Introduction
Atopic dermatitis (AD) is a chronic inflammatory disease characterized by a severe course. It usually begins in early childhood and is characterized by severe itching, characteristic morphology of lesions, typical location and very often coexists with other atopic diseases. Its development is influenced by defects in the skin barrier function, immune dysregulation, environmental and infectious agents and psychosomatic factors. A combination of skin barrier and immune system defects, influenced by environmental factors, leads to eczemas, dry skin and itching. AD usually begins in early childhood and in most cases the disease becomes apparent before the age of 5. AD is often the initial stage of the “atopic march” that leads to asthma, allergic rhinitis or food allergy [1–4].
Environmental allergens that penetrate the skin cause activation of dendritic cells (DC), which leads to the induction of Th lymphocytes [1]. Allergic factors lead also to excessive protease activity, which contributes to increased production of interleukin 1 (IL-1) or thymic stromal lymphopoietin (TSLP) by the skin. TSLP then contributes to increased production of CC chemokine ligands (CCLs) – CCL17 and CCL24 – and the transformation of Th0 lymphocytes into Th2, which leads to increased synthesis of IL-13 [2]. All of this contributes to damage of the skin barrier [1, 2]. In turn, these skin barrier abnormalities lead to transepidermal water loss and increased penetration of allergens and microorganisms into the body [2]. Penetration of staphylococcal and streptococcal enterotoxins into the deeper layers of the skin stimulates excessive secretion of IL-13 and thus inhibits the production of filaggrin (FLG) and antimicrobial peptides (AMPs). Additionally, it contributes to increased colonization of the skin by Staphylococcus aureus, whose antigens can induce T lymphocytes [1, 2].
On the other hand, psychosomatic factors such as stress contribute to the disturbance of Th2 lymphocytes balance and weakening of immunity through excessive stimulation of the cytokine system. In patients with AD, the cytokine system promotes overproduction of IgE and the development and maintenance of allergic inflammation [1].
The work aims to present the influence of immune system-related gene polymorphisms on the development of AD.
Genetic background of atopic dermatitis
Genetic factors play a significant role in the pathogenesis of AD and interactions between susceptibility genes and environmental factors are important determinants of atopy [1, 5]. AD is a polygenically inherited disease, and only the predisposition to the occurrence of atopy, modified by environmental factors, is inherited. Studies have discovered and characterized many chromosomal loci associated with atopy. The genes responsible for the development of atopy encode, among others, cell receptors, cytokines, and transcription factors [1]. In turn, environmental factors can activate genes related to the skin barrier, immunity, Th2 lymphocytes and signal transduction receptors. Polymorphisms in these genes can affect the severity of AD [1, 3].
Among genes related to the skin barrier, we can mention: FLG, kallikrein 7(KLK7) and serine protease inhibitor Kazal-type 5/lympho-epithelial Kazal-type-related inhibitor(SPINK5/LEKTI). Signal transducer and activator of transcription 6 (STAT6) is associated with both the skin barrier and the immune system. In turn, genes related to the immune system include: Chitinase-3-like protein 1(CHI3L1), Fc epsilon RI, ligand-binding subunit of the high-affinity IgE receptor(FcεRI), toll-like receptors (TLRs) and cytokine encoding genes [1, 2].
Chitinase-3-like protein 1
CHI3L1 is a protein encoded by the CHI3L1 gene located on chromosome 1q32.1, also known as YKL-40 or HC gp-39 (human cartilage glycoprotein 39). CHI3L1 plays an important role in the immune response, acts as a mediator of inflammation in epithelial cells of the respiratory tract, and is likely involved in tissue remodelling [4].
The rs4950928 polymorphism, located in the promoter of the CHI3L1 gene, results in a less severe course of atopic dermatitis compared to the rs2303067 polymorphism of the SPINK5 gene. It has been observed that the G allele (rs4950928) is associated with a later onset of the disease, while the presence of CC+CG genotypes is characterized by a milder course of atopic dermatitis [4].
