NEA Research Team Finds Nearly 1 in 5 Adult Eczema…
Researchers at the National Eczema Association publish a new letter Journal of Investigative Dermatology evaluating the prevalence of different forms of eczema.
Published On: Jul 14, 2023
Last Updated On: Jul 14, 2023
Your immune system is a very complex system that harnesses the coordinated efforts of specific organs, cell types and proteins. Different types of immune cells, and the protein molecules they create (e.g. cytokines, interleukins [IL], etc.) are involved in conveying and receiving messages to and from one another and to and from the rest of the cells in the body to guide immune responses. The exciting journey into understanding how the immune system works and how it goes awry in atopic dermatitis (AD) has led to major breakthroughs in the ability to treat this disease over the last decade and is fueling a surge in drug discovery.1
In this article we will provide a high-level overview of the role and function of the immune system in AD. We will share what is known today about the immune system’s contribution to disease onset and progression, as well as what the future holds for opportunities to leverage immune system modulation as a therapeutic approach.
Although there is not a single root cause of AD (genetics, microbiome, environment, immune system and other factors all play roles in AD), immune dysregulation is a major driver of the disease. Inflammation is the body’s defense against infection, injury and cancer. There are two main branches of the immune system – the innate and the adaptive. The innate immune system can be thought of as a “first responder” and generally involves different non-specific barriers that form the first line of defense to keep harmful pathogens (bacteria, viruses and other microbes that can cause disease) and other external materials like allergens, toxins and irritants from entering the body. The skin, and the cells that reside in the skin, are part of our innate immune system. The adaptive immune system is slower to respond but can specifically and accurately eliminate pathogens that may be causing a more widespread infection throughout the body. The adaptive immune system can also fight against “bad” cells in the body, like cancer cells.2
Several components of the innate immune system do not function normally in AD. For example, the physical skin barrier is disrupted, meaning that the innate immune system in AD is inefficient and unable to defend against the entry of undesired pathogens and external materials past this first line of natural defense. This allows allergens, irritants and pathogens like the Staphylococcus aureus (S. aureus) bacterium to penetrate deeper into the skin where they stimulate a larger coordinated innate and adaptive immune reaction to fight them.3
The resulting adaptive immune response, which includes activation of various inflammatory cytokines, can further drive barrier disruption and reduce innate immune responses.3,4 After this large systemic immune response, it is difficult for the immune system to go back to normal again because the “threat” is always there, so a cycle of inflammation is generated throughout the body, not just in the skin.1
To ensure a comprehensive defense, the immune system has also evolved three main types of attack systems depending upon what is being attacked. In each of these systems, different types of immune cells are activated, with innate immune cells passing information to adaptive immune cells:
All three of these beneficial immune reaction types can also cause diseases if they inappropriately respond to the wrong things and become dysregulated. Types I and III immunity can underlie diseases such as rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease, among others. Cells (Th-2, which stands for helper T cells type II) and cytokines (IL-4, IL-5, IL-9, IL-13 and IL-31) involved in Type II immunity have a prominent role in AD.5
“Type II immunity with the main cytokines (IL-4, IL-5 and IL-13 and their downstream pathways) were primarily developed to control parasites, which are uncommon in Westernized countries today,” said Dr. Lisa Beck, a dermatologist at University of Rochester Medical Center. “Instead, this inflammatory pathway can unfortunately be triggered by a wide range of environmental antigens including allergens like pollens, animal dander, molds, foods [peanut, milk, soy, etc.], bacteria and yeast products. Type III immunity (Th-17) like we see in psoriasis is typically triggered by extracellular bacteria and fungi. This pathway can be seen in autoimmune diseases. Type I immunity (Th-1) arises from exposure to intracellular bacteria or viruses and is the pathway most commonly seen in those with autoimmunity.”
