# Sporiasis Pathogenesis and Treatment
## 2 Pathogenesis
### Genetics
#### Genetic Variants Implicated in Aberrant Keratinocyte Proliferation and Differentiation  
The immunogenetics of IL-23 are strongly associated with psoriasis. IL-23 is a dimer composed of a specific subunit, p19, and a p40 subunit, which is shared with IL-12. IL-23 signals through a heterodimeric receptor expressed by both innate and adaptive immune cells, which include Th17, natural killer T, \(\gamma\)\(\gamma\)\(\gamma\) T cells, and \(\mathrm{RORyt^{+}}\) innate lymphoid cells. The IL-23R signals through JAK2/TYK2 and STAT3 [106]. SNPs in the regions coding for the IL-23 cytokine (both the p40 and p19 subunit) as well as the IL-23R have been identified to convey psoriasis risk [107; 108; 109]. Furthermore, these variants have been found to be associated with [PERSON]'s disease, psoriatic arthritis, and ankylosing spondylitis [110][74; 75]. IL-23 drives the expansion of Th17 T cells that produce IL-17A/F, which is another set of cytokines whose role is pivotal in the pathogenesis of psoriasis. Monoclonal antibodies targeting both the common p40 and the specific p19 subunit of IL-23 have proven to have high clinical efficacy [109]. As mentioned above, STAT3 is found in downstream signaling by IL-23, and is therefore essential in T cell development and Th17 polarization. STAT3 has also been detected in psoriasis GWAS, and its variants are associated with psoriasis risk [107; 111]. Furthermore, transcription factor Runx1 induces Th17 differentiation by interacting with \(\mathrm{RORyt}\). Interestingly, the interaction of Runx1 with Foxp3 results in reduced IL-17 expression [112]. _CARD14_ mapping was shown to correspond to PSORS2. The CARD family encompasses scaffolding proteins that activate NF-kB. It was suggested that in psoriasis patients with respective CARD14 mutations, a triggering event can result in an aberrant NF-kB over activation [96]. CARD14 is expressed in keratinocytes and in psoriatic skin; it is upregulated in the suprabasal epidermal layers and downregulated in the basal layers. In healthy skin, CARD14 is mainly localized in the basal layer. Mutations in _CARD14_ have been shown to be associated with psoriasis, as well as with familial pityriasis rubra pilaris (PRP) [113]. The NF-kB signaling pathway is involved in the production of both IL-17 and TNF-\(\alpha\), and thus participates in adaptive and innate immune responses [73]; it is upregulated in psoriatic lesions and is responsive to treatment [114]. Gene variations in _NFKBIA_, _TNIP1_, and _TRAF3 PI2_ affecting NF-kB regulatory proteins have been linked to psoriasis via GWAS [102; 115; 116; 117]. TRAF3 PI2 codes for the ACT1 adaptor protein and the specific variant TRAF3 IP2 p. Asp10 Asn was associated to both psoriasis and psoriatic arthritis [117]. The different clinical psoriasis variants may have additional genetic modifiers. For instance, mutations in the antagonist to the IL-36 receptor (IL-36 RN), belonging to the IL-1 pro-inflammatory cytokine family, have been linked to pustular psoriasis [118; 119]. Recessive mutations in _IL36 RN_,coding for the IL-36 receptor antagonist, have been associated with generalized pustular psoriasis (GPP). This mutation is also found in palmar plantar pustulosis and acrodermatitis continua of Hallopeau. Furthermore, in patients with pre-existing plaque-type psoriasis, the gain of function mutation in _CARD14_, p.Asp176 His, was found to be a predisposing factor for developing GPP [120]. In addition to studies of genetic variants, the profiling of gene expression in psoriasis has aided in the understanding of the relevant pathophysiological pathways. Transcriptomic studies of psoriatic skin have revealed differentially expressed genes (DEGs) when compared to healthy skin, and also between lesional and nonlesional psoriatic skin [121; 122]. Further underscoring their relevance in psoriasis pathogenesis, IL-17A genes were found to be upregulated in nonlesional psoriatic skin compared to healthy skin.