A critical immune pathway may explain how skin allergies trigger systemic reactions

The human body experiences 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 this 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 bodywide allergic response.

The study was published in Proceedings of the National Academy of Sciences.

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; 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 in Barrier Immunity.

IL-13 puts dendritic cells on alert

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," Harada explains.

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.

How skin sensitization spreads

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.

Evidence points to the same pathway

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 advance 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," Kubo says.

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.

This article was originally published on MedicalXpress Breaking News-and-Events.