In the case of the rs10399805 polymorphism (247C>T), also located in the promoter of the CHI3L1 gene, it has been observed that the T allele occurs more frequently in individuals with atopy. The T allele was associated with higher serum levels of IgE and YKL-40. The elevated level of YKL-40 may be becasue this polymorphism occurs at the binding site for the transcription factors acute myeloid leukemia 1 protein/Runt-related transcription factor 1 (AML-1/RUNX1) and CCAAT enhancer-binding protein (C/EBP). It was observed that the T allele was associated with a higher affinity of the CCAAT-binding protein. This study also examined the influence of other polymorphisms and observed that the C allele (rs2275353 (IVS7+82C>T)), located in intron 7, was more common in individuals with atopy. However, this variant was not associated with IgE and YKL-40 levels. In turn, the rs10399931 (g.-329G>A), rs4950928 (g.-131G>C), rs1538372 (IVS2-20C>T), IVS3-52G/C, R145G (rs880633), and 1365G>T polymorphisms were not associated with atopy or levels of IgE and YKL-40. Furthermore, all polymorphisms studied in this work were not associated with asthma [5].
FcεRI
FcεRI is a receptor with a high affinity for IgE. It represents the central receptor for IgE-induced reactions and consists of one alpha subunit (FCER1A– alpha-chain of the high-affinity receptor for IgE), one beta subunit (FCER1B), and two gamma subunits (FCER1G). In the pathomechanism of AD, the α and γ chains, which are encoded by the FcεRI gene, play significant roles. The alpha chain (FCER1A) regulates IgE-dependent responses and allergic inflammatory states. In turn, the gamma chain (FCER1G) is responsible for the normalization of FcεRI function in dendritic cells and similar to FCER1A, is involved in triggering allergic reactions [6]. However, not much is known about the impact of polymorphisms in this gene on AD. For the rs2427827 (-315C>T) polymorphism in the FCER1A gene, it has been observed that the T allele is more frequent in patients with atopic dermatitis who have elevated IgE levels (≥ 1000 IU/ml) [7]. The rs2427837 polymorphism is also associated with atopic dermatitis, with the A allele being more common in patients and linked to an increased risk of the disease [6]. Conversely, the rs61828219 [6] and rs2251746 (-66T>C) [7] polymorphisms were not found to affect AD. Additionally, the rs2427837 and rs61828219 polymorphisms were not associated with an increased risk of asthma [6].
TLRs
The TLR family regulates both innate and acquired immune responses. Toll-like receptors recognize conserved molecular patterns on specific classes of pathogens and initiate a series of signalling events that lead to the expression of pro-inflammatory genes. Therefore, TLRs can influence the incidence or progression of inflammatory diseases such as asthma, AD, atherosclerosis, and rheumatoid arthritis [8, 9].
TLR1-TLR2 complex recognizes bacterial lipoproteins and glycolipids. Binding of ligands to TLR1 activates intracellular signalling cascades leading to inflammatory responses and the initiation of immune processes. This receptor is encoded by the TLR1 gene, located on chromosome 4 [9]. It has been observed that the C allele of the rs5743595 (2192T>C) polymorphism, located in this gene, is associated with higher mRNA expression and increased receptor levels on the surface of monocytes and B lymphocytes [10]. However, little is known about the impact of this polymorphisms on AD. In the case of rs5743618 (Ser602Ile) and rs5743613 (Leu315Pro) polymorphisms, no association with AD was found [8].
TLR2 is associated with nonspecific immunity and activated on keratinocytes in both healthy individuals and those with AD. Additionally, in patients with AD and high IgE levels, its activity has been observed on DC. TLR2 has also been found to influence immune system function in individuals with AD. TLR2 and TLR9 are involved in recognizing pathogens that worsen AD, such as certain strains of Candida and herpes simplex virus (HSV). This receptor is encoded by the TLR2 gene located on chromosome 4q31.3 [11].
Polymorphisms in the TLR2 gene can disrupt its function, leading to dysregulation of the immune system in patients with AD. This can increase colonization of damaged atopic skin by S. aureus, intensifying inflammation through continuous Th1 immune response stimulation. In the case of the rs4696480 (-16934A>T) polymorphism, located in the TLR2 gene promoter, AA genotype was associated with a higher risk of AD [12] and a more severe course of the disease [8, 13]. This relationship was also visible in individuals with elevated IgE levels. Additionally, the A allele was associated with family history, coexisting asthma, and lower TLR2 transcriptional activity [13]. However, one report found no impact of this polymorphism on AD [14]. The rs5743708 (Arg753Gln, R753Q, 2258G>A) polymorphism also contributes to severe AD. The A allele increases the risk of AD [12, 15], and carriers showing lower receptor expression and reduced IL-8 levels [16]. Moreover, A allel carriers showing higher IL-6 and IL-12 levels in monocytes, which leading to increased skin inflammation [17]. The A allele also raises serum IgE levels [15]. Other studies found no association of this polymorphism with AD [8, 14, 18], asthma [19, 20], allergic rhinitis [19], eczema, or food allergies [21]. Another polymorphism, rs3804100 (596T>C), has not been studied in the context of AD, but one study found that the C allele increases asthma risk [22].
