SERPINB3, Adult-Onset Immunodeficiency, and Generalized Pustular Psoriasis

Abstract

Background: 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 sterile pustules. GPP shares skin manifestations, especially pustular skin reaction, with adult-onset immunodeficiency (AOID) with anti-interferon-γ autoantibodies, an autoimmune disease.

Methods: Clinical examinations and whole-exome sequencing (WES) were performed on 32 patients with pustular psoriasis phenotypes and 21 patients with AOID with pustular skin reaction. Immunohistochemical and histopathological studies were performed.

Results: WES identified three Thai patients presenting with similar pustular phenotypes-two with a diagnosis of AOID and the other with GPP. A heterozygous missense variant chr18:g.61325778C>A NM_006919.2: c.438G>T; NP_008850.1: p.Lys146Asn; rs193238900 in SERPINB3 was identified in two patients: one with GPP and the other with AOID. The other patient who had AOID carried a heterozygous missense variant chr18:g.61323147T>C NM_006919.2: c.917A>G; NP_008850.1: p.Asp306Gly in SERPINB3. Immunohistochemical studies showed overexpression of SERPINA1 and SERPINB3, a hallmark of psoriatic skin lesions.

Conclusions: Genetic variants in SERPINB3 are associated with GPP and AOID with pustular skin reaction. The skin of patients with GPP and AOID carrying SERPINB3 mutations showed overexpression of SERPINB3 and SERPINA1. Clinically and genetically, GPP and AOID appear to share pathogenetic mechanisms.

Keywords: SERPIN; SERPINB3 mutation; adult-onset immunodeficiency syndrome; anti-interferon-γ autoantibody; generalized pustular psoriasis; hyperactive elastase activity; pustular skin reaction.

Figure 1

Electropherograms of SERPINB3 variants and a normal control. (A) The heterozygous base substitution c.438G>T in patients 1 and 2 is predicted to cause the heterozygous missense variant p.Lys146Asn. (B) The heterozygous base substitution c.917A>G in patient 3 is predicted to cause the heterozygous missense variant p.Asp306Gly.

Figure 2

Conservation of SERPINB3 amino acids. The amino acid residues (A) Lys146 and (B) Asp306 are highly conserved across species.

Figure 3

Representative immunohistochemistry images for SERPINB3 in the normal skin control and patients 2 and 3. The epidermis of the normal skin showed very low levels of SERPINB3 expression, while the dermis lacked expression. In comparison to the normal skin tissue, there was a noticeably higher level of SERPINB3 expression in the stratum basale, stratum spinosum, stratum granulosum including the subcorneal pustule, and upper dermis of patients 2 and 3. (Magnification 10×).

Figure 4

Representative immunohistochemistry images for SERPINA1 in the normal skin control and patients 2 and 3. The normal skin expresses SERPINA1 at low levels in the epidermis; no expression is seen in the dermis. SERPINA1 expression is significantly higher in the subcorneal pustule, stratum granulosum, stratum spinosum, stratum basale, and upper dermis of patients 2 and 3 than in the normal skin. (Magnification 10×).

Figure 5

The point mutation at Lys146 alters the salt bridge formation between helix-F and β-sheet A. (A) Superimposition of the homology-based 3D models of the SERPINB3 and its p.Lys146Asn variant (K146N) showing the position of amino acid residue-146 and its inter-reacting partners. The normal SERPINB3 is colored in green, and the p.Lys146Asn variant is colored in salmon. (B) The expanded view of the selected area in A revealed the network of salt bridges between Lys146 and highly conserved Glu132 and Lys106. The disruption of this interaction network caused by the Asn substitution could significantly alter the stability of the SERPIN structure.

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 Asp306Gly 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].