T et al. Interleukin-4 and Atopic Dermatitis. Dermatology and Therapy. Feb 2025. DOI: 10.1007/s13555-025-01352-y; URL: https://doi.org/10.1007/s13555-025-01352-y. Expert synthesis of IL-4/IL-13 centrality. (torres2025interleukin4andatopic pages 14-15) - Urzua IE et al. Skin Barrier Dysfunction… Cureus. Jun 2025. DOI: 10.7759/cureus.86937; URL: https://doi.org/10.7759/cureus.86937. Clinical integration of IL-13 blockade/barrier and JAK inhibitor kinetics. (urzua2025skinbarrierdysfunction pages 3-4) - Sekita A et al. Multifaceted analysis of cross-tissue transcriptomes… Nat Commun. Oct 2023. DOI: 10.1038/s41467-023-41857-8; URL: https://doi.org/10.1038/s41467-023-41857-8. Endotype–phenotype modules and longitudinal clusters. (bilinski2025antiinflammatorytherapiesfor pages 2-4)
Structured ontology annotations - Genes/Proteins (HGNC): FLG; CLDN1; IL4; IL13; IL31; IL31RA; OSMR; TSLP; IL33; JAK1; JAK2; STAT6; CALCA; TRPV1; TRPA1. (katsarou2023theroleof pages 12-12, kamata2025mechanismsofitch pages 2-4, bai2025atopicdermatitisdiagnosis pages 25-26, torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4) - GO Biological Processes: keratinocyte differentiation; tight junction organization; cytokine-mediated signaling; JAK–STAT cascade; Th2 differentiation; sensory perception of itch; neurogenic inflammation. (katsarou2023theroleof pages 12-12, kamata2025mechanismsofitch pages 2-4, urzua2025skinbarrierdysfunction pages 3-4) - GO Cellular Components: tight junction; cornified envelope; plasma membrane; extracellular region. (katsarou2023theroleof pages 12-12, kamata2025mechanismsofitch pages 2-4) - Cell Types (CL): keratinocytes; Langerhans cells; dermal dendritic cells; ILC2; Th2 cells; small-diameter sensory neurons. (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12, torres2025interleukin4andatopic pages 14-15) - Anatomical Sites (UBERON): epidermis; dermis; cutaneous nerve endings. (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12) - Chemical entities (CHEBI): ceramide (CHEBI:17761); histamine (CHEBI:18295). (urzua2025skinbarrierdysfunction pages 3-4, torres2025interleukin4andatopic pages 14-15) - Phenotypes (HPO): pruritus (HP:0000989); eczema (HP:0000988); xerosis (HP:0000958); lichenification (HP:0000984). (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12, bilinski2025antiinflammatorytherapiesfor pages 2-4)
Therapeutic implications (mechanism → therapy mapping) - IL-4/IL-13 axis: Dupilumab (anti–IL-4Rα), tralokinumab/lebrikizumab (anti–IL-13) reduce type 2 signaling, improve lesions and often pruritus; reviews emphasize their disease-modifying potential by interrupting central drivers (2025). (torres2025interleukin4andatopic pages 14-15) - IL-31 axis: Anti–IL-31/IL31RA agents target pruritus; the 2023 mechanistic study suggests monitoring for inflammatory shifts due to loss of IL-31–CGRP restraint in chronic exposure contexts (Oct 2023). (bai2025atopicdermatitisdiagnosis pages 25-26) - JAK inhibitors: Oral JAK1/2 and topical JAK inhibitors rapidly reduce itch and inflammation—a pharmacodynamic signature of blocking multi-cytokine signaling via JAK–STAT (2025). (urzua2025skinbarrierdysfunction pages 3-4) - Barrier-directed adjuncts: Because Th2 cytokines downregulate CLDN1/FLG, upstream cytokine blockade plus barrier repair strategies target both cause and consequence (2023–2025 syntheses). (katsarou2023theroleof pages 12-12, torres2025interleukin4andatopic pages 14-15)
