# Generalized Pustular Soriasis: Divergence of Innate and Adaptive Immunity
## 2 Gene Mutations in GPP
### Mutations of IL-36 Receptor Antagonist  
The IL-36 family is a relatively novel group of cytokines that belongs to the IL-1 superfamily and consists of three pro-inflammatory agonists, IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\), and two antagonists, IL-36 receptor antagonist (IL-36 Ra) and IL-38. These IL-36 cytokines are expressed in epithelial and immune cells and function through a shared receptor (IL-36R) to modulate innate and adaptive immune responses [54]. IL-36 cytokines can induce the downstream pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\(\kappa\)B) and mitogen-activated protein kinase (MAPK) pathways via an intracellular signaling cascade by binding to IL-36R. Subsequently, the release of inflammatory mediators and chemotaxis that promote activation of neutrophils, macrophages, dendritic cells, and T cells is induced, ultimately causing the amplification of inflammatory responses [55]. _IL36 RN_ encodes the IL-36 Ra, which suppresses the pro-inflammatory effects of IL-36 cytokines (namely IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\)) by binding their receptor, interleukin-1 receptor-like 2 (IL-1 RL2), and preventing the release of chemokines that stimulate the activation of neutrophils, macrophages, dendritic cells, and T cells; inducing neutrophil chemokine expression, infiltration, and pustule formation in GPP [56; 57]. In vitro and ex vivo observations revealed that GPP alleles abolish the antagonistic effect of IL-36 Ra; thus, IL-36 stimulation of patients' cells results in enhanced production of pro-inflammatory cytokines such as IL-1, IL-6, and IL-8 [46; 47]. Mutations in _IL36 RN_, which were first described in 2009 in two families with severe pustular psoriasis, lead to functional impairment of IL-36 Ra and subsequent amplification of the downstream inflammatory responses [46; 47]. Such mutations in _IL36 RN_ gene were initially identified in north-African families sufferingfrom autosomal recessive GPP. They were homozygous missense mutations, with the substitution of proline for leucine at position 27 (p.Leu27 Pro) [46]. In another pioneering study of five European cases of GPP, three individuals were found to have mutations in _IL36 RN_, including a novel homozygous missense mutation (p.Ser113 Leu) and one compound heterozygote carrier (p.Ser113 Leu and p.Arg48 Trp) [47]. _IL36 RN_ mutations do not contribute to the risk of plaque psoriasis. In fact, most _IL36 RN_ mutations are identified in patients with GPP that do not suffer from concurrent plaque psoriasis [58]. This observation was confirmed by [PERSON] et al., who first screened for _IL36 RN_ gene within two subgroups of patients with GPP (GPP alone and GPP with concurrent psoriasis vulgaris). They showed that all GPP patients without psoriasis vulgaris carried homozygous or compound heterozygous mutations in the _IL36 RN_ gene, whereas only 2 out of 20 cases of GPP with psoriasis vulgaris harbored compound heterozygous mutations [24]. Based on these results, it was suggested that GPP alone may represent a distinct subtype of GPP that is etiologically distinguishable from GPP occurring with psoriasis vulgaris [24]. Several types of _IL36 RN_ mutations, including substitution, frameshift, and splicing defects, have been reported as the causative genetic background in numerous GPP cases, in various geographical regions [59; 60; 61; 62; 53; 24; 46; 8; 25; 44; 47; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62; 63]. In addition, [PERSON] et al. demonstrated that _IL36 RN_ mutation carriers exhibit a more severe clinical phenotype (e.g., earlier age of disease onset, increased risk of systemic manifestations) and the absence of co-existing plaque psoriasis, when compared to individuals without _IL36 RN_ mutation [64]. The most recent analysis, which included a cohort of 251 unrelated patients with GPP from multiple countries, also showed that _IL36 RN_ gene mutations were associated with an early age of onset, prevalence of psoriasis vulgaris, and high recurrence rate of GPP [8].