Occurrence of autoantibodies against skin proteins in patients with hereditary epidermolysis bullosa predisposes to development of autoimmune blistering disease

Abstract

Skin blistering disorders are associated with inherited defects in proteins involved in the dermal-epidermal adhesion or autoantibodies targeting those proteins. Although blistering in hereditary epidermolysis bullosa (EB) is pathogenetically linked to genetic deficiency of distinct proteins of the epidermis or the dermal-epidermal junction, circulating autoantibodies against these proteins have also been identified in EB patients. So far, autoantibodies have been considered bystanders in EB and active pathogenicity of them in EB has not been disclosed. In sera of a cohort of 258 EB patients, we found by ELISA in 22% of the patients autoantibodies against the bullous pemphigoid antigen BP180. The titers correlated negatively with collagen VII skin expression and positively with disease severity. Among those patients, we identified six (2.33%) with clinical features of an autoimmune bullous disorder (AIBD) and positive indirect immunofluorescence (IIF) staining. In literature, we found four more cases of EB patients developing disease-aggravating AIBD. Co-existence of these two rare skin disorders suggests that EB patients have a predisposition for the development of AIBD. Our work highlights that EB patients with increased itch or blister formation should be evaluated for additional AIBD and repeated screening for changes in autoantibody titers and skin-binding specificities is advised.

Keywords: BP180; PD-1 inhibitor; autoimmune bullous disease; collagen VII; epidermolysis bullosa; skin blistering.

Figure 1

Anti-BP180 autoantibody titers of the patients in our EB-cohort. Anti-BP180 autoantibodies were detected by BP180 NC16A ELISA in patient sera. The red line indicates the upper limit norm level of 9 U/ml. EBS, EB simplex; JEB, junctional EB; DDEB, dominant dystrophic EB; RDEB, recessive dystrophic EB.

Figure 2

Clinical pictures of the patients with EB and AIBD described in this study: (A–F): Patients present with tense blisters, erosions and ulcerations simultaneously, which are characteristic for both, EB and AIBD. Therefore, conclusive clinical differentiation is challenging. (A) patient 1, (B) patient 2, (C) patient 3, (D) patient 4, (E) patient 5 under therapy with programmed cell death protein 1 inhibitor (PD1i) and (F) patient 6 under therapy with PD1i.

Figure 3

Immunofluorescence results. (A) DIF of patient 1 shows discrete linear deposition of IgG at the DEJ (white arrows); (B–F): ss-IIF show IgG staining on the epidermal side of the split, indicated by white arrows (B) = Pat. 1, (C)= Pat. 2, (D) = Pat. 3, (E) = Pat. 4, (F) = Pat. 5); (G) ss-IIF IgA shows IgA staining on the epidermal side of the split (white arrows); (H) ss-IIF IgG positive control with IgG staining on the epidermal side of the split, indicated by white arrows; (I) ss-IIF IgG negative control without IgG staining on the epidermal side of the split, indicated by white arrows. The IgA positive control was comparable to the staining in (H) (not shown).