TLR4, also known as cluster of differentiation 284 (CD284), activation triggers the intracellular nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signalling pathway, resulting in the production of pro-inflammatory cytokines that stimulate the immune system. The most important feature of TLR4 is the recognition of the presence of lipopolysaccharide, components of many gram-negative bacteria [23]. This receptor is encoded by the TLR4 gene located on chromosome 9q33.1. Polymorphic variants in this gene may influence the development and course of AD. It has been observed that the G allele of the rs4986790 (Asp299Gly, D299G, 896A>G) polymorphism is associated with a higher risk of AD [18, 21], more severe course of the disease and is more common in AD patients susceptible to acute respiratory viral infections [18]. However, other studies found no association of this polymorphism with AD [8], asthma [19, 20, 24], allergic rhinitis [19], eczema or food allergies [21]. The rs4986791 (Thr399Ile, 1196C>T) polymorphism also showed no association with AD [8, 12, 18, 25] or asthma [20, 24, 25].
In the case of the rs11536891 polymorphism, it was shown that the C allele is associated with a lower risk of AD. Additionally, the T allele of the rs7869402 polymorphism is associated with a greater risk of severe AD. The rs19277914 and rs11536889 polymorphisms were not associated with the risk of AD [25]. In turn, children with the CC genotype of the rs1927911 polymorphism, allergic to dust mites, had a higher risk of allergic rhinitis and conjunctivitis, and allergies to other inhalant allergens [26].
TLR9 is active in B lymphocytes and plasmacytoid dendritic cells (pDC). It influences the course of bacterial infections by detecting unmethylated CpG sequences in bacterial genetic material. This receptor is encoded by the TLR9 gene located on chromosome 3p21.2. Polymorphisms in TLR9 are responsible not only for AD but also for non-atopic dermatitis. The rs5743836 (-1237T>C) polymorphism in the TLR9 gene promoter is associated with immune mechanism disruption in some patients with AD [11]. The TT genotype may increase the risk of atopy and is associated with higher promoter activity [27], while the T allele increases asthma risk [20]. Other studies found no association of this polymorphism with AD [8] or IgE [28] levels in patients with atopy. Similar results were obtained for the rs187084 (-1486C>T) polymorphism, with no association with AD [8], asthma [20], or IgE levels [28] in AD patients. Moreover the rs352144 (-1923A>C), rs352139 (1174G>A), and rs352140 (2848G>A) polymorphisms were not associated with IgE levels in patients with atopy [28].
Cytokines and interleukins (IL)
Cytokines are proteins that play an active role in the progression of various diseases. They contribute to the development of conditions such as AD, bronchial asthma, dermatomyositis, and urticaria. Their function involves the activation of leukocytes and cells responsible for skin inflammation [29, 30].
One type of cytokines is interleukins, which are primarily produced by lymphocytes. Th2 lymphocytes produce interleukins such as IL-4, IL-5, and IL-13. In contrast, Th17 and Th22 lymphocytes secrete IL-17, IL-19, and IL-22. Excessive activity of Th2 lymphocytes leads to the dysregulation of the epidermal barrier, and thus increases skin inflammation. Th22 and Th2 lymphocytes are present in patients with extrinsic and intrinsic forms of AD, while Th17 and Th9 lymphocytes predominate in those with the intrinsic form of atopic dermatitis [30, 31].
CCL2, also known as monocyte chemoattractant protein 1 (MCP1), is a cytokine that attracts T lymphocytes, basophils, and myeloid cells. It is involved in the development of diseases such as rheumatoid arthritis (RA), AD, asthma, urticaria, and psoriatic arthritis (PsA). The role of CCL2 in these conditions includes recruiting monocytes and dendritic cells to the site of inflammation caused by tissue structure disruption, intensifying inflammatory states [30, 32].
Polymorphisms in the gene encoding CCL2, located on chromosome 17q12, can contribute to the development of AD. In the case of the rs1024611 (-2518A>G) polymorphism, it was observed that the G allele was more common in children with asthma and in atopic patients without asthma. This allele is also associated with increased blood eosinophil levels [33]. However, other studies have not observed an association between this polymorphism and atopy, IgE levels, blood eosinophil levels [34, 35], clinical severity of AD, or bronchial hyperreactivity [34].
