-
Clinical, Cosmetic and Investigational... 2022Darier's disease (DD) is a rare autosomal dominant genodermatosis caused by mutations in gene, which encodes for the sarcoendoplasmic reticulum calcium ATPase type 2...
Darier's disease (DD) is a rare autosomal dominant genodermatosis caused by mutations in gene, which encodes for the sarcoendoplasmic reticulum calcium ATPase type 2 isoform (SERCA2). In epidermal keratinocytes, the decrease in SERCA2 inhibits the transportation of desmosomal proteins to the plasma membrane, resulting in acantholysis and dyskeratosis. We present the first case of DD with a novel missense mutation in the gene and successfully treated with calcipotriol/betamethasone dipropionate two-compound ointment. A 34-year-old Japanese woman presented with erythema and scales on the scalp and clusters of keratotic papules on the neck and groin. Similar symptoms were observed in her father, younger sister, and daughter. Histopathological examination revealed corps ronds in the granular layer and grains in the horny layer of the epidermis and acantholytic lacuna just above the basal layer. She was diagnosed with DD. A novel heterozygous missense mutation, c.616A>C (p.Asn206His), was detected in the gene in both the patient and her daughter. The patient was treated with calcipotriol/betamethasone dipropionate two-compound ointment, which resulted in improvement of the skin eruption. This two-compound topical ointment may be a promising therapeutic strategy in the treatment for DD.
PubMed: 35283639
DOI: 10.2147/CCID.S354694 -
Dermatologic Therapy May 2022
Topics: Acantholysis; Antibodies, Monoclonal, Humanized; Humans; Ichthyosis
PubMed: 35261140
DOI: 10.1111/dth.15429 -
Journal of Toxicologic Pathology Jan 2022Pemphigus is an autoimmune blistering disease characterized by lesions on the skin and mucous membranes. To date, no spontaneous cases of this disease have been reported...
Pemphigus is an autoimmune blistering disease characterized by lesions on the skin and mucous membranes. To date, no spontaneous cases of this disease have been reported in cynomolgus monkeys. This report describes the histopathological characteristics of spontaneous pemphigus in a cynomolgus monkey. Macroscopically, redness and scaling with pruritus were observed on the skin of the entire body. Histopathologically, the epidermis showed intercellular edema, and eosinophils and mononuclear cells infiltrated the epidermis. There was no obvious acantholysis in the epidermis. The perivascular area showed edema, and eosinophils and mononuclear cells infiltrated the vessels in the dermis. Immunohistochemically, the intercellular area in the epidermis was positive for Immunoglobulin G and Complement component 3. Serologically, anti-desmoglein 1 and desmoglein 3 antibodies in the serum were negative. From these findings, this case was diagnosed as an autoimmune skin disease, suspected to be pemphigus, and concluded as lesions being similar to those in human "pemphigus herpetiformis".
PubMed: 35221502
DOI: 10.1293/tox.2021-0048 -
Vaccines Jan 2022Pemphigus vulgaris (PV) is a chronic, life-altering autoimmune disease due to the production of anti-desmoglein antibodies causing the loss of cell-cell adhesion in...
Pemphigus vulgaris (PV) is a chronic, life-altering autoimmune disease due to the production of anti-desmoglein antibodies causing the loss of cell-cell adhesion in keratinocytes (acantholysis) and blister formation in both skin and mucous membranes. The dispase-based keratinocyte dissociation assay (DDA) is the method of choice to examine the pathogenic effect of antibodies and additional co-stimuli on cell adhesion in vitro. Despite its widespread use, there is a high variability of experimental conditions, leading to inconsistent results. In this paper, we identify and discuss pitfalls in the application of DDA, including generation of a monolayer with optimized density, appropriate culturing conditions to obtain said monolayer, application of mechanical stress in a standardized manner, and performing consistent data processing. Importantly, we describe a detailed protocol for a successful and reliable DDA and the respective ideal conditions for three different types of human keratinocytes: (1) primary keratinocytes, (2) the HaCaT spontaneously immortalized keratinocyte cell line, and (3) the recently characterized HaSKpw spontaneously immortalized keratinocyte cell line. Our study provides detailed protocols which guarantee intra- and inter-experimental comparability of DDA.
PubMed: 35214667
DOI: 10.3390/vaccines10020208 -
Biology Feb 2022Pemphigus vulgaris (PV) is an IgG-mediated autoimmune disease characterised by epithelial cell-cell detachment (acantholysis) resulting in mucocutaneous blistering. The... (Review)
Review
BACKGROUND
Pemphigus vulgaris (PV) is an IgG-mediated autoimmune disease characterised by epithelial cell-cell detachment (acantholysis) resulting in mucocutaneous blistering. The exact pathogenesis of blister formation is unknown and this has hampered the development of non-steroidal, mechanism-based treatments for this autoimmune disease. This systematic review aims to investigate the role of caspases in the pathogenesis of PV to inform the choice of more targeted therapeutic agents.