“Autoimmune” is a term used to describe when the immune system inappropriately recognizes tissue in our own body as foreign just as it would other foreign invaders like microbes, parasites, bacteria or fungi. In contrast, an immune-mediated disease means there is an error in the immune system where it tries to do too much of what it was created to do like mounting an exaggerated response to S. aureus bacteria. AD is not truly an autoimmune disorder, but rather an immune-mediated disease. Scientists have frequently been able to identify the actual cellular components that trigger an autoimmune response (called self-antigens). As an example, a blistering skin disease called pemphigus occurs when immune cells make antibodies against the main proteins that connect keratinocytes to one another to give skin its strong structure.6 In lupus, another autoimmune disease, autoantibodies are made against lipids that make up the cell or nuclear membrane.7 No self-antigen for AD has been found.
Confusion about whether AD in an autoimmune or immune-mediated condition has arisen because the media and literature have previously described AD as ‘autoimmune. For example, in 2014 a press release from Mount Sinai University announcing exciting results from dupilumab when it was still in its development stage used the terms immune-mediated and autoimmune interchangeably.8 Several reports in the scientific literature have discussed AD as an autoimmune disease due to high production of an antibody called IgE, an allergy-related antibody that attacks the body’s cells, found in up to one in three people with AD.9,10 Another term has since been coined for this phenomenon, called autoallergy.10 Autoallergy is being discussed for its role in AD in fairly recent literature,11 but the predominant thinking is that the immune system overresponds in its attacks of foreign bodies like bacteria and allergens, fueling the kind of hypersensitivity that can result in the atopic march.
True autoimmune disorders include ulcerative colitis, celiac disease, certain types of anemia, type I diabetes, autoimmune hypothyroidism, Graves’ disease, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, Sjögren’s syndrome, vitiligo, alopecia areata and multiple sclerosis.12 While AD is not an autoimmune disorder, there have been recent reports in the literature about links between the immune disturbance that drives AD and development of other diseases that are autoimmune.12,13 In one large scale study of 173,709 children and adults with new-onset AD and 694,836 age-, sex- and general practitioner practice-matched controls, there was a significant increased risk of patients with severe AD developing several types of autoimmune disease, including some of those listed above.12 Another large-scale study of over a million AD patients showed an association between AD and risk of systemic lupus erythematosus, Sjögren’s syndrome, vitiligo and psoriasis.13 It is clear that once the immune system begins its dysregulation in AD, the chances are higher that other diseases, both atopic and autoimmune, can follow.
Because of our deepening understanding of the immune system in AD, we have moved from broadly suppressing the immune system through medicines like topical and oral steroids and steroid-sparing agents like calcineurin inhibitors14 to being able to target single molecule drivers of the disease more specifically, leaving the rest of the immune system free to do its job.
A little history on the evolution of knowledge about the specific immune mediators driving AD takes us back to the 1990s. The fact that AD was driven by a Th-2 or Type II immune response and that IL-4 was involved in the disease’s cause and progression has been known since the early 1990s.15-17 IL-13 was discovered in 1993 and found to be upregulated at the mRNA level by 2004.4 While several other cytokines, interleukins and antibodies have also been shown to be involved in AD, specifically inhibiting IL-4 and IL-13 signaling became a central focus of drug development. Many mouse models of AD were developed to help test drugs, such as mice overexpressing IL-4 and IL-13 which show many features of AD. While none of these mouse models exactly replicates human AD, information learned about interleukins and how to modulate their activity led to new therapeutics.18 Dupilumab, a major revolution in AD treatment, targets the IL-4 receptor, thereby blocking signaling by both IL-4 and IL-13.1 Drug development always takes time, but the last 10 years have seen a very rapid expansion of drugs that can target various immune contributors in AD.
