Our bodies experience allergic reactions when the immune system mistakenly overreacts to harmless substances, known as allergens, such as pollen, dust, or certain foods. While this often causes mild symptoms such as sneezing or a runny nose, it can sometimes trigger a severe, life-threatening reaction called anaphylaxis.
In people with atopic dermatitis, the skin's protective barrier is damaged, allowing allergens to enter the body through the skin. Once the immune system has been sensitized to an allergen, later exposure can trigger allergic reactions throughout the body, a progression known as the "atopic march." This entire process is primarily driven by cutaneous allergen sensitization (CAS). Though therapeutic approaches involving monoclonal antibodies are available, the detailed mechanism behind the trajectory remains elusive.
Now, researchers from Tokyo University of Science (TUS) and Kyoto University in Japan have uncovered a key mechanism explaining how allergic inflammation in the skin can progress to a body-wide allergic response.
The study was made available online on July 09, 2026, and published in Volume 123, Issue 28 of the journal Proceedings of the National Academy of Sciences (PNAS) on July 9, 2026. The research team was led by Professor Emeritus Masato Kubo (at the time of this research, affiliated with the Division of Molecular Pathology, TUS, RIKEN, IMS, and currently affiliated with the Kyoto University Immunomonitoring Center), together with Technical Staff Researcher Yasuyo Harada from the Division of Immunology and Allergy, TUS, and Dr. Takanori Sasaki from Keio University School of Medicine, and Associate Professor Yasutaka Motomura from the Division of Immunology and Allergy, TUS. A review article that provides a deeper discussion of these findings was published shortly afterward in Volume 2, Issue 2, of Barrier Immunity on July 23, 2026.
The study found that IL-13, an immune signaling protein (cytokine) involved in allergic inflammation, acts on dendritic cells, enhancing their ability to present allergens to other immune cells, a process known as “licensing.” This promotes immune responses that produce antibodies, which can trigger systemic anaphylaxis.
"We discovered that the type 2 cytokine IL-13 acts not on B cells or T cells, but on type 2 classical dendritic cells or cDC2, significantly increasing their antigen-presenting ability, thereby inducing the production of high-affinity IgE antibodies against allergens and leading to systemic anaphylaxis," explains Ms. Harada.
To investigate this process, the researchers developed a murine CAS model that mimics the atopic march by repeatedly exposing the skin to an allergen. This sensitized the immune system and primed the mice to produce large amounts of high-affinity IgE antibodies when they later encountered another allergen. The researchers found that IL-13 acts specifically on cDC2 cells carrying the proteins IL13RA1, CX3CR1, and CD301b on their surface.
They also discovered that CX3CR1-positive cDC2 cells circulate in the bloodstream and transport allergens to secondary lymphoid organs, such as the spleen. When the researchers blocked CX3CR1 with a drug, the migration of these cDC2 cells was severely impaired, and the production of high-affinity IgE antibodies dropped dramatically. This showed that the movement of cDC2 cells through the bloodstream is essential for allowing allergic sensitization that begins in the skin to develop into a systemic allergic response. These findings further suggest that inhibiting the fractalkine receptor CX3CR1 may represent a promising therapeutic strategy for interrupting the atopic march and advancing new treatments for allergic diseases.
The researchers then looked for the same mechanism in humans. They found increased numbers of IL13RA1-positive, CX3CR1-positive cDC2 cells in skin samples from patients with atopic dermatitis and in blood samples from patients with allergic diseases. Importantly, higher numbers of these cells were associated with increased levels of IgE antibodies, suggesting that the same mechanism also operates in human allergic disease.
The findings also reshape scientists’ understanding of IL-13. Previous research established that IL-4 directly causes B cells to switch to producing IgE antibodies. In contrast, this study shows that IL-13 works indirectly by licensing cDC2 to coordinate the immune responses that lead to high-affinity IgE antibodies. These findings provide a molecular explanation for why IL-13-targeting drugs, such as tralokinumab and lebrikizumab, are effective in treating atopic dermatitis. They also identify the IL-13-cDC2-CX3CR1 pathway as a promising therapeutic target for developing strategies to interrupt the atopic march and for advancing new treatments for allergic diseases.
"By blocking the crucial cDC2 licensing, these therapies likely sever the link between skin inflammation and systemic IgE production, thereby preventing the atopic march,” says Prof. Kubo.
As allergic diseases such as atopic dermatitis, asthma, and food allergies continue to increase worldwide, these findings provide important mechanistic insights that may support the development of new therapeutic strategies to interrupt allergic disease progression and improve the treatment of severe allergic disorders.
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References
Title of original paper:IL-13 signaling in cDC2 is required for systemic anaphylactic responses
Journal: Proceedings of the National Academy of Sciences (PNAS)
DOI: 10.1073/pnas.2608478123
Title of original paper: A Role of the IL-13 Signal and Type 2 Conventional Dendritic Cell in the Atopic March
Journal: Barrier Immunity
DOI: 10.1002/dni2.70014
About The Tokyo University of Science
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society," TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
Website: https://www.tus.ac.jp/en/mediarelations/
About Professor Emeritus Masato Kubo from Tokyo University of Science
Professor Masato Kubo, at the time of this research, affiliated with the Division of Molecular Pathology, TUS, RIKEN, IMS, and currently affiliated with the Kyoto University Immunomonitoring Center. He is also an Emeritus Professor of Tokyo University of Science. His expertise includes signaling pathways, inflammation, cytokines, allergy, immune system, autoimmunity, B cells, dendritic cells, immune response, skin, Th1 cells, T cell differentiation, T lymphocytes, CD4-positive T-lymphocytes. He has over 325 publications to his credit.
Funding information
This research was supported by AMED-CREST (19gm1310002), a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS KAKENHI Grant No. 25K10403), the MOST-RIKEN Collaboration Program, the Kobayashi Foundation, the Allen Discovery Center program of the Paul G. Allen Family Foundation, the Doris Duke Charitable Foundation, LEO Pharma, the U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; Grant Nos. AR077007 and AR080392), and the National Institute of Allergy and Infectious Diseases (NIAID; Grant Nos. AI167933 and AI167047).
Proceedings of the National Academy of Sciences
Experimental study
Animals
IL-13 signaling in cDC2 is required for systemic anaphylactic responses
9-Jul-2026
The authors declare no competing interest.