INTRODUCTION
Atopic dermatitis (AD) is an inflammatory allergic disease characterized by a severe course and it often coexists with other atopic diseases. Its development is influenced by numerous factors including predisposing genes, innate susceptibility, environmental and infectious agents, impaired structure and function of the skin barrier and immune response, abnormal colonization of the skin by microorganisms. The patient’s age and population membership also play a significant role in development of AD. Atopic dermatitis often begins in early childhood and can last throughout the patient’s life [1–4].
A characteristic feature of AD is the variability of its course in each age group. Additionally, it often co-occurs with conditions such as asthma, allergic rhinitis, and food allergy. In the course of this disease, a decrease in nonspecific immunity (reduced activity of antimicrobial peptides), infections caused by Staphylococcus aureus (very often), fungi, and viruses are observed [3, 5].
The balance between Th1 and Th2 lymphocytes determines the correct immune response. In AD, however, a preference for differentiating of CD4+ lymphocytes into Th2 can be observed with impaired proliferation of Th1 cells. Increased activity of Th2 lymphocytes may be a consequence of exposure to allergens [1]. Allergens as well as chemical substances or infections can contribute to the formation of reactive oxygen species (ROS). ROS responsible for oxidative stress will intensify inflammatory reactions and damage to the skin barrier. In addition, they activate nuclear κB transcription factor (NF-κB), which induces the expression of proinflammatory cytokines. This causes an increase in the intensity of inflammatory infiltration of the skin and the release of histamine, which only intensifies the symptoms of AD. ROS can also directly cause damage and dysfunction of keratinocytes [2].
Histamine also plays an important role in AD. It activates mast cells, which leads to inflammatory cascade and is a key mechanism of an IgE-mediated allergic reaction. Histamine can also enhance the secretion of Th2 cytokines and inhibit Th1 cytokines and exacerbate skin barrier dysfunction by reducing the expression of loricrin, filaggrin and keratin [6].
The aim of this work is to present the genetic basis of atopic dermatitis. Polymorphisms of selected genes related to skin barrier maintenance and their influence on the development of atopic dermatitis will be described. STAT6 (signal transducer and activator of transcription 6), which is related to skin barrier maintenance and the immune system, will also be included. Many of the mechanisms presented above and below ultimately lead to damage of the skin barrier integrity, therefore this work will focus on these genes.
THE PATHOMECHANISM OF AD
The pathomechanism of AD includes the immune system, the skin barrier, environmental factors and psychosomatic factors, all of which can be altered by genetic factors. Damage of the skin barrier is a complex process in AD patients and depends on on many factors. In addition, a damaged skin barrier contributes to excessive activation of the immune system and worsening of skin lesions which lead to a vicious circle of immune dysregulation [1, 7]. Impairment of the skin’s protective properties may be a consequence of abnormal expression of filaggrin. As a result, the skin is improperly moisturized, cells adhere improperly to each other, and the skin no longer constitutes a barrier to microorganisms, allergens or other factors. This allows them to penetrate deep into the skin and contact Langerhans cells, which leads to stimulation of T lymphocytes [1]. In this case, we can observe increased local expression of proinflammatory cytokines and chemokines. They bind to specific receptors of the vascular endothelium, which facilitates the migration of proinflammatory cells and a significant increase in IL-4, IL-5, and IL-13 can be observed. This leads to the differentiation of B cells into plasma cells that produce IgE [7].
Environmental allergens, such as house dust mites, contribute to the disruption of the immune system by deregulating its mechanisms and facilitating easier penetration of allergens into the body [1, 7]. Mite excrements are the main allergenic factor, leading to excessive protease activity, which consequently contributes to the intensified production of IL-1 (interleukin 1) or thymic stromal lymphopoietin (TSLP) by the skin. TSLP, in turn, causes increased production of CC chemokine ligand 17 (CCL17) and CC chemokine ligand 24 (CCL24) by Langerhans cells, thereby contributing to the conversion of Th0 lymphocytes into Th2. This leads to increased synthesis of IL-13 and stopping the production of proteins that build the stratum corneum of the epidermis (filaggrin and involucrin). Consequently, intercellular connections are destroyed, generating further defects in the skin [3, 4]. Increased TSLP expression may also be a consequence of filaggrin deficiency [7].