Twenty-five years from the first understanding of AD as a type II immune disease with IL-4 involvement, dupilumab was first approved by the FDA for adult AD patients in 2017 followed by approval for a wider age range of patients. Tralokinumab, which targets IL-13, was FDA approved to treat AD in 2021, and lebrikizumab (which targets IL-13), is nearly through clinical trials and is awaiting approval, perhaps even in the coming year.1,19,20 Many of these molecule-specific drugs are administered systemically (via injections), but other new medications can be administered orally or topically, including JAK inhibitors, which have already been approved. As we speak, many other novel topical treatments are making their way through clinical trials.14 The JAK/STAT signaling pathway is activated by IL-4 and IL-13 in AD. Its inhibitors do not specifically target a cytokine – rather, the signaling activated downstream of the cytokine.14
IL-31 was discovered in 200421 and is most directly implicated in mediating itch. IL-31 is released by many types of immune cells, including T cells, mast cells, macrophages, basophils, eosinophils and dendritic cells. Even keratinocytes, the most common cells in the skin, release IL-31.21-23 IL-31: a neuroimmune mediator that binds to the IL-31 receptor on peripheral nerves and activates signaling pathways that mediate the feeling of itch.21 A new drug, nemolizumab (which targets the IL-31 receptor) is showing great promise for reducing itch in AD patients and may also be FDA approved in the coming year. The itch/scratch cycle is a known driver of the disease, so reducing or eliminating itch may play a big role in controlling the disease, perhaps in combination with other treatments.24,25
In addition to our findings about the contributions of the immune system to AD onset and progression, we have also recently learned that people with AD do not all have the same changes in their immune systems.26 Exciting work is being done to characterize subtypes (called endotypes) of AD based on the exact immune signals involved as a method in the hope of improving personalized treatment. While the recently developed therapies greatly improve AD symptoms in many patients, not all patients respond – having more treatment options and greater knowledge of individual immune profiles will enhance targeted, personalized treatments for patients.”
JiaDe “Jeff” Yu, MD of Massachusetts General Hospital sums up the treatment revolution by saying, “Identification of key molecules such as Janus Kinase, and Interleukins 4, 13 and 31 have allowed pharmaceutical companies to create novel drugs targeting and blocking these molecules. In turn, these therapies have revolutionized health care providers’ ability to treat patients with moderate to severe AD, and more drugs are being developed. Understanding of AD and how to treat it, is advancing far more rapidly than ever before.” Dr. Yu also mentions potential barriers to prescribing multiple drugs to treat AD saying, “As we develop intimate knowledge of the nuanced differences in immunology to lead to more personalized approaches to treating AD, we hope systems like insurance companies will allow their use in patients, but this may take time.”
While so much about AD has been elucidated and treatment options are rapidly expanding, there remain many important questions in the field. Dr. Yu asked, “How does the immune system interact with the environment to cause AD? Why do some patients develop AD in infancy and others as adults? What about the immune system leads to different presentations of AD in different patients? What factors drive its distribution?
Dr. Beck also has many remaining questions including, “Would blockade of type II immunity early in life change the course of AD (i.e. make it milder or lead to disease remission) or reduce the likelihood or severity of other allergic atopic comorbidities? Is adult-onset AD also driven by type II immunity? How important are skin or gut microbial changes in driving AD inflammation and disease severity?” Together, these important questions and more will be addressed in scientific studies over the coming decades.
Despite the great success of newer therapies to treat AD, further work is still needed. Dr. Beck says, “All of our treatments are primarily anti-inflammatory. We still do not have treatments for other things that are responsible for aspects of AD, such as improving the skin barrier, targeting itch specifically and reducing pathogenic S. aureus colonization of the skin.” Learning more about molecules like IL-31 (with nemolizumab on the way), the skin barrier and S. aureus colonization could lead to improvements in itch and other as yet untreated AD symptoms as well as new treatments for patients who still experience persistent disease even after use of medications specifically targeting IL-4 and IL-13. We expect to continue to see great advances in the ability to treat AD and its symptoms as knowledge about the immune system’s contribution to AD pathogenesis continues to rapidly improve.
Article medically reviewed by Vivian Shi, MD, FAAD Associate Professor of Dermatology, University of Arkansas for Medical Sciences (Reviewed June 2023)
References:
1. MoMoyle 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):756-768.
2. Institute for Quality and Efficiency in Health Care. The innate and adaptive immune systems. In: Informedhealth.org. Germany 2020. https://www.ncbi.nlm.nih.gov/books/NBK279396/. Accessed 5-3-23.
3. De Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA. Atopic dermatitis: a disease caused by innate immune defects? J Invest Dermatol. 2009;129(1):14-30.
