Introduction to Atopic Dermatitis (AD)

Dermatologist Hua-Ching Chang

Atopic dermatitis (AD), often referred to as "atopic eczema," is a chronic, recurrent inflammatory skin disease characterized by itching and eczema. Its pathogenesis is believed to result from a combination of multiple factors, which can be categorized into four main aspects: "genetic susceptibility," "skin barrier dysfunction," "environmental stimuli," and "immune dysregulation." These factors interact with and influence each other, creating a complex network of causative and contributing elements. This article introduces these four major pathophysiological mechanisms.

Genetic Susceptibility

AD patients and their relatives often have a history of atopic diseases such as AD, allergic rhinitis, and asthma. Studies indicate that if one parent has any of these allergic conditions, the child has a 1.5–3 times higher risk of developing AD. If both parents have AD, the child's risk increases fivefold. Genetic research has yet to identify a single gene variation that fully explains the occurrence of AD, and variations differ among ethnic groups. However, the discovered abnormal genes are often related to skin barrier function and immune system homeostasis. The strongest association with AD is the loss-of-function mutation in the filaggrin gene, leading to impaired skin barrier function.

Skin Barrier Dysfunction

The skin is the largest organ of the body and the first line of defense against environmental stimuli. Structurally, it consists of three layers from outside to inside: the epidermis, dermis, and subcutaneous tissue. The outermost epidermis mainly comprises keratinocytes, which arrange like bricks and differentiate into multiple layers, ultimately forming the stratum corneum. In AD patients, the skin behaves like a damaged wall, unable to effectively prevent water loss internally and block environmental stimuli externally. This barrier dysfunction primarily arises from reduced differentiation proteins in keratinocytes (e.g., filaggrin, loricrin, and involucrin) and significantly decreased ceramides in the intercellular matrix of the stratum corneum, leading to altered skin microbiota, especially overgrowth of Staphylococcus aureus, which often exacerbates AD.

Environmental Stimuli

Due to skin barrier dysfunction in AD, various environmental factors can easily penetrate the skin, such as dust mites, pollen, sweat, animal dander, bacteria, and fungi, potentially triggering or worsening AD. Lower humidity in autumn and winter exacerbates the already insufficient moisture in the skin. Conversely, the intense summer sun and the combined effects of heat and sweat often worsen the condition. These environmental stimuli aggravate itching, creating a vicious cycle of scratching and further barrier damage.

Immune Dysregulation

While insufficient immunity is commonly thought to cause diseases, AD results from immune system dysregulation leading to abnormal activation of inflammatory cells. When keratinocytes in AD patients' epidermis are exposed to external stimuli, they release various alarm signals (alarmins) such as IL-25, IL-33, and TSLP, and chemokines like CCL5, CCL11, CCL17, and CCL26. These factors chemotactically attract and activate type 2 innate lymphoid cells (ILC2) in the dermis. Additionally, dendritic cells in the skin migrate to peripheral lymph nodes to induce differentiation of type 2 helper T cells (Th2). Both ILC2 and Th2 cells secrete various pro-inflammatory cytokines like IL-4, IL-5, IL-13, and IL-31, collectively known as type 2 immunity. These cytokines induce B cells to produce and release IgE antibodies, which bind to mast cells. When stimulated by antigens, mast cells release large amounts of histamine, causing itching. Other inflammatory cells like eosinophils and macrophages also participate in the AD inflammatory response. Moreover, IL-4, IL-5, and IL-31 activate skin sensory nerves, enhancing itch sensation. Cytokines, especially IL-4 and IL-13, feedback to the epidermis, causing abnormal differentiation, decreased lipid content, and reduced antimicrobial peptide production, further worsening the already compromised skin barrier.

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