# SERPINB3, Adult-Onset Immunodeficiency, and Generalized Pustular Sporiasis
## 4 Discussion
### SERPINB3 Variant Predisposed Patients to GPP  
The roles of _SERPINB3_ are to regulate the immune system, modulate proteolysis homeostasis, and attenuate physiologic apoptosis [25] in order to defend against the invasion of microorganisms and prevent self-tissue destruction as a result of excessively unrestrained proteolysis. Our findings raise the question of how a genetic variant in _SERPINB3_ predisposed the patient to GPP. _SERPINB3_ functions by inhibiting cysteine protease cathepsins L, S, and K, and subsequently suppresses inflammatory reactions [25; 26] (Figure 7). This is supported by the finding of an excessive pro-inflammatory response in _SerPINB3_ knockout mice [27].  
Figure 6: Molecular model of dimeric SERPINB3. (**A**) The ribbon diagram of the modelled polymeric serpin reveals the position of conserved residue Asp306 in the loop region of the proteins. (**B**) The superimposed structures of the wildtype and Asp306 Gly variant show significant structural alteration in the loop region of SERPINB3, implying that glycine substitution at this position could potentially affect the conformational flexibility of the loop region (white arrow heads), which may promote polymerization of the variant proteins.  
Figure 7: Hypothetical flowchart of the pathogenetic pathways that result from _SERPINB3_ mutation. Mutations in _SERPINA1_ and _SERPINB3_ share “over-activation effects of elastase”, which result in unrestrained activities of IL36 cytokines and the subsequent “domino effects” that lead to GPP and AOID with neutrophil recruitment at the end. Refs. [25; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46].  
The main function of SERPINB3 is to suppress inflammation by inhibiting cathepsin L [25], and cathepsin L inactivates SERPINA1 (\(\alpha\)-1-antiprotease inhibitor) [28], which subsequently inhibits the downstream elastase [29], the key enzyme that activates IL36 cytokines (Figure 7) [30; 31]. Mutations in _SERPINA1_ are implicated in autoimmunity diseases, including emphysema, liver cirrhosis, and skin paniculitis, as a result of over-activation of elastase and accumulation of mutant polymers [32]. In addition, very recently, we reported a rare variant in _SERPINA1_ in patients with GPP and AOID [5]. Therefore, it is hypothesized that the aberrant expression of _SERPINAB3_ as a result of its mutation may result in protein misfolding and polymerization leading to endoplasmic reticulum stress; overproduction of cathepsin L; impaired SERPINA1 function; overactivation of elastase; unrestrained activity of IL36 cytokines; over-production of pro-inflammatory cytokines, including IFN-\(\gamma\), IL-17, IL-22, IL1B, IL6, IL8, LTB4, TNF-\(\alpha\), and TGF-\(\beta\); overexpression of _KRT17_; hyperactive NFkB-MAPK-STAT3 signaling; impaired epidermal differentiation; epidermal hyperproliferation; and subsequent GPP with neutrophil recruitment (Figure 7) [29; 31; 33].  
In addition to the effects of an elevated expression of _IL8_, _IL6_, and _LTB4_ as a result of the _SERPINB3_ variant, neutrophil recruitment in patients with the _SERPINB3_ variant may be the result of inactivated SERPINA1 [34] and overproduction of cathepsin L because cathepsin L via chemokine processing produces active forms of angiogenic ELR-CXC chemokines that result in neutrophil recruitment (Figure 7) [47].