# SERPINB3, Adult-Onset Immunodeficiency, and Generalized Pustular Sporiasis
## 1 Introduction  
Generalized pustular psoriasis (GPP; MIM 614204) is a rare and severe pustular autoinflammatory skin disease in which acute generalized erythema and scaling develop with numerous aseptic pustules. GPP shares skin manifestations, especially pustular skin reaction, with adult-onset immunodeficiency (AOID) with anti-interferon (IFN)-\(\gamma\) autoantibodies, an autoimmune disease [1]. Patients with AOID have symptoms of AIDS-like illness with disruptive IFN-\(\gamma\) signaling, including recurrent and disseminated opportunistic infections, especially non-tuberculous mycobacteria and varicella zoster virus. The clinical manifestations of patients with AOID resemble those in patients with inborn deficiencies of IFN-\(\gamma\) response or IFN-\(\gamma\)- production. Patients with AOID may have pustular skin reactions similar to those found in patients with GPP [1; 2]. Genetic variants in _IL36 RN_, _IL1 RN_, _CARD14_, _APIS3_, _MPO_, and _TNIP1_ have been shown to be implicated in GPP [1; 2; 3]. Very recently, genetic variants in _SERPINA1_ (Serine peptidase inhibitor, clade A, member 1; MIM 107400) [3] and _SERPINA3_ (Serine peptidase inhibitor, clade A, member 3; MIM 107280) [4] have been reported as predisposing risk factors for GPP as well as AOID [3; 5], indicating that variants in serine peptidase inhibitors are implicated in pathogenetic mechanisms of both disorders. The SERPIN protein superfamily represents the largest group of proteases. Although most are highly effective inhibitors of serine proteases, some members also, or even exclusively, only inhibit cysteine proteases. SERPINS are expressed in a diverse array of tissues and control many biological responses, including apoptosis and inflammation [6; 7]. Given the implication of a role for _SERPINA1_ and _SERPINA3_ variants in the pathogenetic mechanisms of GPP and AOID, we hypothesized that genetic variants in other members of the SERPIN superfamily, particularly those highly expressed in skin and/or the immune system, might also predispose patients to GPP and AOID. In this regard, SERPINB3 (clade B member; MIM 600517) represented an ideal candidate, as _SERPINB3_ is expressed in normal epithelial cells and overexpressed in various damaged cell types, including hepatocytes and cancer cells [8]. Regarding skin, _SERPINB3_ is expressed in the spinous and granular layers of the normal epithelium and has an important role in regulating differentiation of the squamous epithelium [9]. In addition, _SERPINB3_ is highly expressed in psoriatic skin because it is induced by pro-inflammatory cytokines secreted by infiltrated immune cells. Here, its expression helps prevent apoptosis. It is also found to be overexpressed in neoplastic tissue of epithelial origin [9; 10; 11]. The roles of _SERPINB3_ are to regulate the immune system, proteolysis homeostasis, and apoptosis. Patients with _SERPINB3_ dysfunction are known to be prone to altered immune responses and autoantibody production [12]. In addition, the over-accumulation of abnormal SERPINB3 might increase the levels of Pso p27, an autoanti derived from SERPINB3 and SERPINB4, which is highly involved in the inflammatory process in psoriasis [13]. To provide insight into the genetic architecture of pustular skin reactions, we undertook whole-exome sequencing of 53 patients of Thai descent that presented with either GPP or AOID. We describe herein the identification of rare genetic variants in _SERPINB3_ in three unrelated Thai patients: two with AOID and a pustular skin reaction and the third with GPP. One AOID patient and a patient with GPP carried the same heterozygous missense variant in _SERPINB3_. The other AOID patient had a novel heterozygous missense variant in _SERPINB3_. We further show that both SERPINA1 and SERPINB3 are highly expressed in the pustular skin biopsies of patients with _SERPINB3_ mutations.