The Primary Role of Type 2 Helper T Cells in Atopic Dermatitis
Atopic dermatitis is closely associated with the activation of type 2 helper T cells (Th2 cells). Upon exposure to allergens, the immune system produces allergen-specific IgE antibodies, which bind to high-affinity receptors on the surface of mast cells. Once allergens cross-link with these IgE antibodies, they trigger mast cell degranulation, releasing a massive amount of inflammatory mediators like histamine, leukotrienes, and various prostaglandins.
These inflammatory substances induce a series of pathological reactions, including bronchial smooth muscle spasms leading to airway obstruction, increased mucus secretion, vasodilation causing edema, etc. These are precisely the main clinical manifestations of atopic dermatitis. Therefore, the Th2 cell-mediated IgE production and subsequent mast cell reaction is considered the key pathogenic mechanism of atopic dermatitis.
Differences in Immune Responses in Early and Late Stages of Atopic Dermatitis
However, the primary immune cell types mediating the pathogenesis of atopic dermatitis differ between the early and late stages of the disease. In the initial phase, the Th2 cell response dominates, with IgE-mediated allergic reactions being the main feature. However, as the inflammatory response progresses, the immune response pattern shifts.
In the late stage of atopic dermatitis, the inflammatory response becomes increasingly driven by other types of cytokines, such as pro-inflammatory cytokines secreted by Th1, Th17 cells, including interferons and interleukins. At this stage, the infiltrating inflammatory cells at the lesion site are no longer limited to mast cells but are predominantly inflammatory monocytes and neutrophils.
Due to this change in the immune mechanism and the cell types involved, simply suppressing IgE or blocking the Th2 response is no longer sufficient to control the disease. Therefore, in the treatment of late-stage atopic dermatitis, more potent immunosuppressive drugs, such as corticosteroids or other immunomodulators, are typically required to induce apoptosis of the activated T cells and inflammatory cells, thereby effectively controlling the symptoms.
Impaired Skin Barrier Function in Atopic Dermatitis Patients
Apart from abnormal immune responses, patients with atopic dermatitis also exhibit structural and functional defects in their skin. Research has found that the fatty acid composition in the blood of these patients differs from that of normal individuals, leading to poorer water retention ability in their skin, and easier transepidermal water loss. Consequently, the skin of atopic dermatitis patients often appears dry and scaly, and this dry skin further exacerbates the symptoms of atopic dermatitis, forming a vicious cycle.
This is precisely why it is crucial for atopic dermatitis patients to use appropriate skincare products and moisturizers to maintain skin integrity and moisture balance. Proper skin care can not only alleviate symptoms like dryness and itching but also help prevent the entry of allergens, bacteria, and other exogenous substances, reducing excessive stimulation of the immune system.
The latest research has further revealed that mutations in the filaggrin gene are closely related to the development of atopic dermatitis. Filaggrin is a major component of the epidermal barrier, playing a crucial role in maintaining skin integrity. If filaggrin is defective, the skin barrier function is severely compromised, allowing bacteria, allergens, and other exogenous substances to penetrate the skin more easily, triggering allergic inflammatory responses.
In the future, a deeper understanding of the precise role of filaggrin in the pathogenic mechanism of atopic dermatitis may lead to the development of novel therapeutic strategies for this condition. Some researchers have even proposed the possibility of using gene therapy to repair the filaggrin gene defects in the skin cells of patients, fundamentally resolving the skin barrier issue, which would undoubtedly be an attractive research direction.
The “Hygiene Hypothesis” and Its Link to Overly Sterile Environments
Why has the incidence of allergic diseases like atopic dermatitis been rising sharply in recent years? Apart from the genetic and immunological factors mentioned above, environmental factors are also believed to play a crucial role. The “hygiene hypothesis” attempts to explain this phenomenon.
According to large-scale epidemiological studies, over the past 50 years, the incidence of certain infectious diseases such as hepatitis, measles, mumps, and rheumatic fever, caused by pathogens, has significantly decreased due to vaccination and improved environmental hygiene. However, during the same period, the incidence of some autoimmune diseases like inflammatory bowel disease, multiple sclerosis, type 1 diabetes, and allergic diseases like asthma has been on the rise.
Proponents of the “hygiene hypothesis” argue that this paradoxical phenomenon is likely due to the “excessive cleanliness” of the human living environment. Over the past century, with the development of vaccines and widespread use of antibiotics, human exposure to pathogens has become increasingly rare. However, moderate exposure to and infection by pathogens is crucial for training and developing the body’s normal immune function. A lack of such stimulation may lead to an imbalance in the immune system, increasing the risk of autoimmune diseases and allergic tendencies.
Empirical Research Supporting the “Hygiene Hypothesis”
Several studies have provided empirical support for the “hygiene hypothesis”:
1. Early Group Living Reduces Allergy Risk: A study in the United States showed that children who entered daycare or preschool at an earlier age, or those who had siblings regularly bringing home pathogens from school, were more likely to experience infectious symptoms during early childhood. However, they were less likely to develop allergic diseases as they grew older. 2. BCG Vaccination Reduces Allergy Risk: Research in Japan found that children who received the BCG (Bacillus Calmette-Guérin) vaccine had significantly lower rates of developing allergic diseases later in life. Researchers speculate that the BCG vaccine effectively induces a robust type 1 helper T cell response, thereby reducing the dominance of the type 2 allergic response. 3. Second-hand Baby Products Reduce Allergy Incidence: Studies have shown that babies who used second-hand cribs or other products had a significantly lower rate of developing allergic diseases later in life compared to those who used brand-new products. Researchers explained that the second-hand products might harbor trace amounts of pathogens, which moderately stimulated the development of the infants’ immune systems. 4. Farm Environment Reduces Allergy Risk: Children raised on farms, although continuously exposed to high concentrations of dust mites, pollen, and microorganisms from an early age, had a much lower incidence of allergic diseases compared to those raised in urban environments. This natural environmental exposure is considered a key factor in triggering proper immune development.