The inflammatory response in AD is mainly associated with activation of the T cells, dendritic cells, keratinocytes, macrophages, mast cells and eosinophils [7]. The predominance of Th2 lymphocytes and their increased activity is observed, among others, as a result of exposure to allergens. This leads to the secretion of interleukins (IL) by Th2 cells, which stimulate B lymphocytes to produce IgE. This mechanism also involves other cells of the immune system such as dendritic cells (DC), innate lymphoid cells (ILC2), eosinophils and basophils. T cell activation may also be a consequence of skin barrier dysfunction due to abnormal expression of FLG (filaggrin) [1].
GENETIC BACKGROUND OF ATOPIC DERMATITIS
Atopic dermatitis is a disease with a complex genetic and pathophysiological basis, where only the susceptibility for developing atopy is inherited. It has been observed that regions such as 3q21, 13q14, 15q14-15, and 17q2 are associated with a more severe course of the disease. Additionally, areas associated with excessive skin flaking include 1q21, 17p25, and 20p, as well as 3q21 were also identified. Furthermore, the 3q21 region also predisposes to asthma and rheumatoid arthritis (RA) [3, 8].
In recent years, numerous GWAS (genome-wide association studies) studies have been conducted to find genes associated with diseases, including identifying genetic risk loci for AD. The latest meta-analysis from 2024 based on GWAS studies identified 81 loci in the European-only analysis and 10 additional loci in the multi-ancestry analysis associated with AD. These loci included, among others, genes such as FLG, IL6R, TNF, STAT3 or CREB [8]. In turn, other studies using the transcriptome-wide association study (TWAS) identified 51 genes significantly associated with AD, 19 genes showed putatively causal associations and seven not implicated in the previous GWAS, such as AQP3, PDCD1, ADCY3 and DOLPP1 [9].
Gene groups associated with AD primarily include genes responsible for the epidermal barrier dysfunction, associated with the impairment of innate or adaptive immune response mechanism, interleukin genes produced by keratinocytes exposed to stress and genes implicated in the vitamin D metabolism and its receptors [10]. The genes responsible for forming the epidermal barrier are mainly FLG and SPINK5/LEKTI (serine protease inhibitor Kazal type 5/lymphoepithelial Kazal-type-related inhibitor). Filaggrin is responsible for binding cells in the stratum corneum, and mutations in its gene cause excessive water loss and dry skin. In turn, blocked expression of the SPINK5/LEKTI gene leads to activation of the pro-inflammatory pathway. Consequently, this can result in excessive activation of the immune system and the production of large amounts of cytokines, which causes disturbances in the functioning of the epidermal barrier. Other genes involved in this process include TSLP, STAT6, TLRs (toll-like receptors), and FcεRI (Fc epsilon RI, ligand-binding subunit of the high-affinity IgE receptor) [3, 4, 11].
FILAGGRIN (FILAMENT AGGREGATING PROTEIN)
Filaggrin is a histidine-rich protein, whose precursor is profilaggrin, a heavily phosphorylated inactive polymer. Profilaggrin consists of 10-12 FLG polypeptide units, an N-terminal S100 domain that binds calcium, and an adjacent B domain. The conversion of profilaggrin to filaggrin occurs through the hydrolysis of peptide bonds by caspase-14, resulting in many active FLG monomers that subsequently undergo dephosphorylation [12, 13]. In the stratum corneum, filaggrin monomers are incorporated into the lipid envelope responsible for the skin barrier function. Filaggrin is further processed in the upper stratum corneum to release free amino acids, serving as natural moisturizing factors (NMF) [14]. As the water gradient decreases in the outer skin layers, filaggrin is hydrolysed, producing hygroscopic amino acids. These amino acids (arginine, glutamine, histidine) are located in the intercellular space and are crucial for NMF production, which maintains the stratum corneum’s moisture, pH, and produces urocanic acid and pyrrolidone-5-carboxylic acid (PCA) [13]. Trans-Urocanic acid, derived from histidine, absorbs ultraviolet radiation and protects against thymine dimer formation in keratinocytes. However, PCA together with trans-Urocanic acid helps maintain the skin’s pH gradient, as evidenced by the higher skin pH in carriers of loss-of-function (LOF) mutations in FLG [14].