METHODS
A systematic search of MEDLINE/PubMed and Scopus databases was conducted to identify eligible studies. Multiple phases of inclusion and exclusion of the primary articles were conducted in pairs, and studies were recorded and analysed according to the latest version of the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Risk of bias assessment was conducted for extracted in vivo animal intervention studies using SYRCLE's risk of bias tool.
RESULTS
Eight articles from a total of 2338 in vitro, in vivo, and human studies met the inclusion criteria, with a high degree of inter-rater reliability. By and large, the results show that caspase activation was pathogenic in experimental PV because pan-caspase inhibitors could block or reduce PV acantholysis and blistering in vitro and in vivo, respectively. The pathogenic pathways identified involved caspase-1 and caspase-3. One study failed to show any improvement in the PV model with a caspase inhibitor. The majority of animal studies had high or unclear risk of bias.
CONCLUSION
There are consistent data pointing towards a pathogenic role of caspase activation in PV acantholysis. However, high-quality evidence to confirm that caspase inhibition can prevent PV-induced blistering in vivo is limited. Therefore, further research is required to test the preclinical efficacy of caspase inhibitors in PV.
PubMed: 35205180
DOI: 10.3390/biology11020314 -
The Journal of Biological Chemistry Mar 2022Pemphigus vulgaris (PV) is a potentially lethal autoimmune mucocutaneous blistering disease characterized by binding of IgG autoantibodies (AuAbs) to keratinocytes...
Pemphigus vulgaris (PV) is a potentially lethal autoimmune mucocutaneous blistering disease characterized by binding of IgG autoantibodies (AuAbs) to keratinocytes (KCs). In addition to AuAbs against adhesion molecules desmogleins 1 and 3, PV patients also produce an AuAb against the M3 muscarinic acetylcholine (ACh) receptor (M3AR) that plays an important role in regulation of vital functions of KCs upon binding endogenous ACh. This anti-M3AR AuAb is pathogenic because its adsorption eliminates the acantholytic activity of PV IgG; however, the molecular mechanism of its action is unclear. In the present study, we sought to elucidate the mode of immunopharmacologic action of the anti-M3AR AuAb in PV. Short-term exposures of cultured KCs to PV IgG or the muscarinic agonist muscarine both induced changes in the expression of keratins 5 and 10, consistent with the inhibition of proliferation and upregulated differentiation and in keeping with the biological function of M3AR. In contrast, long-term incubations induced a keratin expression pattern consistent with upregulated proliferation and decreased differentiation, in keeping with the hyperproliferative state of KCs in PV. This change could result from desensitization of the M3AR, representing the net antagonist-like effect of the AuAb. Therefore, chronic exposure of KCs to the anti-M3AR AuAb interrupts the physiological regulation of KCs by endogenous ACh, contributing to the onset of acantholysis. Since cholinergic agents have already demonstrated antiacantholytic activity in a mouse model of PV and in PV patients, our results have translational significance and can guide future development of therapies for PV patients employing cholinergic drugs.
Topics: Acantholysis; Animals; Autoantibodies; Humans; Immunoglobulin G; Keratinocytes; Mice; Pemphigus; Receptors, Muscarinic
PubMed: 35143842
DOI: 10.1016/j.jbc.2022.101687 -
SAGE Open Medical Case Reports 2022Pemphigus includes a group of blistering autoimmune diseases that affect the skin and mucosa, characterized by the formation of epidermal bullous and the presence of...
Pemphigus includes a group of blistering autoimmune diseases that affect the skin and mucosa, characterized by the formation of epidermal bullous and the presence of antibodies against binding proteins. Pemphigus is classified according to clinical presentation, target molecule, and IgG production as pemphigus vulgaris, foliaceous, IgA-pemphigus, and paraneoplastic pemphigus. Thus, the identification of autoantibodies class and site of deposition is mandatory. The gold standard to identify the immune complex deposition is the direct immunofluorescences technique, performed in fresh tissue; unfortunately, this method is unavailable in the regional hospital at the Mexican provinces. Nevertheless, IgG subclass-4 is the prevalence of immunoglobulin in acantholysis. Therefore, this IgG subclass could be detected using IgG4 immunohistochemistry. Because direct immunofluorescences technique is absent in provinces or patients denied a new biopsy to confirm the diagnosis, this work presented pemphigus vulgaris confirmation using the IgG4 immunohistochemistry technique in patients with clinical lesions suggestive of pemphigus vulgaris and intraepidermal blister manifestation in histopathology.
PubMed: 35070321
DOI: 10.1177/2050313X211072982 -
Experimental and Therapeutic Medicine Feb 2022Transient acantholytic dermatosis (TAD) is a benign, non-familial, non-immune mediated acantholytic disorder of unknown etiology. The presence of polymorphous,...