Limitations and gaps - While reviews integrate barrier, IL-4/IL-13, IL-31, and JAK–STAT mechanisms with therapeutic success, high-resolution causal links for all epithelial alarmins in human endotypes and long-term remodeling remain under active investigation. Multi-omic signatures are promising but require prospective validation for treatment selection in routine care. (bilinski2025antiinflammatorytherapiesfor pages 2-4)
References with URLs/dates - Science Immunology, Oct 2023: https://doi.org/10.1126/sciimmunol.abi6887. (bai2025atopicdermatitisdiagnosis pages 25-26) - Nature Communications, Oct 2023: https://doi.org/10.1038/s41467-023-41857-8. (bilinski2025antiinflammatorytherapiesfor pages 2-4) - Journal of Clinical Medicine, Feb 2023: https://doi.org/10.3390/jcm12041538. (katsarou2023theroleof pages 12-12) - Juntendo Medical Journal, Jan 2025: https://doi.org/10.14789/ejmj.jmj24-0036-r. (kamata2025mechanismsofitch pages 2-4) - Dermatology and Therapy, Feb 2025: https://doi.org/10.1007/s13555-025-01352-y. (torres2025interleukin4andatopic pages 14-15) - Cureus, Jun 2025: https://doi.org/10.7759/cureus.86937. (urzua2025skinbarrierdysfunction pages 3-4)
References
(katsarou2023theroleof pages 12-12): Spyridoula Katsarou, Michael Makris, Efstratios Vakirlis, and Stamatios Gregoriou. The role of tight junctions in atopic dermatitis: a systematic review. Journal of Clinical Medicine, 12:1538, Feb 2023. URL: https://doi.org/10.3390/jcm12041538, doi:10.3390/jcm12041538. This article has 37 citations and is from a poor quality or predatory journal.
(kamata2025mechanismsofitch pages 2-4): YAYOI KAMATA, MITSUTOSHI TOMINAGA, and KENJI TAKAMORI. Mechanisms of itch in atopic dermatitis. Juntendo Medical Journal, 71:43-50, Jan 2025. URL: https://doi.org/10.14789/ejmj.jmj24-0036-r, doi:10.14789/ejmj.jmj24-0036-r. This article has 6 citations.
(torres2025interleukin4andatopic pages 14-15): Tiago Torres, Pedro Mendes-Bastos, Maria J. Cruz, Bruno Duarte, Paulo Filipe, Maria J. P. Lopes, and Margarida Gonçalo. Interleukin-4 and atopic dermatitis: why does it matter? a narrative review. Dermatology and Therapy, 15:579-597, Feb 2025. URL: https://doi.org/10.1007/s13555-025-01352-y, doi:10.1007/s13555-025-01352-y. This article has 18 citations and is from a poor quality or predatory journal.
(urzua2025skinbarrierdysfunction pages 3-4): Irisdey Espinoza Urzua, María Isabel Vidal Vidal, Manrique Vega Solano, Julian Eduardo Bedoya Jaramillo, Gifneth Giselle de la Cruz Donis, and Andrés Romero Valverde. Skin barrier dysfunction in chronic dermatoses: from pathophysiology to emerging therapeutic strategies. Cureus, Jun 2025. URL: https://doi.org/10.7759/cureus.86937, doi:10.7759/cureus.86937. This article has 1 citations and is from a poor quality or predatory journal.
(bai2025atopicdermatitisdiagnosis pages 25-26): Ruimin Bai, Yan Zheng, and Xiaofeng Dai. Atopic dermatitis: diagnosis, molecular pathogenesis, and therapeutics. Molecular Biomedicine, Oct 2025. URL: https://doi.org/10.1186/s43556-025-00313-3, doi:10.1186/s43556-025-00313-3. This article has 7 citations.
(zhakparov2026protectiveandsusceptibility pages 22-23): Damir Zhakparov, Nonhlanhla Lunjani, Marco Schmid, Kathleen Moriarty, Damian Roquero, Anita Dreher, Jeannette I. Heldstab-Kast, Kari C. Nadeau, Cezmi Akdis, Michael Levin, Carol Hlela, Milena Sokolowska, Liam O’Mahony, and Katja Baerenfaller. Protective and susceptibility clusters of environmental factors, gene expression, antibody responses, and cytokines in pediatric atopic dermatitis: insights from multi-modal data integration. Unknown journal, Jan 2026. URL: https://doi.org/10.64898/2026.01.10.26343854, doi:10.64898/2026.01.10.26343854.
(bilinski2025antiinflammatorytherapiesfor pages 2-4): Karol Biliński, Katarzyna Rakoczy, Anna Karwowska, Oliwia Cichy, Aleksandra Wojno, Agata Wojno, Julita Kulbacka, and Małgorzata Ponikowska. Anti-inflammatory therapies for atopic dermatitis: a new era in targeted treatment. Journal of Clinical Medicine, 14:5053, Jul 2025. URL: https://doi.org/10.3390/jcm14145053, doi:10.3390/jcm14145053. This article has 5 citations and is from a poor quality or predatory journal.
name: Atopic Dermatitis
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-03-05T00:25:00Z'
category: Complex
parents:
- Dermatological Disease
- Chronic Inflammatory Disease
- Allergic Disease
has_subtypes:
- name: Early-Onset Atopic Dermatitis
description: Onset in infancy or early childhood, often associated with the
atopic march progressing to asthma and allergic rhinitis.
- name: Adult-Onset Atopic Dermatitis
description: First presentation in adulthood, often with different clinical
distribution and associations compared to childhood-onset disease.
- name: Extrinsic Atopic Dermatitis
description: Associated with IgE-mediated sensitization to environmental
allergens. Elevated serum IgE and positive skin prick tests.
- name: Intrinsic Atopic Dermatitis
description: Without IgE-mediated sensitization. Normal serum IgE levels.
Represents approximately 20% of cases.
pathophysiology:
- name: Epidermal Barrier Dysfunction
description: Loss-of-function mutations in filaggrin (FLG) and other barrier
proteins lead to impaired skin barrier integrity, increased transepidermal
water loss, and enhanced allergen penetration. This is the primary
initiating event in many patients.
genes:
- preferred_term: FLG
term:
id: hgnc:3748
label: FLG
biological_processes:
- preferred_term: Keratinization
term:
id: GO:0031424
label: keratinization
cell_types:
- preferred_term: Keratinocyte
term:
id: CL:0000312
label: keratinocyte
evidence:
- reference: PMID:16550169
reference_title: "Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Filaggrin is a key protein that facilitates terminal
differentiation of the epidermis and formation of the skin barrier. Here
we show that two independent loss-of-function genetic variants (R510X
[sic, correct designation is R501X] and 2282del4) in the gene encoding
filaggrin (FLG) are very strong predisposing factors for atopic
dermatitis.
explanation: Landmark study establishing FLG loss-of-function as the
strongest genetic risk factor for atopic dermatitis, with ~9% carrier
frequency in Europeans.
- reference: PMID:21388665
reference_title: "Contrasting pathogenesis of atopic dermatitis and psoriasis--part I: clinical and pathologic concepts."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: They are similar in that they are complex inherited diseases
involving genes that encode immune components and structural proteins that
regulate differentiation of epidermal cells. Each disease is characterized
by proliferation of epidermal keratinocytes and abnormal cornification or
terminal differentiation in the epidermis
explanation: Describes the epidermal barrier dysfunction in atopic
dermatitis including abnormal cornification and keratinocyte
differentiation.
- name: Type 2 Immune Response
description: Th2-skewed immune response drives the hallmark inflammation.
IL-4, IL-13, and IL-31 promote IgE production, eosinophil recruitment, and
pruritus. IL-4/IL-13 signaling through JAK1/STAT6 further impairs barrier
function by downregulating filaggrin and other barrier proteins.
genes:
- preferred_term: IL4
term:
id: hgnc:6014
label: IL4
- preferred_term: IL13
term:
id: hgnc:5973
label: IL13
- preferred_term: IL31
term:
id: hgnc:19372
label: IL31
- preferred_term: STAT6
term:
id: hgnc:11368
label: STAT6
downstream:
- target: Epidermal Barrier Dysfunction
description: IL-4 and IL-13 downregulate filaggrin expression, creating a
vicious cycle of barrier disruption and immune activation.
- target: Pruritogen-Induced Neuronal Activation
description: IL-31 signaling contributes to neuronal itch signaling in
lesional skin.
biological_processes:
- preferred_term: Type 2 immune response
term:
id: GO:0042092
label: type 2 immune response
- preferred_term: T-helper 2 cell differentiation
term:
id: GO:0045064
label: T-helper 2 cell differentiation
- preferred_term: Interleukin-4-mediated signaling pathway
term:
id: GO:0035771
label: interleukin-4-mediated signaling pathway
- preferred_term: IgE isotype switching
term:
id: GO:0035708
label: interleukin-4-dependent isotype switching to IgE isotypes
cell_types:
- preferred_term: T-helper 2 cell
term:
id: CL:0000546
label: T-helper 2 cell
- preferred_term: Group 2 innate lymphoid cell
term:
id: CL:0001069
label: group 2 innate lymphoid cell
- preferred_term: Eosinophil
term:
id: CL:0000771
label: eosinophil
- preferred_term: Mast cell
term:
id: CL:0000097
label: mast cell
evidence:
- reference: PMID:30819278
reference_title: "Pathophysiology of atopic dermatitis: Clinical implications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Type 2 cytokines as well as interleukin 17 and interleukin 22
contribute to skin barrier dysfunction and the development of AD.
explanation: Confirms the role of type 2 cytokines in AD pathophysiology and
their contribution to barrier dysfunction, supporting the Th2/type 2
immune mechanism.
- reference: PMID:21388665
reference_title: "Contrasting pathogenesis of atopic dermatitis and psoriasis--part I: clinical and pathologic concepts."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: skin lesions contain immune infiltrates of T cells, dendritic
cells, and other types of leukocytes. We review similarities between the
diseases and differences in epidermal barrier defects and immune cells.
explanation: Describes the immune cell infiltrates in AD lesions including T
cells and dendritic cells, consistent with type 2 immune response.
- name: Th17/Th22 Inflammation
description: In addition to the dominant Th2 response, Th17 and Th22 cells
contribute to inflammation, particularly in acute lesions and Asian
patients. IL-17 and IL-22 further disrupt epidermal differentiation.
biological_processes:
- preferred_term: T-helper 17 type immune response
term:
id: GO:0072538
label: T-helper 17 type immune response
cell_types:
- preferred_term: T-helper 17 cell
term:
id: CL:0000899
label: T-helper 17 cell
- name: Pruritogen-Induced Neuronal Activation
description: IL-31 and other pruritogens activate cutaneous sensory neurons,
generating persistent itch in atopic dermatitis.
genes:
- preferred_term: IL31
term:
id: hgnc:19372
label: IL31
downstream:
- target: Scratching-Induced Barrier Injury
description: Persistent itch drives repetitive scratching behavior.
cell_types:
- preferred_term: Sensory neuron
term:
id: CL:0000101
label: sensory neuron
evidence:
- reference: PMID:30819278
reference_title: "Pathophysiology of atopic dermatitis: Clinical implications."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: New insights into the pathophysiology of AD have focused on
epidermal lipid profiles, neuroimmune interactions, and microbial
dysbiosis.
explanation: Supports neuroimmune signaling as a component of AD
pathophysiology.
- name: Scratching-Induced Barrier Injury
description: Repetitive scratching causes mechanical skin injury and worsens
epidermal barrier dysfunction.
downstream:
- target: Secondary Inflammatory Amplification
description: Mechanical barrier injury increases local inflammatory
activation.
cell_types:
- preferred_term: Keratinocyte
term:
id: CL:0000312
label: keratinocyte
- name: Secondary Inflammatory Amplification
description: Barrier injury from scratching perpetuates inflammatory signaling
and contributes to chronic lesion persistence.
biological_processes:
- preferred_term: Inflammatory response
term:
id: GO:0006954
label: inflammatory response
cell_types:
- preferred_term: Keratinocyte
term:
id: CL:0000312
label: keratinocyte
phenotypes:
- name: Eczematoid Dermatitis
category: Dermatological
frequency: VERY_FREQUENT
diagnostic: true
notes: Erythematous, pruritic patches and plaques with scaling, often in
flexural areas.
phenotype_term:
preferred_term: Eczematoid dermatitis
term:
id: HP:0000964
label: Eczematoid dermatitis
evidence:
- reference: PMID:28846349
reference_title: "Atopic Dermatitis."
supports: SUPPORT
snippet: "This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification."
explanation: Eczematous lesions are a defining feature of atopic dermatitis.
- name: Pruritus
category: Dermatological
frequency: VERY_FREQUENT
diagnostic: true
notes: Intense itching is the hallmark symptom, often worse at night.
phenotype_term:
preferred_term: Pruritus
term:
id: HP:0000989
label: Pruritus
evidence:
- reference: PMID:39659858
reference_title: "Atopic Dermatitis: A Review of Diagnosis and Treatment."
supports: SUPPORT
snippet: "Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus."
explanation: Intense pruritus is a defining clinical characteristic of atopic dermatitis.
- name: Xerosis
category: Dermatological
frequency: VERY_FREQUENT
notes: Generalized dry skin reflecting barrier dysfunction.
phenotype_term:
preferred_term: Xerosis
term:
id: HP:0000958
label: Dry skin
evidence:
- reference: PMID:39659858
reference_title: "Atopic Dermatitis: A Review of Diagnosis and Treatment."
supports: SUPPORT
snippet: "Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus."
explanation: Dry skin (xerosis) is a defining clinical characteristic of atopic dermatitis reflecting barrier dysfunction.
- name: Lichenification
category: Dermatological
frequency: FREQUENT
notes: Thickened, leathery skin from chronic scratching.
phenotype_term:
preferred_term: Lichenification
term:
id: HP:0100725
label: Lichenification
evidence:
- reference: PMID:28846349
reference_title: "Atopic Dermatitis."
supports: SUPPORT
snippet: "This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification."
explanation: Lichenification develops from chronic scratching in atopic dermatitis patients.
- name: Elevated Serum IgE
category: Immunological
frequency: FREQUENT
notes: Present in extrinsic subtype (~80% of patients).
phenotype_term:
preferred_term: Elevated serum IgE
term:
id: HP:0003212
label: Increased circulating IgE concentration
evidence:
- reference: PMID:20207111
reference_title: "Extrinsic and intrinsic types of atopic dermatitis."
supports: SUPPORT
snippet: "Extrinsic or allergic AD shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens... While extrinsic AD is the classical type with high prevalence, the incidence of intrinsic AD is approximately 20%"
explanation: Approximately 80% of atopic dermatitis patients have the extrinsic subtype characterized by elevated serum IgE levels.
genetic:
- name: FLG
association: Associated
notes: Loss-of-function variants are the strongest genetic risk factor. R501X
and 2282del4 are common in European populations.
evidence:
- reference: PMID:16550169
reference_title: "Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: two independent loss-of-function genetic variants (R510X
[sic, correct designation is R501X] and 2282del4) in the gene encoding
filaggrin (FLG) are very strong predisposing factors for atopic
dermatitis. These variants are carried by approximately 9% of people of
European origin.
explanation: Landmark Palmer et al. 2006 study establishing FLG
loss-of-function as the major genetic predisposing factor for atopic
dermatitis.
- name: IL4R
association: Associated
notes: Variants in IL-4 receptor alpha chain affect Th2 signaling intensity.
- name: IL13
association: Associated
notes: Variants affecting IL-13 expression or function.
- name: STAT6
association: Associated
notes: Transcription factor downstream of IL-4/IL-13 signaling.
- name: EMSY
association: Associated
notes: Chromatin remodeling factor identified in GWAS.