The dysfunction of FLG plays a critical role in the pathogenesis of AD as it regulates the epidermal barrier, protects against pathogens, and binds keratin fibres in the stratum corneum. Filaggrin expression is disrupted mainly by the overactivity of IL-4 and IL-13, which inhibit its production and dysregulate the epidermal barrier. Filaggrin’s proper function also depends on environmental conditions, which can destabilize it, reduce protein expression in keratinocytes, and cause inflammatory changes [12, 15, 16]. Mutations in FLG are also involved in the development of allergic rhinitis and asthma. Its malfunction increases IgE levels and allergy risk [12].
The profilaggrin gene is located in the epidermal differentiation complex (EDC) on chromosome 1q21 and consists of 3 exons and 2 introns. The translation start codon is in exon 2, while profilaggrin is encoded in exon 3. Exon 3 is large (12753 bp) and encodes most of the N-terminal domain and all filaggrin repeats [12, 14].
Mutations in the FLG gene may contribute to the exacerbation of AD, cause earlier onset of symptoms, and increase side effects associated with viral infections. Deletions in the FLG gene shorten profilaggrin and reduce its activity, increasing the likelihood of AD. In turn, loss-of-function mutations in exon 3 of filaggrin lead to the deprivation of profilaggrin’s C-terminus and, consequently, to the lack of its production. An insufficient amount of filaggrin leads to increased skin permeability to allergens and microbes, worsening AD symptoms and causing inflammatory changes. FLG gene mutations account for 30% of AD cases in the European population [12, 15, 16].
FLG mutations show significant ethnic differences, most of them are specific to the European, Japanese, Singaporean, Chinese or Taiwanese population. Only two of the 27 mutations, rs61816761 (R501X) and E2422X, are found in both European and Asian populations [14]. Moreover, the rarity of FLG mutations makes it difficult to study them in the context of AD. It has been shown that LOF mutations like rs61816761 and rs558269137 (2282del4) cause early-onset AD in children (mainly before the age of 2). One such study showed that the 2282del4 mutation (deletion of 4 base pairs at position 2282 in exon 3 of the filaggrin gene) increases disease risk over twofold [17], which was confirmed in other reports [18–22]. This mutation is also linked to allergic rhinitis, intense itching [17], and asthma [19, 21]. However, not all studies confirmed its association with AD [23]. The lack of a relationship with AD has also been demonstrated in many studies regarding the R501X mutation [17, 20, 21, 23]. However, it has been observed that this mutation is associated with coexisting asthma in AD patients [17] and a higher incidence of herpes [24]. Moreover, some studies have shown a relationship between R501X and the risk of AD [18, 19] and asthma [19].
In the case of the 3321delA and pK4022X mutations, they were reported to be more common in people with AD. However, the latter did not show statistical significance [25].
