# The Immunogenetics of Psoriasis and Implications for Drug Repositioning
## 2 The Immunogenetics of Psoriasis
### Genes Associated with Innate Immunity  
The innate immune system provides an early response mechanism to host damage by identifying pre-formed non-specific effectors. There is evidence of psoriasis-associated inherent immune system disorders. For example, clinical observations indicate the importance of the congenital cytokine, interferon-alpha, as a psoriasis inducer [17]. NF-kB is a key regulatory element involved in a variety of intrinsic immunoregulatory and inflammatory pathways, cellular proliferation and differentiation, and apoptosis. Studies have confirmed that the NF-kB pathway is activated in psoriatic lesions and is downregulated after successful treatment [18]. We analyzed the genome-wide association study (GWAS) data and found that _TYK2_, caspase recruitment domain family member 14 (_CARD14_) [15], _NFK-BIA_[19], _TNFA193_[19], _TNIP1_[19], _IL-36 RN_[20], and other genetic polymorphisms in this pathway are associated with the pathogenesis of psoriasis. _CARD14_ expressed and regulated NF-kB in keratinocytes and was recently found to be a pathogenic gene of PSORS2 [21]. Moreover, all NF-kB proteins contain the Rel homologous domains that mediate DNA binding and dimerization. Generalized pustular psoriasis (GPP) is often found in patients that exhibit or previously exhibited psoriasis vulgaris (PV). Interestingly, the interleukin-36 receptor antagonist gene (_IL-36 RN_) is mainly expressed in the skin. It is largely responsible for encoding a soluble molecule, IL-36 receptor antagonist (_IL-36 Ra_), which neutralizes the activation of NF-kB downstream signaling via the IL-36 receptors [20]. Animal experiments and population studies have found that most individual GPP cases were caused by homozygous or complex heterozygous mutations of _IL-36 RN_[22; 23]. RNF114 regulates innate immune system-related signaling molecules, such as _IL-1_, _IL-6_, and _IL-29_, which eventually results in the _EXOC2_-mediated production of _IF-1_. The _IF-1_ gene encodes a viral RNA-activated apoptotic protein that initiates cellular antiviral and apoptotic responses upon sensing viral nucleic acids in the cytoplasm and protects the body by sensing and triggering the removal of virus-infected cells. The gene has been confirmed to be associated with psoriasis in both the Chinese and European populations [24]. Skin barrier function plays a dominant position in non-specific immunity, as the skin and mucous membranes constitute the body's first immune barrier. Recently, researchers have focused on identifying new genetic markers associated with psoriatic skin barrier function. The terminal step of the keratinization process was associated with the formation of a highly specialized insoluble protein-lipid structure called the keratinized envelope (CE). The corneal capsule was essential for the normal functioning of the epidermal barrier. Thus, any abnormality in the expression of genes encoding portions of the envelope's structure or of proteins involved in the enzymatic process may cause interference at different stages of keratinocyte differentiation, ultimately leading to the dysfunction of the epidermal barrier [25]. The epidermal differentiation complex (EDC) in the PSORS4 locus located on chromosome 1q21 contains genes that are expressed at various stages of the keratinization process. Currently, more than 45 genes have been identified in this complex. The EDC contains genes for epidermal regeneration (such as the S100 gene family) and terminally differentiated keratinocytes (small proline-enriched protein and advanced envelope protein (LCE protein)). These genes have different expression profiles in psoriasis. The LCE gene cluster is located in the PSORS4 locus of chromosome 1q21.3 and is a part of the EDC complex. More recently, the gene family encoding the late keratinized envelope (LCE) proteins has gathered increasing interest from researchers. The family can be divided into six subfamilies named LCE1-LCE6.