These research findings support the premise of the “hygiene hypothesis” that moderate exposure to microbes and environmental endotoxins (bacterial cell wall components) helps activate type 1 helper T cell responses during infancy and childhood, fostering a more balanced immune response and reducing the risk of developing an allergic predisposition later in life.
The Importance of Endotoxins and Innate Immune Training
“Endotoxins” refer to the major components of certain bacterial cell walls, such as lipopolysaccharides (LPS) found in Gram-negative bacteria. Although endotoxins are indeed toxic to a certain degree, moderate exposure is crucial for training and activating the innate immune system in infants and young children.
Endotoxins can be effectively recognized by various cellular receptors in the human body, such as the TLR4 receptor, triggering a cascade of inflammatory signaling reactions. This process not only activates effector cells of the innate immune system (e.g., macrophages, neutrophils), but also initiates adaptive immune responses, promoting the development of type 1 helper T cell (Th1) responses. Over time, this “immune training” from environmental exposure shapes a balanced and robust immune state.
Conversely, a lack of such low-level endotoxin stimulation means that an infant’s immune system will struggle to receive proper “tempering,” making it more prone to skewing towards the Th2 response and increasing the risk of developing an allergic predisposition in the future. Some researchers have likened it to the notion that “the immune system is like a muscle, requiring appropriate exercise to become strong and healthy.”
Exposure to Pathogens Conducive to Immune Balance Development
However, not all pathogen infections contribute to the cultivation of a well-balanced immune response; some viral or bacterial infections may actually cause the immune response to deviate further from the normal path. This is a blind spot that needs to be addressed in the “hygiene hypothesis.”
For instance, pathogens like the respiratory syncytial virus, Streptococcus pneumoniae (commonly known as the pneumococcus), and the measles virus tend to enhance the activity of type 2 helper T cells upon infection, which can increase the risk of developing an allergic predisposition over the long term.
Taking Streptococcus pneumoniae as an example, it most commonly infects children aged 2-5 years old, causing symptoms such as wheezing, coughing, and breathing difficulties that are strikingly similar to the clinical manifestations of asthma. More problematically, the immune response triggered by Streptococcus pneumoniae infection differs from that of typical pathogens, making it difficult to generate sufficient immunity to prevent subsequent infections. Consequently, recurrent infections are common. Research indicates that recurrent Streptococcus pneumoniae infections significantly increase the risk of children developing asthma later in life.
Role of Specific Pathogens in Allergic Predisposition
Not all infectious diseases have the effect of promoting a type 1 immune response. Specific pathogens such as the respiratory syncytial virus, Mycoplasma pneumoniae, and the measles virus tend to increase the type 2 helper T cell response. The more frequent the infections caused by these pathogens, the more likely the development of a type 2 helper T cell response, thereby promoting an allergic immune reaction.
Respiratory Syncytial Virus (RSV): RSV typically affects younger infants, presenting as acute bronchiolitis. Although acute bronchiolitis caused by RSV in otherwise healthy infants does not require specific treatment, for infants with underlying lung conditions or congenital heart disease leading to lung dysfunction, treatment with an antiviral drug (ribavirin) during RSV infection has been shown to reduce the risk of developing asthma later in life.
Measles Virus: As most children receive the measles vaccine after birth, the impact of the measles virus on the development of allergic diseases is relatively minor.
Mycoplasma pneumoniae: Among these pathogens, Mycoplasma pneumoniae is particularly noteworthy because it most commonly infects children aged 2-5 years old, causing pneumonia symptoms such as wheezing, coughing, and breathing difficulties, which can be challenging to distinguish from the clinical manifestations of asthma.
Moreover, the immune response triggered by Mycoplasma pneumoniae infection differs from that of typical pathogens. Mycoplasma pneumoniae does not readily induce sufficient immunity to prevent subsequent infections, making recurrent infections more likely.
Research has indicated that recurrent Mycoplasma pneumoniae infections can lead to the development of asthma. Therefore, when wheezing occurs in children aged 2-5 years, it is essential to consider the possibility of concomitant Mycoplasma pneumoniae infection, which may require concurrent treatment to control the disease effectively.
In summary, while most pathogens contribute to the development of a balanced type 1 helper T cell response in the immune system, recurrent infections with certain specific pathogens can increase the risk of developing an allergic predisposition.
Allergy Q&A – Is Allergy Testing Suitable for Infants?
Currently, only a simple blood draw is required to test for major allergens in infants and young children. The recommended age for allergy testing is around 2 years old, but it can be considered earlier if symptoms of atopic dermatitis appear before 1 year of age.
Historically, allergy testing was primarily conducted using skin tests, where various allergens were injected into the skin of the tested individual, and the resulting redness and swelling reactions were observed. However, this method was relatively inconvenient, causing pain and discomfort, as each allergen required a separate injection. It was not uncommon to see tested children with injection sites covering their arms and backs.
Nowadays, allergy testing methods have become much more precise, allowing the determination of allergens using only a small blood sample, thus avoiding unnecessary distress for infants and young children.
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