Due to the rarity of FLG mutations, many studies analysed their co-occurrence. Such a study linked R501X, 2282del4, R2447X, and S3247X mutations with AD in the Polish and Irish populations [26, 27]. Additionally, in the Polish population, a higher frequency of the 2282del4 mutation was observed in patients (the result was borderline to statistical significance) [26]. Similar results were obtained in American and German populations. AD patients with FLG mutations had an earlier onset, more severe and persistent disease [28]. In the German population, it was observed that these mutations are associated with a higher incidence of atopic eczema, asthma and allergic rhinitis [29]. In the Finnish population, R501X, 2282del4, R2447X mutations were associated with early-onset disease (before age 2), asthma (R501X, 2282del4), and keratosis pilaris (R501X) [30]. Further studies showed R501X and 2282del4 mutations were linked to AD [22, 24, 31] and asthma [22, 31–33], atopic eczema, frequent allergies, and less frequent outgrowing of the disease [33]. In the case of the S2554X and 3321delA mutations, an association with AD and increased IgE levels has been demonstrated in the Japanese population [34].
In addition to rare mutations, numerous polymorphisms in the profilaggrin gene have also been reported. These polymorphisms disrupt gene function, contributing to allergic diseases. One such polymorphism, rs11584340 (P478S), involves a cytosine-to-thymine substitution, resulting in a proline-to-serine change at the protein level. Chinese and Korean studies found that the TT genotype and T allele were more common in AD patients than controls [35, 36]. These observations may be confirmed by the results of another study, which showed that the rs11584340 polymorphism is associated with a greater risk of developing severe AD in children. In this study, it was observed that the TT genotype was associated with increased concentrations of monobutyl phthalate (MBP) and monobenzyl phthalate (MBzP) in the urine of children with AD compared to healthy controls. A comparison of the concentration of these compounds among people with AD was also performed. AD patients with the TT genotype had higher concentrations of MBP and MBzP in urine compared to CC homozygotes. This may be due to the fact that the skin of TT homozygotes is more permeable. Therefore, children with the TT genotype will be characterized by greater chemical and allergen penetration and a stronger Th2 lymphocyte response, which leads to damage of the epidermal barrier [37]. Moreover, one study observed that the TT genotype of this polymorphism also increases the risk of asthma in children with AD [38].
Many other polymorphisms also influence the occurrence of AD symptoms. The A allele of the rs71626704 polymorphism is associated with asthma and the A allele of the rs76413899 polymorphism is associated with cheilitis in AD patients. In the case of the rs71625199 polymorphism, the A allele increases susceptibility to environmental allergens in AD patients [39]. The A allele of rs3126085 and the C allele of rs12144049 are linked to a higher AD risk. In turn, rs12130219, rs6661961, rs471144, rs10888499, rs77199844 and rs4363385 polymorphisms are not associated with AD [23] similarly to the rs7927894 polymorphism. However, it was observed that the CC genotype was associated with a lower risk of AD in combination with seasonal allergic rhinoconjunctivitis and/or perennial allergic rhinitis [40].
SPINK5
The SPINK5 gene is located on chromosome 5q32 and its product is responsible for the proper functioning of the skin barrier. It encodes the serine protease inhibitor LEKTI, which is primarily synthesized in epithelia and the thymus. LEKTI participates in regulating proteolysis during keratinocyte differentiation and the formation of normal epithelium by inhibiting the activity of kallikreins (KLKs) [41]. A deficiency of this inhibitor leads to increased activity of serine proteases in the stratum corneum, premature splitting of corneodesmosomes, increased desquamation, and loss of skin barrier function. This results in increased penetration of pathogens into the skin and the formation of inflammatory lesions. LEKTI also plays a crucial role in the occurrence of inflammatory reactions in infancy (infantile eczema) [42].
Mutations in the SPINK5 gene can contribute to the development of Netherton syndrome (NS), a life-threatening condition associated with excessive proteolysis of the stratum corneum. Characteristic symptoms of this disease include bamboo hair, severe desquamation of the skin, and elevated levels of IgE [42].
