Phenotypic variation of quantitative traits is orchestrated by a complex interplay between the environment (e.g. diet) and genetics. However, the impact of gene-environment interactions on phenotypic traits mostly remains elusive. To address this, we feed 1154 mice of an autoimmunity-prone intercross line (AIL) three different diets. We find that diet substantially contributes to the variability of complex traits and unmasks additional genetic susceptibility quantitative trait loci (QTL). By performing whole-genome sequencing of the AIL founder strains, we resolve these QTLs to few or single candidate genes. To address whether diet can also modulate genetic predisposition towards a given trait, we set NZM2410/J mice on similar dietary regimens as AIL mice. Our data suggest that diet modifies genetic susceptibility to lupus and shifts intestinal bacterial and fungal community composition, which precedes clinical disease manifestation. Collectively, our study underlines the importance of including environmental factors in genetic association studies.

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Chronic blistering at the skin and/or mucous membranes, accompanied by a varying degree of inflammation, is the clinical hallmark of pemphigoid diseases that impose a major medical burden. Pemphigoid diseases are caused by autoantibodies targeting structural proteins of the epithelial basement membrane. One major pathogenic pathway of skin blistering and inflammation is activation of myeloid cells following Fc gamma receptor-dependent binding to the skin-bound immune complexes. This process requires activation of specific kinases, such as PI3Kδ, which have emerged as potential targets for the treatment of pemphigoid diseases. Yet, it is unknown if global cutaneous kinase activity present in lesional pemphigoid disease correlates with therapeutic effects following treatment with a given target-selective kinase inhibitor. To address this, we here first determined the kinase activity in three different mouse models of pemphigoid diseases: Antibody transfer-induced mucous membrane pemphigoid (MMP), antibody transfer-induced epidermolysis bullosa acquisita (EBA) and immunization-induced EBA. Interestingly, the kinome signatures were different among the three models. More specifically, PI3Kδ was within the kinome activation network of antibody transfer-induced MMP and immunization-induced EBA, but not in antibody transfer-induced EBA. Next, the therapeutic impact of the PI3Kδ-selective inhibitor parsaclisib was evaluated in the three model systems. In line with the kinome signatures, parsaclisib had therapeutic effects in antibody transfer-induced MMP and immunization-induced EBA, but not in autoantibody-induced EBA. In conclusion, kinase activation signatures of inflamed skin, herein exemplified by pemphigoid diseases, correlate with the therapeutic outcomes following kinase inhibition, demonstrated here by the PI3Kδ inhibitor parsaclisib.

Pemphigus and pemphigoid diseases are organ-specific autoimmune diseases of the skin and/or mucous membranes, which are caused by autoantibodies targeting structural proteins of the skin. In other autoimmune diseases, a high prevalence of primary antibody deficiencies was noted. Conversely, a high prevalence of autoimmune diseases is reported in patients with primary antibody deficiencies. With the exception of one study, pointing toward a decrease of IgG in pemphigus patients, with a relative enrichment of IgG4, serum immunoglobulin (Ig) concentrations had not been studied in pemphigus and pemphigoid. Hence, we here aimed to investigate serum concentrations of IgM, IgA, IgG, and IgG1-4 in pemphigus and pemphigoid patients, as well as in healthy controls. Serum Ig concentrations were determined by ELISA in 105 healthy controls, 100 pemphigus vulgaris (PV), 100 pemphigus foliaceus, 99 bullous pemphigoid (BP), and 55 linear IgA bullous dermatosis (LAD) patients. In healthy controls, age had a significant impact on Ig serum concentrations: In controls at ages of 69 years or older, IgM and IgG were decreased, while all other Ig, except IgA and IgG4, were increased. When stratified by sex, lower IgM concentrations were observed in males. When corrected for age and/or sex, and compared to controls, an increase in serum IgA was noted in LAD. In almost all patient cohorts, an increase in IgG1 and IgG4 was observed, while a decrease in IgG2 or IgG3 was seen in BP or PV patients. This points toward a possible association of BP with IgG2 deficiency and warrants evaluation of IgG2 in BP patients prior to immunosuppressive therapy.

A Corrigendum onCutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases.