A new autoimmune disease: atopic dermatitis in children

Emanuela Flocaa, Remus Gagaa, Genel Sura, Iulia Lupanb, Ionel Armatc, Gabriel Samascad*, Lucia M. Sure

aPediatrics II Department, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania

bMolecular Biology Department, Babes Bolyai University, Cluj-Napoca, Romania

cCardiovasculare and Transplant Emergency Institute of Târgu Mureș, Romania

dDepartment of Immunology, University of Medicine and Pharmacology “Iuliu Hațieganu”, Cluj-Napoca, Romania

ePediatrics Department, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania


Atopic dermatitis (AD) is mainly considered an allergy, exacerbated by allergic factors. Is there evidence to suggest the existence of autoimmune components in the pathophysiology of the illness? Studies in the literature that dealt with the occurrence of autoimmunity in children with AD were analyzed. We followed the studies published in PubMed for 10 years, from 2001 to 2021. Clinical signs and symptoms were similar to other autoimmune diseases, having periods of remission and relapses. Other correlations between AD and autoimmune diseases have been described, and patients with AD can also present with a wide range of autoimmune comorbidities. Three major factors contribute to the pathogenesis of AD: damage of the skin barrier, disorders of the immune response, and imbalances of the skin microbiome—all based on genetic changes and influenced by environmental factors. Predominant activation of Th 2 cells, with the increase of Th 1, Th 17, and Th 22 subsets, promotes skin inflammation. All this evidence suggests that AD might be classified as an autoimmune disease, not just as an allergic reaction.

Key words: atopic dermatitis, autoimmune disease, clinical signs, immune response, symptoms

*Corresponding author: Gabriel Samasca, Department of Immunology, University of Medicine and Pharmacology “Iuliu Hațieganu”, -Cluj-Napoca, Romania. Email address: [email protected]

Received 25 April 2022; Accepted 6 July 2022; Available online 1 November 2022

DOI: 10.15586/aei.v50i6.655

Copyright: Floca E, et al.
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0).


Atopic dermatitis (AD) is a chronic relapsing skin disease manifested trough extreme itching along with other symptoms.1 The inflammation in AD is complex, with remissions and relapses and a clinical course that strikingly resembles autoimmune diseases.1,2 The condition was first designated as AD in 1933 by Wise and Sulzberger. The prevalence of the illness is rising, affecting about 15–30% of children and 2–10% of adults. It is important to take into consideration the socioeconomic impact as well as the impairment of quality of life for patients and their families.3 The etiology is not fully known, even though there have been attempts to tie the symptoms to allergic factors. Several studies emphasized the allergic factors which are more likely implicated in the exacerbations of AD.4 However, concerning the physiopathogenesis of this complex disease, there are three major mechanisms: (1) skin barrier dysfunction, (2) disturbance of the immune response, and (3) alteration of the skin microbiota.2,5 These mechanisms are influenced by genetic as well as environmental factors.

One of the most studied aspects of AD is skin barrier dysfunction. Considered as a barrier between the internal and external environments, the skin provides protection and support to the organism. Primary functions of the epidermal barrier include limiting passive water and preventing environmental chemical absorption and microbial infection.6 Keratinocytes are the main cells that sustain the skin. After mitosis, keratinocytes differentiate and migrate from the stratum basale toward the stratum corneum. This differentiation process forms the following keratinocyte layers: stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum.7 The corneocytes are responsible for protection against mechanical and chemical injury. The lipid matrix provides the essential component of the water barrier.8 Most of the mechanical strength provided by the epidermal barrier is due to corneocytes. A protein shell surrounds each corneocyte, consisting of loricrin, involucrin, and filaggrin. In immediate contact with the corneocyte sits the corneocyte lipid envelope, a structure of specialized lipids which is important for the formation of the functional skin barrier.

AD has been linked to genetic abnormalities related to filaggrin. Filaggrin deficiency has been found to have an important role in AD in children, increasing the severity of allergies, infection rates, and vulnerability. Filaggrin can be broken down into free amino acids, forming the urocanic acid, which is responsible for the acidity level in the skin, and pyrrolidine carboxylic acid, a natural moisturizer. Filaggrin abnormalities are related to dry skin in patients with AD because of transepidermal water loss. Skin barrier dysfunction leads to an inflammatory response and autoimmune reactions that result in the production of IgE by B cells and interleukins (ILs) by Th2 cells.9

We studied PubMed articles that were found from keywords autoimmunity and atopic dermatitis. We analyzed the articles that described elements of autoimmunity in AD and the occurrence of autoimmunity in children with the disease.

Immune Mechanisms that Initiate and Sustain Inflammation

Th2 lymphocytes also represent an important source of pruritus-generating cytokines, such as IL-31. Studies show that there is a strong correlation between the presence of pruritus and IL-31 secretion; individuals with severe forms of pruritus have increased serum levels of IL-31, while those with mild symptoms have normal or low levels of IL-31.2,10,11 In an average individual, the different types of T cells, specifically Th1 and Th2 cells, are in balance. One of the immunological hypotheses suggests an imbalance between the Th1 and Th2 cells, the former being excessively activated and producing interleukins such as IL-4, IL-5, and IL-13, which results in increased IgE production.11,12

The T and B lymphocytes play an important role in the activation of eosinophiles (Eo), mastocytes, and basophiles. It has been proven that basophiles are another important source of IL-4, IL-5, and IL-13. These cytokines are potentially regulated by another family of cytokines, produced by epithelial cells, for example, thymic stromal lymphopoietin, IL-25, and IL-33.4,13 Nemolizumab, a monoclonal antibody that targets IL-31 specifically, can be potentially used as a treatment for AD. Dupilumab, also a monoclonal antibody, may influence the production and intensity of pruritus by blocking IL-4 and IL-13.14 Biological therapies represent a new direction in the treatment of AD.2,15,16

Disturbances of the epidermal functions can lead to the apparition of signs and symptoms characteristic of AD. Destruction of the skin barrier increases antigen penetration into the body and also cytokine production.17 Xerosis and ichthyosis are common manifestations associated with AD, although it has been proven that half of the patients with vulgar ichthyosis have other atopic diseases as well, and 37% of AD patients present this skin lesion.17,18 According to recent findings, mutations in the gene encoding filaggrin are also responsible for skin barrier dysfunctions and are thus implicated in the pathogenesis of vulgar ichthyosis. Other consequences of skin barrier lesions are transepidermal water loss and increased permeability to environmental allergens. These allergens lead to increased levels of inflammatory cytokines and other inflammatory processes, and their increased penetration into the body also represents an important step in the atopic march.19,20

Thymus and activation-regulated chemokine (TARC) have an important role in the pathogeny of AD by enhancing the inflammation mediated by Th2 lymphocytes. TARC can be used as a marker of the short-term evolution of AD. It may represent a potential molecular target in the treatment of AD, and blocking it significantly reduces epithelial inflammation.9,21 Immune system dysfunction, along with changes in the epidermal barrier function, facilitates lesions with the possibility of bacterial colonization, especially of Staphylococcus aureus. Colonization with Staphylococcus increases inflammation, hyperkeratinization, and the production of proteases. The persistence of chronic inflammation, even after allergic factors have been eliminated, is caused by Staphylococcus aureus infection. Staphylococcus aureus colonization was identified in 90% of patients with severe clinical forms of the disease.2224

It also involves the innate defense system: T cells activate superantigens through enterotoxins. There can be direct stimulation of the mast cell (MC) degranulation. Susceptibility to herpes simplex virus infection is also a result of the combination of the defects in the epidermal barrier and those of the innate defense system and adaptive immune response.25 The cross talk between immune cell disorders and keratinocytes produces an intensification of pruritus. Excess mediators secreted by both cell groups stimulate sensitive nerve endings. Thymic stromal lymphopoietin, which is derived from keratinocytes, plays a role in the effect on the sensory nerves and the increased production of Th2 cytokines such as IL-31 and IL-13, resulting in neurogenic inflammation with numerous and important consequences.26

Autoimmune Mechanisms in AD

Even if, historically, the pathogenesis of AD is considered to be allergic and inflammatory, there is accumulating evidence that hints at the existence of an autoimmune component of the disease.2,21,23 There are more than 30 studies that associate the presence of autoantibodies with AD, by identifying IgE autoantibodies in AD patients. Most of these studies focus on the identification of autoantigens in epithelial cell extracts, which are targeted by IgE.27 All of the studies included in this review concluded that IgE autoantibodies are more frequent in patients with AD compared to control groups.6,28

Other studies following up on the autoimmune nature of AD have identified antinuclear antibody (ANA) as a potential indicator. Eight studies have shown that ANA are significantly more frequent in patients with AD, compared to the control group.16,29 Some studies tried to associate IgG autoantibodies with the illness, but there were no quantitative measurements conducted, and so they did not yield statistically significant conclusions.4,18

Concerning the association of autoantibody levels and disease severity, 16 studies managed to prove the existence of a positive correlation between IgE autoantibody levels and the severity of clinical symptoms.10,30 It was also proven that there was an increased autoreactive response of the T lymphocytes in patients with AD.8,31 It is hypothesized that there is a modified ratio of CLA+/CLA- and CCR4+/CCR4- cells involved in the process.32 Studying these autoimmunity indicators can lead to promising results concerning the correlation with AD. Other studies have shown that the suppressive effect of regulatory T lymphocytes on the proliferation of CD8+ CLA+ T lymphocytes is absent in AD.33,34 This mechanism is similar to other autoimmune conditions, such as psoriasis.2,24

Skin barrier damage and the consequent release of self-peptides that play the role of autoantigens can lead to three activation pathways.9,32 In the first path, the epidermal autoantigens are presented by the dendritic cell to the naïve T cell. The naïve T cells can differentiate into Th2 cells through IL-4, IL-5, IL-13, and IL-31, and into Th1 cells through interferon (IFN) gamma.2,18,35 Of these two, in AD, Th2 cells play the main role. Activated Th2 cells stimulate the Eo through IL-5 and, through IL-4, they stimulate B cells which secrete excessive amounts of IgE autoantibodies.3234,36,37 These IgE autoantibodies get attached to the MC membrane, as well as the epidermal self-peptides, through the second activation pathway, leading to MC degranulation and histamine release.15,31 Histamine and IL-31, also secreted by Th2 cells, act on the nervous fibers, producing pruritus.9 In the third activation pathway, the self-peptides act on the skin T cells, producing a cytotoxic reaction.28,32 Because of the skin damage, the keratinocytes secrete IL-33, which stimulates the innate immune response. The interface of autoimmunity with AD is presented in Figure 1.

Figure 1 Interface of autoimmunity with atopic dermatitis.


AD is a chronic inflammation of the skin, manifested mainly by pruritus and dry skin, and is more prevalent in pediatric patients. Three major factors contribute to the pathogenesis of AD: damage of the skin barrier, disorders of the immune response, and imbalances of the skin microbiome—all based on genetic changes and influenced by environmental factors. Predominant activation of Th 2 cells, with the increase of Th 1, Th 17, and Th 22 subsets, promotes skin inflammation. Our study highlights the fact that an autoimmune component exists in the pathogenesis of AD, upheld by the association of other autoimmune conditions with AD and the similar clinical course of autoimmune diseases and AD.


This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.


1. Thomsen S. Atopic dermatitis: Natural history, diagnosis, and treatment. ISRN Allergy. 2014;2014:1–7. 10.1155/2014/354250

2. Holmes J, Fairclough L, Todd I. Atopic dermatitis and autoimmunity: The occurrence of autoantibodies and their association with disease severity. Arch Dermatol Res. 2019;311(3):141–62. 10.1007/s00403-019-01890-4

3. Ali F, Vyas J, Finlay A. Counting the burden: Atopic dermatitis and health-related quality of life. Acta Derm Venereol. 2020;100(2):adv00161. 10.2340/00015555-3511

4. Katoh N, Ohya Y, Ikeda M, Ebihara T, Katayama I, Saeki H, et al. Japanese guidelines for atopic dermatitis 2020. Allergol Int. 2020;69(3):356–69. 10.1016/j.alit.2020.02.006

5. Arakawa H, Shimojo N, Katoh N, Hiraba K, Kawada Y, Yamanaka K, et al. Consensus statements on pediatric atopic dermatitis from dermatology and pediatrics practitioners in Japan: Goals of treatment and topical therapy. Allergol Int. 2020;69(1):84–90. 10.1016/j.alit.2019.08.006

6. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007; 120(1):150–5. 10.1016/j.jaci.2007.04.031

7. Wickett RR, Visscher MO. Structure and function of the epidermal barrier. Am J Infect Control. 2006;34:S98–110. 10.1016/j.ajic.2006.05.295

8. Lee SH, Jeong SK, Ahn SK. An update of the defensive barrier function of skin. Yonsei Med J. 2006;47(3):293–306. 10.3349/ymj.2006.47.3.293

9. Yang G, Seok JK, Kang HC, Cho YY, Lee HS, Lee JY. Skin barrier abnormalities and immune dysfunction in atopic dermatitis. Int J Mol Sci. 2020;21(8):2867. 10.3390/ijms21082867

10. Kim BS. Atopic dermatitis: Practice essentials, background, pathophysiology [Internet]. 2021. Available from:

11. Duca E, Sur G, Armat I, Samasca G, Sur L. Correlation between Interleukin 31 and clinical manifestations in children with atopic dermatitis: An observational study. Allergol Immunopathol (Madr). 2022; 50(1): 75–9. 10.15586/aei.v50i1.521

12. Kim J, Kim B, Leung D. Pathophysiology of atopic dermatitis: Clinical implications. Allergy Asthma Proc. 2019;40(2):84–92. 10.2500/aap.2019.40.4202

13. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016; 387 (10023): 1109–22. 10.1016/S0140-6736(15)00149-X

14. Tanei R. Atopic dermatitis in older adults: A review of treatment options. Drugs Aging. 2020;37(3):149–60. 10.1007/s40266-020-00750-5

15. Guttman-Yassky E, Bissonnette R, Ungar B, Suárez-Fariñas M, Ardeleanu M, Esaki H, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;143(1):155–72. 10.1016/j.jaci.2018.08.022

16. Pravin K, Dinesh SK, Mahendra AS. Pathophysiology and management of atopic dermatitis: A laconic review. Curr Drug Ther. 2020;15(4):321–36. 10.2174/1574885514666190828152316. Available from:

17. Möbus L, Weidinger S, Emmert, H. Epigenetic factors involved in the pathophysiology of inflammatory skin diseases. J Allergy Clin Immunol. 2020;145(4):1049–60. 10.1016/j.jaci.2019.10.015

18. Drislane C, Irvine A. The role of filaggrin in atopic dermatitis and allergic disease. Ann Allergy Asthma Immunol. 2020;124(1):36–43. 10.1016/j.anai.2019.10.008

19. Nakahara T, Kido-Nakahara M, Tsuji G. Basics and recent advances in the pathophysiology of atopic dermatitis. J Dermatol. 2021;48(2):130–9. 10.1111/1346-8138.15664

20. Campione E, Lanna C, Diluvio L, Cannizzaro M, Grelli S, Galluzzo M, et al. Skin immunity and its dysregulation in atopic dermatitis, hidradenitis suppurativa and vitiligo. Cell Cycle. 2020;19(3):257–67. 10.1080/15384101.2019.1707455

21. Fujii M. Current understanding of pathophysiological mechanisms of atopic dermatitis: Interactions among skin barrier dysfunction, immune abnormalities and pruritus. Biol Pharm Bull. 2020;43(1):12–9. 10.1248/bpb.b19-00088

22. Alexander H, Paller A, Traidl-Hoffmann C, Beck LA, De Benedetto A, Dhar S, et al. The role of bacterial skin infections in atopic dermatitis: Expert statement and review from the International Eczema Council Skin Infection Group. Br J Dermatol. 2019;182(6):1331–42. 10.1111/bjd.18643

23. Yang T, Kim B. Pruritus in allergy and immunology. J Allergy Clin Immunol. 2019;144(2):353–60. 10.1016/j.jaci.2019.06.016

24. Chan B, Lam C, Tam L, Wong C. IL33: Roles in allergic inflammation and therapeutic perspectives. Front Immunol. 2019;10:364. 10.3389/fimmu.2019.00364

25. Hendricks A, Eichenfield L, Shi V. The impact of airborne pollution on atopic dermatitis: A literature review. Br J Dermatol. 2020;183(1):16–23. 10.1111/bjd.18781

26. Boguniewicz M, Fonacier L, Leung D. Atopic and contact dermatitis. Clin Immunol. 2019;611–624.e1. 10.1016/B978-0-7020-6896-6.00044-2. Available from:

27. Paller A, Kong H, Seed P, Naik S. The microbiome in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;143(1):26–35. 10.1016/j.jaci.2018.11.015

28. Tsakok T, Woolf R, Smith CH, Weidinger S, Flohr C. Atopic dermatitis: The skin barrier and beyond. Br J Dermatol. 2019;180(3):464–74. 10.1111/bjd.16934

29. Ahn K, Kim BE, Kim J, Leung DY. Recent advances in atopic dermatitis. Curr Opin Immunol. 2020;66:14–21. 10.1016/j.coi.2020.02.007

30. Furue M, Ulzii D, Vu YH, Tsuji G, Kido-Nakahara M, Nakahara T. Pathogenesis of atopic dermatitis: Current paradigm. Iran J Immunol. 2019;16(2):97–107. 10.22034/IJI.2019.80253

31. Moyle M, Cevikbas F, Harden JL, Guttman-Yassky E. Understanding the immune landscape in atopic dermatitis: The era of biologics and emerging therapeutic approaches. Exp Dermatol. 2019;28(7):756–68. 10.1111/exd.13911

32. Nguyen HLT, Trujillo-Paez JV, Umehara Y, Yue H, Peng G, Kiatsurayanon C, et al. Role of antimicrobial peptides in skin barrier repair in individuals with atopic dermatitis. Int J Mol Sci. 2020;21(20):7607. 10.3390/ijms21207607

33. Zhang BX, Lyu JC, Liu HB, Feng DQ, Zhang DC, Bi XJ, et al. Attenuation of peripheral regulatory T-cell suppression of skin-homing CD8-T cells in atopic dermatitis. Yonsei Med J. 2015;56(1):196–203. 10.3349/ymj.2015.56.1.196

34. Park HJ, Lee SW, Park SH, Van Kaer L, Hong S. Selective expansion of double-negative iNKT cells inhibits the development of atopic dermatitis in Vα14 TCR transgenic NC/Nga mice by increasing memory-type CD8+ T and regulatory CD4+ T cells. J Invest Dermatol. 2021;141(6):1512–21. 10.1016/j.jid.2020.09.030

35. Bassin EJ, Piganelli JD, Little SR. Autoantigen and immunomodulatory agent-based approaches for antigen-specific tolerance in NOD mice. Curr Diab Rep. 2021;21(3):9. 10.1007/s11892-021-01376-6

36. Yang Y, Li X, Ma Z, Wang C, Yang Q, Byrne-Steele M, et al. CTLA-4 expression by B-1a B cells is essential for immune tolerance. Nat Commun. 2021;12(1):525. 10.1038/s41467-020-20874-x

37. Furue M, Chiba T, Tsuji G, Ulzii D, Kido-Nakahara M, Nakahara T, et al. Atopic dermatitis: Immune deviation, barrier dysfunction, IgE autoreactivity and new therapies. Allergol Int. 2017;66(3):398–403. 10.1016/j.alit.2016.12.002