- name: BACH2
association: GWAS
notes: Transcription factor regulating Treg/effector T cell balance and B cell
class switching
- name: TNFAIP3
association: GWAS
notes: Encodes A20, a ubiquitin-editing enzyme that negatively regulates NF-kB
signaling
- name: EGR2
association: GWAS
notes: Transcription factor involved in T cell anergy and peripheral tolerance
- name: ETS1
association: GWAS
notes: Transcription factor regulating T and B cell development and immune
cell differentiation
- name: IRF4
association: GWAS
notes: Transcription factor essential for Th17 and Th2 cell differentiation
and plasma cell development
- name: SATB1
association: GWAS
notes: Chromatin organizer regulating T cell development and lineage
commitment
- name: SMAD3
association: GWAS
notes: TGF-beta signaling mediator regulating T cell differentiation and
immune tolerance
- name: REL
association: GWAS
notes: NF-kB subunit c-Rel controlling lymphocyte activation and survival
environmental:
- name: Allergen Exposure
description: House dust mites, pet dander, and pollens can trigger or
exacerbate disease.
effect: TRIGGERS
- name: Skin Irritants
description: Soaps, detergents, and harsh fabrics disrupt the already
compromised barrier.
effect: TRIGGERS
- name: Microbial Dysbiosis
description: Staphylococcus aureus colonization is found in >90% of lesional
skin and amplifies inflammation through superantigens and biofilm formation.
effect: WORSENS
treatments:
- name: Emollients and Moisturizers
description: First-line treatment to restore skin barrier function and reduce
transepidermal water loss.
- name: Topical Corticosteroids
description: First-line anti-inflammatory treatment for flares, applied to
affected areas.
- name: Dupilumab
description: Monoclonal antibody targeting IL-4 receptor alpha, blocking both
IL-4 and IL-13 signaling. FDA-approved for moderate-to-severe atopic
dermatitis.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: dupilumab
term:
id: NCIT:C162455
label: Dupilumab
- name: JAK Inhibitors
description: Oral (baricitinib, upadacitinib, abrocitinib) and topical
(ruxolitinib) JAK inhibitors targeting the JAK-STAT pathway downstream of
type 2 cytokines.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
- name: Phototherapy
description: Narrowband UVB phototherapy for moderate-to-severe disease.
disease_term:
preferred_term: atopic dermatitis
term:
id: MONDO:0004980
label: atopic eczema
references:
- reference: DOI:10.1007/s13555-025-01352-y
title: 'Interleukin-4 and Atopic Dermatitis: Why Does it Matter? A Narrative Review'
findings: []
- reference: DOI:10.1038/s41467-023-41857-8
title: Multifaceted analysis of cross-tissue transcriptomes reveals
phenotype–endotype associations in atopic dermatitis
findings: []
- reference: DOI:10.1126/sciimmunol.abi6887
title: IL-31–dependent neurogenic inflammation restrains cutaneous type 2
immune response in allergic dermatitis
findings: []
- reference: DOI:10.1186/s43556-025-00313-3
title: 'Atopic dermatitis: diagnosis, molecular pathogenesis, and therapeutics'
findings: []
- reference: DOI:10.14789/ejmj.jmj24-0036-r
title: Mechanisms of Itch in Atopic Dermatitis
findings: []
- reference: DOI:10.3390/jcm12041538
title: 'The Role of Tight Junctions in Atopic Dermatitis: A Systematic Review'
findings: []
- reference: DOI:10.3390/jcm14145053
title: 'Anti-Inflammatory Therapies for Atopic Dermatitis: A New Era in Targeted
Treatment'
findings: []
- reference: DOI:10.64898/2026.01.10.26343854
title: 'Protective and Susceptibility Clusters of Environmental Factors, Gene Expression,
Antibody Responses, and Cytokines in Pediatric Atopic Dermatitis: Insights from
Multi-Modal Data Integration'
findings: []
- reference: DOI:10.7759/cureus.86937
title: 'Skin Barrier Dysfunction in Chronic Dermatoses: From Pathophysiology to
Emerging Therapeutic Strategies'
findings: []