Mutations and polymorphisms in this gene can also be associated with the risk of AD developing and the severeity of its symptoms (Table 1). The SPINK5 gene polymorphism rs2303067 (1258G>A, Glu420Lys, E420K) is associated with a higher risk of skin barrier damage, contributing to the early onset of AD and a more severe course of the disease. This polymorphism involves a missense mutation where guanine is substituted by adenine, leading to the replacement of glutamine with lysine at the protein level [43]. As a result, during the proteolytic processing of LEKTI, the D6D9 fragment (37 kDa), which inhibits KLK5 responsible for the proteolysis of desmoglein-1 (DSG1), is not formed [44]. The A allele of this polymorphism has been associated with an increased risk of AD [45, 46], asthma, and higher IgE levels [46]. Additionally, the A allele is more frequent in patients with early-onset AD [44] and may be linked to a more severe disease course and a higher incidence of food allergies [47]. This is supported by other studies where the GG genotype was less frequently observed in individuals with AD [48]. Functional studies have found that the A variant is associated with higher activity of KLK5, KLK7, and elastase 2 (ELA2). Moreover, lower expression of filaggrin and DSG1 and the associated accelerated proteolysis of profilaggrin were observed, which may affect the abnormal permeability of the skin barrier. Additionally, increased expression of TSLP was observed in carriers of the A allele (mainly the AA genotype) [44]. In a few studies, no association between this polymorphism and AD was found [18, 49–52].
Table 1
List of SPINK5 gene polymorphisms associated with AD
| Locus | Gene | SNP | Risk allele | Phenotype |
|---|---|---|---|---|
| 5q32 | SPINK5 | rs2303067 | A | Risk of AD [45, 46], early onset [43] and more severe course of AD [47], asthma, higher IgE level [46], higher incidence of food allergies [47], higher activity of KLK5, KLK7 and ELA2, lower expression of filaggrin and DSG1, accelerated proteolysis of profilaggrin, increased expression of TSLP [44] |
| rs2303064 | A | Risk of AD [25] | ||
| rs17860502 | G | Risk of AD [51] | ||
| rs2303070 | T | Risk of AD [53, 49] | ||
| rs2303063 | G | Risk of AD [45, 52] | ||
| rs6892205 | G | Non-atopic dermatitis in patients without AD [53] | ||
| rs2303065 | T | Risk of AD [48] | ||
| rs2303062 | A | Risk of AD [48] | ||
| rs2303061 | C | Risk of AD [48] | ||
| rs17718511 | A | Risk of AD [51] | ||
| IVS6-39A>G | A | Risk of AD [51] | ||
| rs60978485 | A | Risk of AD [51] | ||
| rs17718737 | T | Risk of AD [51] | ||
| rs1422985 | A | Risk of AD [51] |
For the rs2303064 polymorphism (1156G>A, Asp386Asn, D386N), most studies have not shown a connection to AD or asthma [45, 48–52]. However, the A allele was more frequently observed in individuals with AD in the Korean population [25]. The association with AD was also not demonstrated in the case of rs17860502 (316G>A, Asp106Asn, p.D106N) [50, 52] and rs2303070 (2475G>T, Glu825Asp, E825D) [50–52]. However, it was observed that the GG genotype (rs17860502) is more common in people with AD in the Korean population [51]. In turn, the T allele (rs2303070) was associated with a higher risk of AD developing [49, 53] and atopic eczema in individuals with atopy [53]. Association with AD was also observed for rs2303063 (1103A>G, Asn368Ser, S368N), where the G allele was linked to a higher risk of AD [45, 52], and the AA genotype was less frequently observed in patients [48]. In other studies, however, the A allele was associated with the risk of AD, although the result was on the verge of statistical significance, and no link to asthma was found [46]. In the Japanese and Chinese populations, no association of this polymorphism with AD was observed [49, 50]. No association with AD was also found for rs6892205 (Q267R) [50, 51], although one study indicated that the G allele was linked to the risk of non-atopic dermatitis in individuals without AD [53].
