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

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.

Immunological phenotype of the murine Lrba knockout.

Biallelic mutations in the human lipopolysaccharide responsive beige-like anchor (LRBA) gene lead to a primary immunodeficiency known as LRBA deficiency, characterized by a broad range of clinical manifestations including autoimmunity, organomegaly, hypogammaglobulinemia and recurrent infections. Considering the phenotypic heterogeneity in patients and the severity of the disease, our aim was to assess the role of LRBA in immune cells and to understand the underlying pathomechanisms through the study of a Lrba knockout (Lrba-/-) mouse model. LRBA-deficient mice did not show severe clinical or immunological signs of disease, either at steady state under specific-pathogen-free conditions, after vaccination with T-dependent and T-independent antigens, or in the context of acute infections with lymphocytic choriomeningitis virus (LCMV) or Salmonella Typhimurium. Although Lrba-/- mice were able to produce normal serum immunoglobulin M (IgM) and IgG and to mount a specific immune response after immunization, they showed elevated serum and secretory basal IgA levels. LRBA was dispensable for B- and T-cell development, as well as for in vitro B-cell proliferation, survival, isotype switching and plasmablast differentiation. Interestingly, Lrba-/- mice displayed decreased cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) expression by regulatory T cells and activated conventional CD4+ and CD8+ T lymphocytes, reduced frequency of peritoneal B-1a cells along with diminished interleukin-10 production and increased percentages of T follicular helper cells in Peyer's patches, but without developing overt signs of autoimmunity. Our findings expand the role of LRBA in immune regulatory mechanisms previously reported in patients, and suggest a novel role in IgA production that is crucial for the protection of mucosal surfaces and gut-associated immune tolerance.