From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

Kridin, Khalaf; Kowalski, Eric H.; Kneiber, Diana; Laufer-Britva, Rimma; Amber, Kyle T.

doi:10.1111/jdv.15816

Cited by 11 publications

(7 citation statements)

References 225 publications

(483 reference statements)

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“…In addition to omalizumab, there are other biological targeted therapies in development for BP ( 142 ). Dupilumab, a human IgG4 monoclonal antibody binding the IL4-Rα inhibits IL-4 and IL-13.…”

Section: Lessons From the Bedside And Targeted Therapiesmentioning

confidence: 99%

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

et al. 2022

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Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies targeting BP180 and BP230. While deposits of IgG and/or complement along the epidermal basement membrane are typically seen suggesting complement -mediated pathogenesis, several recent lines of evidence point towards complement-independent pathways contributing to tissue damage and subepidermal blister formation. Notable pathways include macropinocytosis of IgG-BP180 complexes resulting in depletion of cellular BP180, direct induction of pro-inflammatory cytokines from keratinocytes, as well as IgE autoantibody- and eosinophil-mediated effects. We review these mechanisms which open new perspectives on novel targeted treatment modalities.

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Section: Lessons From the Bedside And Targeted Therapiesmentioning

confidence: 99%

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

et al. 2022

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“…Clinically, most patients manifest with tense bullae often in conjunction with pruritic urticarial plaques [2]. BP is associated with a life-threatening potential and often necessitates prolonged administration of topical or systemic corticosteroids, as well as adjuvant immunosuppressive agents [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Presence of Cutaneous Complement Deposition Distinguishes between Immunological and Histological Features of Bullous Pemphigoid—Insights from a Retrospective Cohort Study

Ständer

Holtsche

Schmidt

et al. 2020

JCM

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The practical implications of complement deposition in direct immunofluorescence (DIF) microscopy and its influence on the disease phenotype are poorly understood. We aimed to investigate whether the presence of complement deposition in DIF microscopy gives rise to differences in the morphological, immunological, and histological characteristics of patients with BP (bullous pemphigoid). We performed a retrospective study encompassing patients with BP in a specialized tertiary referral center. Logistic regression model was utilized to identify variables independently associated with complement deposition. The study included 233 patients with BP, of whom 196 (84.1%) demonstrated linear C3 deposition along the dermal-epidermal junction (DEJ) in DIF analysis. BP patients with C3 deposition had higher mean (SD) levels (645.2 (1418.5) vs. 172.5 (243.9) U/mL; p < 0.001) and seropositivity rate (86.3% vs.64.9%; p = 0.002) of anti-BP180 NC16A and less prevalent neutrophilic infiltrate in lesional skin specimens (29.8% vs. 52.4%; p = 0.041). C3 deposition was found positively associated with the detection of anti-BP180 NC16A autoantibodies (OR, 4.25; 95% CI, 1.38–13.05) and inversely associated with the presence of neutrophils in lesional skin (OR, 3.03; 95% CI, 1.09–8.33). To conclude, complement deposition influences the immunological and histological features of BP. These findings are in line with experimental data describing the pathogenic role of complement in BP.

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“…Both MMP and EBA are difficult to treat and mainly rely on immunosuppressive therapy (3)(4)(5)(6)(7). Novel treatment options are urgently needed, whereby the phosphatidylinositol-3-kinase (PI3K) pathway represents a promising target for the treatment of autoimmune blistering diseases (8,9).…”

Section: Introductionmentioning

confidence: 99%

Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases

Ghorbanalipoor

Emtenani²,

Parker³

et al. 2022

Front. Immunol.

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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.

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From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

Cited by 11 publications

References 225 publications

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms

Presence of Cutaneous Complement Deposition Distinguishes between Immunological and Histological Features of Bullous Pemphigoid—Insights from a Retrospective Cohort Study

Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases

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