CCL11, also known as eotaxin 1 or eosinophil chemotactic protein (eoCP), is a cytokine produced by eosinophils, mast cells, and fibroblasts. Together with Th2 lymphocytes, it takes an active part in the formation of the skin microenvironment. The interaction between CCL11 and the CCR3 receptor (C-C motif chemokine receptor 3) contributes to the exacerbation of hypersensitivity symptoms to allergens by increasing eosinophil migration to inflamed areas [29, 30].
This cytokine is encoded by the CCL11 gene located on chromosome 17q12. It was observed that the T allele of the -426C>T polymorphism was associated with the allergic form of AD [36] and lower IgE levels [37]. However, Tsunemi et al. did not demonstrate an association of this polymorphism with AD [37], and Rigoli et al. with IgE levels [36]. The association of AD and IgE levels was also not demonstrated for the -384A>G and 67G>A polymorphisms [36].
CCL17, also known as thymus and activation regulated chemokine (TARC), is a cytokine primarily produced by DC. It significantly influences the development of urticaria and AD. Along with the CCR4 receptor (C-C motif chemokine receptor 4), it is involved in the induction of macrophages. Furthermore, it plays a crucial role in regulating Th2 responses and, in the pathogenesis of inflammatory diseases, contributes to the dysfunction of Treg lymphocytes. These lymphocytes are essential for suppressing excessive Th2 activity and thus controlling the immune response to allergens. Abnormal TARC function also contributes to epidermal barrier dysfunction by intensifying inflammatory processes. Additionally, it intensifies the symptoms of AD in infants [29, 30, 38, 39].
It was observed that the 431C>T polymorphism in the TARC gene increases its promoter activity (T allele) but is not associated with susceptibility to AD in the Japanese population [40, 41].
Thymic stromal lymphopoietin (TSLP) is encoded by the TSLP gene located on chromosome 5q22.1. TSLP exerts its activity through the thymic stromal lymphopoietin receptor (TSLPR), which is found on DC, T lymphocytes, NK cells, type 2 innate lymphoid cells, eosinophils, and basophils [42]. Its role in the development of AD involves inhibiting the production of IL-12 and stimulating the production of IL-4 and IL-13, thereby activating a Th2 response. This process intensifies skin inflammation in people with this condition. Additionally, along with IL-31, it contributes to excessive itching in individuals with AD by stimulating sensory neurons [43]. TSLP is also involved in the pathogenesis of Netherton syndrome along with tumor necrosis factor a (TNF-a) by excessively triggering a Th2 lymphocyte response, leading to increased levels of IgE and the development of allergic reactions [44].
Polymorphisms in the TSLP gene may play a role in the pathomechanism of allergic diseases. The CC genotype of the rs2289278 polymorphism is associated with a higher risk of developing AD. Additionally, in children allergic to dust mites, the CC genotype increased the risk of AD. There was also observed an increased likelihood of asthma in children with AD carrying the C allele [45]. In turn, the C allele of the rs1837253 polymorphism may be associated with eczema, although this result was not statistically significant [43]. However, one study showed that the TT genotype is a protective factor against AD [46]. In the case of the rs1898671 polymorphism, the C allele was associated with a lower risk of AD, although this result was not statistically significant after Bonferroni correction [45]. Other studies did not find an association between this polymorphism and the severity of AD, IgE levels, visual analogue scale (VAS) scores, or coexisting asthma [47]. The rs2289277, rs11466741, and rs11466749 polymorphisms did not show an association with AD [45, 48], and the rs3806933 and rs2289276 polymorphisms were not associated with eczema [45, 49].
IL-4 is an interleukin mainly produced by Th2 lymphocytes. It stimulates the differentiation of Th cells and innate lymphoid cells (ILC). IL-4 also participates in the pathogenesis of AD. Along with TLR2, by increasing the production of IL-12 and decreasing the secretion of IL-10, it exacerbates skin inflammation in AD. Additionally, high levels of IL-4 and IL-13 have been observed to inhibit the production of FLG and other important proteins like loricrin and involucrin, leading to epidermal barrier damage [50].