4. Bieber T. Interleukin-13: Targeting an underestimated cytokine in atopic dermatitis. Allergy. 2020;75(1):54-62.
5. McCormick JP, Lee JT. Insights into the Implications of Coexisting Type 2 Inflammatory Diseases. J Inflamm Res. 2021;14:4259-4266.
6. Olbrich M, Kunstner A, Witte M, Busch H, Fahnrich A. Genetics and Omics Analysis of Autoimmune Skin Blistering Diseases. Front Immunol. 2019;10:2327.
7. Riemekasten G, Hahn BH. Key Autoantigens in SLE. Rheumatology. 2005;44(8):975-982.
8. Atopic Dermatitis Found to be an Immune-Driven Disease. Press Release, December, 2014. Mount Sinai Newsroom. December, 2014. https://www.mountsinai.org/about/newsroom/2014/atopic-dermatitis-found-to-be-an-immunedriven-disease.
9. Boehncke WH, Brembilla NC. Autoreactive T-Lymphocytes in Inflammatory Skin Diseases. Front Immunol. 2019;10:1198.
10. Hradetzky S, Werfel T, Rosner LM. Autoallergy in atopic dermatitis. Allergo J Int. 2015;24(1):16-22.
11. Roesner LM, Werfel T. Autoimmunity (or Not) in Atopic Dermatitis. Front Immunol. 2019;10:2128.
12. de Lusignan S, Alexander H, Broderick C, et al. Atopic dermatitis and risk of autoimmune conditions: Population-based cohort study. JAllergy Clin Immunol. 2022;150(3):709-713.
13. Kokkonen J, Niinimaki A. Increased incidence of autoimmune disorders as a late complication in children with early onset dermatitis and/or milk allergy. Autoimmun. 2004;22(4):341-344.
14. Pinto LM, Chiricozzi A, Calabrese L, Mannino M, Peris K. Novel Therapeutic Strategies in the Topical Treatment of Atopic Dermatitis. Pharmaceutics. 2022;14(12).
15. van der Heijden FL, Wierenga EA, Bos JD, Kapsenberg ML. High frequency of IL-4-producing CD4+ allergen-specific T lymphocytes in atopic dermatitis lesional skin. J Invest Dermatol. 1991;97(3):389-394.
16. Wierenga EA, Snoek M, de Groot C, et al. Evidence for compartmentalization of functional subsets of CD2+ T lymphocytes in atopic patients. J Immunol. 1990;144(12):4651-4656.
17. Wierenga EA, Snoek M, Jansen HM, Bos JD, van Lier RA, Kapsenberg ML. Human atopen-specific types 1 and 2 T helper cell clones. J Immunol. 1991;147(9):2942-2949.
18. Gilhar A, Reich K, Keren A, Kabashima K, Steinhoff M, Paus R. Mouse models of atopic dermatitis: a critical reappraisal. Exp Dermatol. 2021;30(3):319-336.
19. ClinicalTrials.gov. U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=Atopic+Dermatitis&term=&cntry=&state=&city=&dist=. Accessed 5-3-2023.
20. Makowska K, Nowaczyk J, Blicharz L, et al. Immunopathogenesis of Atopic Dermatitis: Focus on Interleukins as Disease Drivers and Therapeutic Targets for Novel Treatments. Int J Mol Sci. 2023;24(1).
21. Cevikbas F, Lerner EA. Physiology and Pathophysiology of Itch. Physiol Rev. 2020;100(3):945-982.
22. Mollanazar NK, Smith PK, Yosipovitch G. Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out? Clin Rev Allergy Immunol. 2016;51(3):263-292.
23. Yosipovitch G, Berger T, Fassett MS. Neuroimmune interactions in chronic itch of atopic dermatitis. J Eur Acad Dermatol Venereol. 2020;34(2):239-250.
24. Labib A, Ju T, Yosipovitch G. Emerging Treatments for Itch in Atopic Dermatitis: A Review. J Am Acad Dermatol. 2023.
25. Labib A, Vander Does A, Yosipovitch G. Nemolizumab for atopic dermatitis. Drugs Today (Barc). 2022;58(4):159-173.
26. Czarnowicki T, He H, Krueger JG, Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics. J Allergy Clin Immunol. 2019;143(1):1-11.
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