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Acantholytic skin disorders, by definition, compromise intercellular adhesion between epidermal keratinocytes. The root cause of blistering in these diseases traces back to direct disruption of adhesive cell-cell junctions, exemplified by autoantibody-mediated attack on desmosomes in pemphigus. However, genetic acantholytic disorders originate from more indirect mechanisms. Darier disease and Hailey-Hailey disease arise from mutations in the endoplasmic reticulum calcium pump, SERCA2, and the Golgi calcium/manganese pump, SPCA1, respectively. Though the disease-causing mutations have been known for nearly 25 years, the mechanistic linkage between dysregulation of intracellular ion stores and weakening of cell-cell junctions at the plasma membrane remains puzzling. The molecular underpinnings of a related idiopathic disorder, Grover disease, are even less understood. Due to an incomplete understanding of acantholytic pathology at the molecular level, these disorders lack proven, targeted treatment options, leaving patients with the significant physical and psychological burdens of chronic skin blistering, infections, and pain. This article aims to review what is known at the molecular, cellular, and clinical levels regarding these under-studied disorders and to highlight knowledge gaps and promising ongoing research. Armed with this knowledge, our goal is to aid investigators in defining essential questions about disease pathogenesis and to accelerate progress toward novel therapeutic strategies.

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Severe junctional epidermolysis bullosa is a rare genetic, postpartum lethal skin disease, predominantly caused by nonsense/premature termination codon (PTC) sequence variants in LAMB3 gene. LAMB3 encodes LAMB3, the β subunit of epidermal-dermal skin anchor laminin 332. Most translational reads of a PTC mRNA deliver truncated, nonfunctional proteins, whereas an endogenous PTC readthrough mechanism produces full-length protein at minimal and insufficient levels. Conventional translational readthrough-inducing drugs amplify endogenous PTC readthrough; however, translational readthrough-inducing drugs are either proteotoxic or nonselective. Ribosome editing is a more selective and less toxic strategy. This technique identified ribosomal protein L35/uL29 (ie, RpL35) and RpL35-ligands repurposable drugs artesunate and atazanavir as molecular tools to increase production levels of full-length LAMB3. To evaluate ligand activity in living cells, we monitored artesunate and atazanavir treatment by dual luciferase reporter assays. Production levels of full-length LAMB3 increased up to 200% upon artesunate treatment, up to 150% upon atazanavir treatment, and up to 170% upon combinatorial treatment of RpL35 ligands at reduced drug dosage, with an unrelated PTC reporter being nonresponsive. Proof of bioactivity of RpL35 ligands in selective increase of full-length LAMB3 provides the basis for an alternative, targeted therapeutic route to replenish LAMB3 in severe junctional epidermolysis bullosa.

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BACKGROUND: Epidermolysis bullosa (EB) represents a group of rare disorders, genetically determined, characterized by skin fragility, blister formation and erosions due to minimal trauma. Depending on the ultrastructural level of skin cleavage, above or below the basement membrane, epidermolysis bullosa can be classified into four major types: simplex, junctional, dystrophic and Kindler Syndrome. In the junctional form of EB, the cleavage level is at the dermo-epidermal junction and the targeted proteins are laminin, type XVII collagen and integrins. The dystrophic form of EB is characterized by cleavage in the dermal layer, collagen VII being the targeted protein. In Kindler EB, multiple levels of cleavage have been described. The mutated gene is FERMT1. Another classification of this disease refers to phenotypic aspects such as extracutaneous lesions, severity, and distribution. The management of epidermolysis bullosa includes supportive wound treatments as well as nutritional support.
METHODS: We present a case of epidermolysis bullosa presented at birth, in a newborn with no family history of bullous skin conditions. The clinical presentation revealed extensive denuded areas and significant skin fragility as well as mucous and nail involvement. Prenatal diagnosis is very hard to achieve due to increased genetic heterogeneity of the disease. The short-term results were good. The importance of prenatal testing and possibilities of diagnosis are reviewed in this article.
CONCLUSIONS: EB is a devastating disease. The presented case had a favorable evolution, with good short-term results. Significant morbidity can result from secondary infections of blisters and complications of the extracutaneous manifestations.

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Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Its presentation is polymorphic.
To investigate different clinical and biological profiles of BP.
We conducted a retrospective 2-center study including all BP patients seen between January 1, 2015, and February 28, 2021. We performed hierarchical clustering on principal components.
Three clusters were identified. Patients in cluster 1 (n = 155) were older than those in clusters 2 (n = 89) and 3 (n = 35; P < .0001), more frequently presented pauci-bullous BP (n = 63 [41%] vs 14 [16%] and 2 [6%], respectively; P < .0001) and had anti-BP230 antibodies in 87% of cases. More than 100 blisters were observed in 14 patients (40%) from cluster 3, versus 3 (2%) from cluster 1 and 0 (0%) from cluster 2 (P < .0001). Frequency of mucosal involvement was higher in cluster 3 (n = 32 [91%, including epiglottis in 40%] vs 11 [7%] and 34 [38%]; P < .0001). In clusters 2 and 3, 70% and 74% of patients had antibodies targeting only BP180. Those in cluster 3 received more lines of systemic treatment and experienced more relapses.
Retrospective study without immunoelectron microscopy.
We identified 3 different BP clusters, including one corresponding to severe BP180+ BP230- BP with features common to mucous membrane pemphigoid.

The classification of autoimmune blistering skin diseases is based on the skin antigen(s) targeted by pathogenic autoantibodies. In humans and dogs, there is increasing evidence that autoimmune subepidermal bullous diseases represent different nosological entities. This study establishes the existence of the canine equivalent of epidermolysis bullosa acquisita (EBA) in humans. Canine EBA, like the inflammatory variant of its human counterpart, is characterized by spontaneous vesicles arising from an inflammatory eruption. Dermo-epidermal separation occurs in association with neutrophilic infiltration in the superficial dermis. Tissue-fixed and circulating IgA and IgG autoantibodies specific for the lower basement membrane zone can be detected by immunofluorescence methods. Using immunoelectron microscopy, autoantibodies are shown to target the distal end of anchoring fibrils in the sublamina densa. ELISA and immunoblotting utilizing eukaryotically expressed recombinant collagen VII subdomains confirm that the circulating autoantibodies are specific for the aminoterminal globular non-collagenous NC1 domain of type VII collagen.