IL-4 is encoded by a gene located on chromosome 5q31.1. It has been shown that the rs2243250 (-590C>T, -589C>T) polymorphism of this gene may be associated with AD. The TT genotype [51] and T allele [52, 53] of this polymorphism increased the risk of AD. Additionally, the T allele was associated with higher IL-4 levels in AD patients [52], and the TT genotype increased IgE levels [53, 54]. One study did not find an association with AD, but the TT genotype was more common in patients with atopy and elevated IgE levels (above 2000 IU/ml) compared to those with AD and IgE levels below 500 IU/ml [55]. Besides, in the Iranian population, the C allele increased the risk of AD [56]. Other studies did not find an association between this polymorphism and AD [54, 57–63], asthma [61], IgE levels [61, 64], or IL-4 levels [54].
For the rs2243248 (-1098T>G) polymorphism, the TT genotype [59] and T allele increased the risk of AD [56, 63]. This is confirmed by the results of other studies, in which the G allele was associated with a lower risk of AD [60]. One study did not find an association between this polymorphism and AD [65]. The rs2227284 polymorphism was not associated with AD either, but the TT genotype was associated with higher IgE levels [61]. In turn, the C allele of the rs2070874 (33C>T) polymorphism was associated with a higher risk of AD [56]. However, another study showed that the T allele was associated with a higher risk of developing AD [63], and the TT genotype was responsible for an increased level of IgE. However, this study did not show any association between this genotype and the level of IL-4 [54].
The described polymorphisms were also subjected to haplotype analysis. It was shown that the GTT haplotype (rs2243283, rs2243250 and rs2243248) was associated with a lower risk [60], while the TCC haplotype (rs2243248, rs2243250, rs2070874) with a higher risk of developing AD [56].
The variable number of tandem repeats (VNTR) polymorphism rs79071878, located in intron 3 of the IL-4 gene, was also analyzed for its association with AD. It is characterized by the presence of the wild-type A1 allele (Rp2 – three repeats, 253 bp), the A2 allele (Rp1 – two repeats, 183 bp), and the A3 allele (Rp3 – four repeats, 323 bp). The A1 allele was found to reduce the risk of AD [66], while the A2 allele was associated with the risk of asthma and elevated IL-4 levels [67].
Polymorphisms located in the gene encoding the IL-4 receptor (IL4R) may also be associated with the risk of AD. It has been shown that the G allele of the rs1805010 (148A>G, 4679A>G, I50V, I75V) polymorphism of the IL-4 receptor may increase the risk of developing AD [54, 58, 66]. The GG genotype was also associated with higher levels of IgE [54]. Other studies did not observe an association between this polymorphism and AD [55, 61, 68, 69], asthma [61, 69], IL4R gene expression [70], or IgE levels [61, 64]. For the rs1801275 polymorphism (1902A>G, Q576R, Gln551Arg), the G allele was more frequently found in individuals with AD, but the result was borderline statistically significant. However, it was associated with a more severe form of food allergy [71]. This is supported by other studies where the G allele increased the risk of AD [54, 66] and asthma [67], and the GG genotype was associated with higher IgE levels. However, no association with IL-4 levels was shown [54]. Other studies did not find an association between this polymorphism and AD [68, 72], asthma [72], IL4Ra gene expression [70], allergic rhinitis [73], or IgE levels [64]. The rs1805015 (Ser478Pro) polymorphism was also not associated with IgE levels [64], and rs2057768 (3223C>T) polymorphism was not associated with IL4Ra gene expression [70]. In turn, the C allele of the rs1805011 (E400A, Glu375Ala) polymorphism increases the risk of asthma and AD [61].
IL-5 is an interleukin produced by Th2 lymphocytes and is involved in the development of AD and asthma. In asthma, it can lead to tissue damage by stimulating the production of a large number of eosinophils. In turn, its role in the pathogenesis of AD likely involves excessive IgE production, thereby exacerbating symptoms of the disease [74, 75].
It has been observed that polymorphisms of the IL-5 gene may contribute to the development of allergic diseases. The T allele of the rs2522411 (-4597T>A) polymorphism has been associated with the development of AD and extrinsic AD but did not affect IL-5 levels. However, the IL-5 level was higher in carriers of the T allele with extrinsic atopy compared to those with intrinsic atopy. This study did not find an association of the rs2706400 (3237A>C) polymorphism with AD. Nevertheless, the TA haplotype (rs2522411, rs2706400) was associated with an increased risk of AD [75].
In the case of the -703C/T polymorphism, no association with AD was found [76], although the TT genotype was associated with the risk of asthma. However, this result was borderline statistically significant [74]. Additionally, the C allele was more frequently found in individuals with elevated IgE levels (above 2000 IU/ml) [76], and the TT genotype was associated with elevated levels of IL-5 and eosinophils [74].