Other SPINK5 gene polymorphisms are less well understood and studied. The CC genotype of rs2303065 (1188T>C, His396His), GG genotype of rs2303062 (IVS12-10A>G), and TT genotype of rs2303061 (IVS12-26C>T) were less frequently observed in individuals with AD [48]. In turn, the AA genotype of rs17718511 (IVS3-139A>G), AA genotype of KN0001820 (IVS6-39A>G), AA genotype of rs60978485 (IVS7-49A>T), TT genotype of rs17718737 (A617A), and AA genotype of rs1422985 (IVS21+107A>C) were more frequently observed in individuals with AD [51]. No association with AD was found for the polymorphisms rs34482796 (A335V), rs3777134 (R711Q), rs11168017 (-5022C>T), rs2287772 (IVS1-125A>G), rs4333302 (IVS4+5887C>G), rs1363725 (IVS4-337C>T), rs7711953 (IVS6+66C>G), rs4529181 (IVS6-86C>G), KN0001823 (IVS7-136C>G), rs1862446 (IVS13-362A>C), rs880687 (G518G), rs41291431 (IVS17+46C>T), and rs3777134 (R711Q) [51].
KLK7 (KALLIKREIN 7)
KLK7 is a serine protease secreted by lamellar granules, also known as SCCE (stratum corneum chymotryptic enzyme). This protein is encoded by the KLK7 gene located on chromosome 19. The function of KLK7 in the pathomechanism of AD and Netherton syndrome involves stimulating the extracellular proteolysis of corneodesmosome components (e.g., desmocollin 1, desmoglein 1, or corneodesmosin), which leads to intense desquamation of the epidermis. This process disrupts the skin structure and leads to its keratinization [54].
It has been observed that the LEKTI inhibitor is likely one of the factors inhibiting KLK7 expression in AD. The destabilization of the protease-inhibitor interaction contributes to prolonged proteolysis of skin elements, resulting in excessive keratinization. Environmental factors, in turn, can cause an increase in skin pH, leading to increased KLK7 expression in the outermost layer of the epidermis. Mutations in the KLK7 gene can also affect protease activity. It has been observed that a 4-bp insertion in the 3’UTR (3-UTR AACCins5874) may contribute to the development of AD. This mutation likely intensifies protease activity, leading to premature damage to of corneodesmosomes and disruption of the epidermal barrier [54]. The insertion allele was associated with a higher risk of AD [55], and homozygotes were more frequently observed among AD patients [25]. However, one study did not observe an association between this mutation and AD [18].
STAT6
STAT6 is a transcription factor belonging to the STAT protein family. This protein is encoded by the STAT6 gene, located in the 12q13.3 region [56]. The activity of STAT6 is dependent on cytokines associated with Th2 lymphocytes, such as IL-4 and IL-13. It plays a significant role in stimulating transcription and signal transduction. STAT6 regulates the production of IL-31 (responsible for the occurrence of itching) and skin barrier proteins [57]. This protein participates in the pathogenesis of AD by stimulating the excessive production of IgE, which leads to damage of the integrity of the epidermal barrier. STAT6 activation occurs as a result of IL-4/IL-13 binding to its membrane receptor. IL-4/IL-13 induces the Janus kinases (JaKs) which phosphorylate the conserved tyrosine residue on the cytokine receptors. Then STAT6 is recruited to the cytokine receptor and activated. When activated, STAT6 homodimers translocate to the nucleus and induce or suppress the transcription of target genes. The target genes of STAT6 include the genes located in the epidermal differentiation complex that are important for the development of a functional skin barrier. Therefore, altered STAT6 activation may contribute to the hallmarks of dermatitis: allergic sensitization and impaired epidermal barrier. It has also been observed that STAT6 plays a role in controlling infections by reducing the proliferation of regulatory T lymphocytes (Tregs), thereby inhibiting the excessive immune response. This process leads to a reduction in the severity of infections [57–59].
