# The Immunogenetics of Psoriasis and Implications for Drug Repositioning
## 2 The Immunogenetics of Psoriasis
### Genes Associated with Adaptive Immunity  
Adaptive immunity appears to be crucial for psoriatic pathogenesis, as the human leukocyte antigen (HLA) region is the most important susceptible site for psoriasis. Approximately 40% of the genes in the HLA region encode immune defense-related proteins [27]. A single-nucleotide polymorphism (SNP) possessing strong linkage disequilibrium (LD) along with the HLA-Cw6 allele produces the strongest correlation signal in all GWAS. Moreover, the HLA-Cw6 allele is also closely related to early-onset psoriasis in various races, which is supported by the fact that the antigenicity of the immune system is vital to the pathogenesis of psoriasis. Interestingly, a recent study has revealed a new pathway for the pathogenesis of psoriasis i.e., a melanocyte-specific response pathway where HLA-C*06:02 produces an autoimmune response against melanocytes by antigen presentation [28; 29]. Additionally, the _ERAP1_ gene is mainly involved in the processing of HLA class I molecules. Mutation of _ERAP1_ affects the susceptibility of individuals carrying the HLA-C allele carriers, and studies have confirmed that the HLA-Cw6 allele is associated with this effect. A GWAS study showed a significant interaction between the HLA-Cw6 allele and rs27524-labeled _ERAPI_[30]. The role of _IL-23_/Th17 in psoriatic pathogenesis has become apparent in recent years with the discovery of the Th17 T cell subtype and the key Th17-polarized cytokine, _IL-23_. Many genes (e.g., _IL-12B_, _IL-23A_, _IL-23R_, _TRAF3 IP2_, and _TYK2_) are significantly associated with psoriasis. Th17 cells are a type of novel effector T cell that secretes cytokines such as _IL-21_ and _IL-17_. _IL-23_ is a proinflammatory cytokine expressed in T cells, B cells, monocytes, mast cells, and endothelial cells. Both _IL-12B_ and _IL-23R_ have been validated in the Chinese population. A study found that _TNF_ (SNP rs3093662) is a susceptible gene for psoriasis in the Chinese population [19]. Moreover, _IL-12_ and _IL-23_ contain a common p40 chain, and the _IL-12_p40 subunit binds to a unique subunit, p19, to form _IL-23_ (p19/p40 dimer). The expression levels of the p19 and p40 genes in psoriatic lesions are increased, indicating that _IL-23_ may play a major role in psoriatic lesions. Additionally, a GWAS study found that psoriasis was associated with mutations in _STAT3_ (signal transduction and transcriptional activator 3), which is a key molecule in signaling cascades via several cytokines, including _IL-6_, _IL-10_, _IL-22_, and _IL-23_. Since _STAT3_ is necessary for signal transduction via _IL-23R_, it is essential for Th17 polarization. Furthermore, psoriasis-related mutations in _STAT3_ may reduce the threshold for the _IL-23_ signal required to induce Th17 polarization. Targeted biologics have a high efficacy in psoriasis, and the high expression of _IL-23A_ and _IL-12B_ in psoriatic lesions also supports the above hypothesis regarding the pathogenesis of psoriasis [31; 32]. Interestingly, associations of regions encoding Th2-related genes, particularly _IL-4_, _IL-5_, and _IL-13_, with the region of chromosome 5q31 containing multiple cytokine genes have also been found in patients with psoriasis [33]. _IL-4_ and _IL-13_ not only promote T cells toward Th2 differentiation, but also inhibit the development of mature Th17 cells. _IL-4_ promotes both Th1 cell proliferation and _IL-23_ expression, leading to a reduction in the number of Th17 cells. Although a number of studies have suggested that Th2 is not associated with psoriasis development, the strong correlation found between psoriasis and the GWAS between the genes encoding the cytokines _IL-4_ and _IL-13_ suggests a role for the Th2 pathway in psoriasis pathogenesis [33]. Erythhodermic psoriasis (EP) is among the most serious forms of psoriasis that affects human beings. The balance between Th1 and Th2 cells plays an important role in the pathogenesis of EP. Th1 cells induce the disease, while Th2 cells accelerate the inflammatory process, triggering the risk of infection.