For the IL-5 receptor (IL5RA), no association with AD was found for polymorphisms: rs17026903 (-8380C>A), rs3806681 (-5568G>C), rs35428885 (-3783C>A), rs17881144 (IVS4–866T/A), rs6771148 (IVS6+109G>C), rs9831572 (IVS6+1204T>C), rs2290610 (I129V), rs334809 (IVS10+3687T>A), rs3804797 (IVS10+4276G>A), rs17882210 (IVS10–186T>C), rs340808 (IVS12–1835G>C), and rs340830 (4535G>A) [75].
IL-6 is mainly secreted by monocytes and macrophages in response to IL-1 and other pro-inflammatory cytokines. It stimulates inflammatory processes and is involved in the feedback inhibition of TNF production and polymorphisms in the IL-6 gene may affect the risk of AD. The G allele [77] and GG genotype of the rs1800795 (174G>C) polymorphism, as well as the GG genotype of the rs1800797 (-nt565A>G) polymorphism, were associated with an increased risk of AD [59]. However, not all studies observed this association [63, 77]. In turn, the G allele of the rs2069837 polymorphism increased the risk of AD, although this result was borderline statistically significant. No association with AD was found for rs2069840, rs2066992, and rs1800796 polymorphisms [78].
IL-9 is produced by Th2 lymphocytes and activates various immune cells, including T lymphocytes and eosinophils. It is involved in the response to parasitic infections and the pathogenesis of asthma. The gene encoding IL-9 is located on chromosome 5q31.1. It has been shown that the G allele of the rs31563 polymorphism (-4091G>A), in this gene, increases the risk of AD and gene activity [79].
IL-10 is mainly secreted by monocytes, regulatory T lymphocytes, and Th1 cells, and it plays an active role in regulating the body’s specific immune response. It is active via the interleukin 10 receptor 1 (IL10R1) and interleukin 10 receptor 2 (IL10R2). Disruption of its expression likely leads to excessive activation of Th1 and Th2 lymphocytes, thereby intensifying inflammatory processes [80, 81].
Polymorphisms in the IL-10 gene play an important role in the development of AD in various populations. The results regarding the promoter polymorphism rs1800896 (1082A>G) are divergent. It has been shown that the GG genotype was associated with the risk of AD [82], and the G allele with IL-10 levels in serum [62]. This is confirmed by studies where the AA [63] and GA [83] genotypes were associated with a lower risk of AD. In other studies, it was shown that the A allele [84] or the AA genotype [59] were associated with the risk of AD [84] and asthma [85]. Conversely, the AA genotype was associated with the severity of symptoms in patients with food allergies, atopic asthma, and higher IL-10 levels [86]. In other studies, no association with AD [57, 62, 87–89] and asthma [89, 90] was found. Similar discrepancies were observed for the rs1800872 (592A>C) polymorphism. In one study, the association with AD was shown for the CC genotype [59], in another for the AA genotype [84]. Additionally, the A allele was associated with the risk of asthma, mainly in the Asian population, in adults, and in individuals with atopy [85]. In other studies, no association with AD [63, 82, 83, 86–88] and asthma [90] was found.
For the rs1800871 (-819C>T) polymorphism, the CC genotype was associated with a higher risk of AD [82] and severe disease [59], although many studies did not find associations with AD [63, 83, 88], food allergies [86], and asthma [85, 90].
IL-13 is an interleukin secreted by innate lymphoid cells type 2 (ILC2) and Th2 lymphocytes, participating in type 2 immune stimulation. In the pathogenesis of AD, along with IL-4, it leads to an increase in chemokines such as CCL17 and CCL24, thereby disrupting the epidermal structure and exacerbating inflammatory processes [50, 91]. It has been shown that the T allele of the rs1800925 polymorphism (-1111C>T, -1055C>T, -1112C>T, -1024C>T, -1103C>T), in the IL-13 gene, was associated with the risk of AD [92, 93], asthma [94], and higher IgE levels [92]. Additionally, the TT genotype was associated with the risk of food allergies and allergies to external factors [95], as well as with higher IgE levels [64, 96]. Other studies did not observe an association of this polymorphism with AD [57, 62, 97, 98] or IgE levels [99]. For the rs20541 (4257G>A, c.431G>A, Gln144Arg, 1055T>C, R110Q, Arg130Gln, 2044G>A, Arg110Gln) polymorphism, it was shown that the A allele was associated with a higher risk of AD [97, 98, 100] and elevated IgE levels [64, 96, 99–101]. It was also observed that children with the A allele who took antibiotics, in early childhood, were at greater risk of developing AD [102]. The A allele was also associated with a higher risk of allergic rhinitis, although this result was borderline statistically significant [73]. Other studies did not find an association of this polymorphism with AD [61, 103], asthma [61, 94, 101], or IgE levels [61]. No association with AD was also observed for the -704A>C [98] and rs847 (c.695T>C, 2749T>C) [103] polymorphisms. On the contrary, the 4738G>A (870G>A) polymorphism was not associated with asthma [94]. However, it was shown that the C allele of the rs1881457 (-1470A>C, -1512A>C) polymorphism and the T allele of the rs1295685 polymorphism were associated with elevated IgE levels [96]. Furthermore, the C allele (rs1881457) was a risk factor for AD, asthma, and allergic rhinitis [103].