Polymorphisms in the STAT6 gene can contribute to the development of conditions such as AD and asthma. The rs324011 (2892C>T) polymorphism contributes to the development of AD and atopic asthma. The T allele is associated with a higher risk of both atopic and non-atopic dermatitis in children [58]. It has also been observed that the T allele is linked to an increased risk of early-onset AD [57, 60] and the TT genotype can cause atopic asthma [61]. These findings are supported by other studies, which have observed that the T allele [62] and the TT genotype [58] are associated with higher serum IgE levels. However, this polymorphism was not found to be associated with the IL-4 level [58].
In the case of the rs324015 (2964G>A) polymorphism, no association with AD [57], asthma [56, 61], or IL-4 levels [58] was observed. However, one study indicated that the A allele is linked to a higher risk of atopic and non-atopic dermatitis in children. Additionally, the AA genotype was associated with higher IgE levels [58]. Higher IgE levels were also observed for the rs3024974 polymorphism in CC genotype carriers [63]. In turn, carriers of the T allele (rs167769) have a higher risk of atopic asthma [56] and AD, although the second finding was borderline significant. However, analysis of the TT diplotype (rs167769, rs324011) indicated greater STAT6 activity and this diplotype was more frequently observed in individuals with AD. This study did not find an association between the rs324974, rs703817, rs324012, rs3024948, rs117195019, and rs118014438 polymorphisms and AD [57].
CONCLUSIONS
Atopic dermatitis is an allergic disease characterized by a complex pathomechanism and a recurrent, long-lasting course. Its development is influenced, among other factors, by polymorphisms of genes related to the proper functioning of the immune system and the epidermal barrier. The genes most thoroughly studied about AD that impact the function of the epidermal barrier include FLG and SPINK5/LEKTI. Mutations in the filaggrin gene can lead to the early onset of AD and exacerbate inflammatory conditions on the skin’s surface. Similarly, SPINK5 polymorphisms can result in LEKTI inhibitor deficiencies, leading to the activation of pro-inflammatory responses, skin barrier damage, and worsening of disease symptoms. These processes may also facilitate the easier penetration of pathogens into the skin [3, 43, 54, 64].
The immune system also plays an important role in the development of AD. TLR receptors are responsible for recognizing antigens, initiate a series of signalling events leading to the production of pro-inflammatory factors. It may contribute to increased levels of IL-6 and IL-12, increased inflammation, or increased colonization of damaged skin by various types of pathogens. Cytokines, on the other hand, participate in the pathogenesis of AD through excessive activation of leukocytes and cells responsible for the development of inflammatory conditions. Interleukins also play an important role and may contribute to excessive stimulation of Th2 lymphocytes (IL-17), inhibition of filaggrin activity (IL-33), differentiation of DCs into inflammatory dendritic cells (IL-18), intensification of Th1 and Th2 responses (IL-10) or excessive production of IgE (IL-5) [65–69].
The maintenance of a healthy skin barrier is also supported by KLK7 and STAT6. Kallikrein stimulates the proteolysis of extracellular components of the corneodesmosome, and mutations in its gene can result in severe skin peeling. STAT6 is a transcription factor that promotes the production of both skin barrier proteins and IL-33. Consequently, mutations in the STAT6 gene may contribute to both skin barrier damage and the intensification of inflammatory conditions due to increased IgE production [3, 43, 57].
However, it is important to remember that AD is a multifactorial condition, where polymorphisms in certain genes only increase the risk of developing the disease. Environmental and psychosomatic factors also play a crucial role, especially during the treatment of AD [3, 64, 70]. However, it should be remembered that understanding the genetic basis of AD can translate into the development of new methods of preventing and treating allergic diseases. By learning the function of a given polymorphism, we can determine its effect on the functioning of the protein, and thus determine how the disease will develop in a given patient, how they will respond to treatment, and above all, it will allow us to select the appropriate treatment method. Going further, knowing the genes responsible for the development of AD will allow us to perform genetic panels in patients and thus precisely determine the genetic cause of the disease. Then, combining this with environmental factors such as allergens to which the patient is allergic and psychosocial factors, it will be possible to select the appropriate therapy tailored to the patient.