IL-17 is mainly produced by Th17 lymphocytes and ILC cells. Several subtypes are distinguished: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. IL-17 is involved in the development of conditions such as asthma, psoriasis, and AD. In the pathogenesis of AD, it stimulates Th2 lymphocytes. It also initiates the production of thymopoietin by the thymic stromal cells, IL-8, and CCL17. This phenomenon disrupts the secretion of claudin, integrin, and filaggrin, thereby impairing the functioning of the skin barrier [43].
The genes for IL-17A and IL-17F are located on chromosome 6p12. In contrast, the genes for the other interleukins are distributed on different chromosomes: IL-17B - 5q32-34, IL-17C - 16q24, IL-17E - 14q11.2, and IL-17D - 13q12.11 [104]. In the case of the rs2275913 (152G>A) polymorphism of the IL-17A gene [65, 105] and the rs763780 polymorphism of the IL-17F gene, no association with AD was observed [65]. However, it was shown that the AA genotype (rs1887570) of the IL-17F gene causes increased hypersensitivity to allergens in patients with asthma [106].
IL-18 is mainly produced by macrophages and is used to assess the severity of AD. Its activity depends on genetic factors and the cytokine environment. IL-18 plays an important role in the pathogenesis of AD by stimulating the differentiation of DC cells into inflammatory dendritic cells. It also contributes to increased IgE synthesis by enhancing the production of IL-4 and IL-13, which intensifies the inflammatory processes in AD. Moreover, IL-18 can lead to the development of non-atopic (IgE-independent) AD [107].
IL-18 is encoded by a gene located on chromosome 11q23.1. Polymorphisms of this gene are involved in the pathogenesis of diseases such as asthma, allergic rhinitis, and AD. It has been observed that the C allele of the promoter polymorphism rs187238 (137G>C) is associated with the risk of developing AD [108], elevated IgE levels, and seasonal allergic rhinitis [109]. However, one study did not show an association between this polymorphism and AD [60]. In the case of the rs1946518 (607C>A) polymorphism, the A allele was linked to the pathogenesis of asthma [110, 111] and atopic asthma [111]. However, similar to the rs1946519 (-656T>G) and rs360722 (-920T>C) polymorphisms, it was not associated with IgE levels or allergic rhinitis [109]. Additionally, the rs4988359 (-132A>G) [108, 109], rs360718, and rs7106524 polymorphisms were not associated with AD [60]. Nevertheless, it was observed that the A allele (rs7106524) and the CAA haplotype (rs187238, rs360718, and rs7106524) were associated with a higher risk of severe AD [60]. Additionally, the G allele of the rs360718 (113T>G) polymorphism, the T allele of the rs360717 (127C>T) polymorphism, and the G allele of the rs360721 (-133C>G) polymorphism were more frequently observed in patients with AD [108] and were associated with elevated IgE levels [109]. This study also showed that the G allele (rs360718) and the T allele (rs360717) were linked to allergic rhinitis [109].
IL-31 is mainly produced by dendritic cells and Th2 lymphocytes and consists of four helical strands. Its role in inflammatory processes involves directing monocytes and T lymphocytes to the area where inflammation is located. The signal is transmitted via a heterodimeric receptor composed of interleukin-31 receptor A (IL31RA) and oncostatin M receptor (OSMR). Additionally, IL-31 increases the activity of CCL17, CCL19, and CCL23 located in normal human epidermal keratinocytes (NHEK), thereby intensifying inflammatory processes. It has also been observed that IL-4 stimulates, while transforming growth factor-b1 inhibits, the secretion of IL-31 by Th2 cells [112].
In AD, IL-31 is responsible for excessive, persistent skin itching, and intense scratching leads to the exacerbation of inflammatory conditions on the patient’s body. The itching is likely due to the binding of IL-31 to IL31RA on sensory nerves, which activates the transient receptor potential cation channel subfamily V member 1 (TRPV1) and transient receptor potential cation channel subfamily A member 1 (TRPA1). IL-31 also causes sleep disturbances and interferes with daily functioning. Furthermore, it inhibits the production of skin barrier proteins such as desmoglein 1, desmocollin 1, FLG or KLK7, and enhancing the expression of AMP including S100 calcium-binding protein A7 (S100A7) and b-defensin 2 [112].
IL-31 is encoded by a gene located on chromosome 12q24.31. It has been shown that the G allele of the rs7977931 polymorphism is associated with a higher risk of atopic eczema in individuals with AD [113]. In the case of the rs7977932 polymorphism, the G allele is associated with higher levels of IL-31. On the contrary, rs4758680 does not affect IL-31 levels [1114].
IL-33 is mainly produced by dendritic cells, fibroblasts, endothelial cells, osteoblasts, fat cells, and smooth muscle cells in response to signals from damaged cells. It belongs to the IL-1 family and is also known as an “alarmin” because it transmits an activating signal to Th2 lymphocytes. IL-33 exhibits activity through the suppression of tumorigenicity 2 (ST2) receptor, which forms a heterodimer with the interleukin 1 receptor accessory protein (IL1RAcP). This, in turn, leads to the activation of kinases such as myeloid differentiation primary response gene (88 MyD88), mitogen-activated protein kinases (MAP kinases), and interleukin receptor-associated kinase 1/2 (IRAK 1/2), as well as the transcription factor NF-kB. In AD, the IL33/ST2 pathway is responsible for skin inflammation, contributing to the disruption of the epidermal barrier by inhibiting filaggrin activity [43].
IL-33 is encoded by a gene located on chromosome 9p24.1, and polymorphisms in this gene may contribute to the development of diseases such as asthma, allergic rhinitis, and AD. It has been observed that the G allele of the rs928413 polymorphism increases the risk of asthma [115]. In the case of the rs12551256 polymorphism, the G allele protected against the development of asthma, while the C allele of the rs7037276 polymorphism was associated with higher production of IL-13 and an increased risk of atopic asthma [116]. Besides, the rs1929992 (-9894T>C) polymorphism was not associated with AD, IgE levels, or itch severity in patients, similar to the rs10975519 (11877C>T) polymorphism. However, the TT genotype of this polymorphism was associated with severe and very severe itching [117].
Conclusions
AD is an allergic disease characterized by a complex pathomechanism and a recurrent, long-lasting course. The groups of genes associated with AD primarily include those responsible for the skin barrier, interaction with the environment, and the immune response. Polymorphisms in genes related to the proper functioning of the skin barrier (such as FLG or SPINK5/LEKTI) can lead to increased permeability, premature onset of AD, and intensified inflammation [1, 4, 11].
Elements of the immune system also play an important role in the development of AD. Toll-like receptors, which are responsible for recognizing antigens, initiate a series of signalling events leading to the production of pro-inflammatory factors. Therefore, polymorphisms in these genes may contribute to increased levels of IL-6 and IL-12, exacerbating inflammation or allowing various pathogens to colonize damaged skin. For example, TLR9 polymorphisms may be associated with the development of non-atopic AD. Additionally, cytokines such as CCL17, CCL26, CCL11, CCL27, and CCL2 participate in the pathogenesis of AD by excessively activating leukocytes and cells responsible for inflammatory responses. Interleukins, a class of cytokines, also play a crucial role. TSLP stimulates the production of IL-4 and IL-13, while IL-31 causes persistent itching. Additionally polymorphisms in genes encoding interleukins may lead to excessive stimulation of Th2 lymphocytes (IL-17), inhibition of filaggrin activity (IL-33), differentiation of DC cells into inflammatory dendritic cells (IL-18), enhanced Th1 and Th2 responses (IL-10), increased production of IgE (IL-5), or heightened levels of CCL17 and CCL24 (IL-4 and IL-13) [29, 43, 80, 112].
It is important to note that polymorphisms in certain genes only increase the risk of developing AD. Environmental and psychosomatic factors also play a significant role [1, 11].