Transient acantholytic dermatosis (TAD) is a benign, non-familial, non-immune mediated acantholytic disorder of unknown etiology. The presence of polymorphous, unorganized, pruritic lesions on the trunk, associated with focal acantholysis and dyskeratosis, resembles a wide variety of dermatoses. The etiology of TAD (also known as Grover's disease) is unknown, and the success of treatment relies on the correct identification of the disease; however, some cases are refractory to all forms of therapy. For accurate diagnosis, a comprehensive literature review is required. Here, the case of a 55-year-old male with TAD displaying a Darier-like histopathological pattern was reported. The patient was successfully treated with retinoids and acitretin (Neotigason), as well as dapsone, an anti-inflammatory agent, as maintenance therapy. The presence of more than two histological findings, limited to small foci and clinical information, can diagnose Darier disease. The exact pathogenesis has not been elucidated, thus further studies of the pathogenesis of TAD are required.
PubMed: 35069854
DOI: 10.3892/etm.2021.11096 -
Anais Brasileiros de Dermatologia 2022Anti-desmoglein 1 and 3 autoantibodies justify acantholysis in pemphigus; however, the pathogenesis of anti-desmoglein 2 is hypothetical.
BACKGROUND
Anti-desmoglein 1 and 3 autoantibodies justify acantholysis in pemphigus; however, the pathogenesis of anti-desmoglein 2 is hypothetical.
OBJECTIVE
To compare the participation of desmogleins 1, 2 and 3 through the production of serum autoantibodies, and protein and gene expression in the skin/mucosa of patients with pemphigus foliaceus and pemphigus vulgaris.
METHODS
The autoantibodies were titrated by ELISA in 202 samples of pemphigus foliaceus, 131 pemphigus vulgaris, 50 and 57 relatives of patients with pemphigus foliaceus and pemphigus vulgaris, respectively, and 114 controls. Protein and gene expressions were determined by immunohistochemistry and qPCR in the skin/mucosa of 3 patients with pemphigus foliaceus and 3 patients with pemphigus vulgaris.
RESULTS
Higher titers of anti-desmoglein 2 (optical density) resulted in pemphigus foliaceus and pemphigus vulgaris, when compared to controls (0.166; 0.180; 0.102; respectively; p < 0.0001). There was a correlation between anti-desmoglein 2 and anti-desmoglein 1 titers in pemphigus foliaceus (r = 0.1680; p = 0.0206). There was no cross-reaction of anti-desmoglein 2 with desmoglein 1 and 3. Protein overexpression of desmoglein 2 was observed in intact and lesional skin of patients with pemphigus compared to the skin of controls. Internalization granules of desmoglein 1 and 3, but not of desmoglein 2, were observed in lesions of pemphigus foliaceus and pemphigus vulgaris, respectively. Gene overexpression of desmoglein 2 was observed in the mucosa.
STUDY LIMITATIONS
Small sample size for the statistical analysis of protein and gene expression.
CONCLUSION
Autoantibodies against desmoglein 2 are not pathogenic in pemphigus; protein and gene overexpression of desmoglein 2 in the skin and mucosa may be involved in acantholysis repair.
Topics: Acantholysis; Autoantibodies; Desmoglein 1; Desmoglein 2; Desmoglein 3; Humans; Pemphigus
PubMed: 35058080
DOI: 10.1016/j.abd.2021.06.004 -
BMC Veterinary Research Jan 2022Ichthyosis describes a localized or generalized hereditary cornification disorder caused by an impaired terminal keratinocyte differentiation resulting in excessive...
BACKGROUND
Ichthyosis describes a localized or generalized hereditary cornification disorder caused by an impaired terminal keratinocyte differentiation resulting in excessive stratum corneum with the formation of more or less adherent scales. Ichthyosis affects humans and animals. Two rare bovine forms are reported, the severe harlequin ichthyosis and the less severe congenital ichthyosis, both characterized by a severe orthokeratotic lamellar hyperkeratosis.
RESULTS
A 2-weeks-old purebred Scottish Highland calf was referred because of a syndrome resembling congenital ichthyosis. The clinical phenotype included diffuse alopecia and a markedly lichenified skin covered with large and excessive scales. Additionally, conjunctivitis and ulceration of the cornea were noted. Post-mortem examination revealed deep fissures in the diffusely thickened tongue and histopathological findings in the skin confirmed the clinical diagnosis. Whole-genome sequencing of the affected calf and comparison of the data with control genomes was performed. A search for private variants in known candidate genes for skin phenotypes including genes related with erosive and hyperkeratotic lesions revealed a single homozygous protein-changing variant, DSP: c.6893 C>A, or p.Ala2298Asp. The variant is predicted to change a highly conserved residue in the C-terminal plakin domain of the desmoplakin protein, which represents a main intracellular component of desmosomes, important intercellular adhesion molecules in various tissues including epidermis. Sanger sequencing confirmed the variant was homozygous in the affected calf and heterozygous in both parents. Further genotyping of 257 Scottish Highland animals from Switzerland revealed an estimated allele frequency of 1.2%. The mutant allele was absent in more than 4800 controls from various other cattle breeds.
CONCLUSIONS
This study represents the first report of combined lesions compatible with congenital ichthyosis, alopecia, acantholysis of the tongue and corneal defects associated with a DSP missense variant as the most likely underlying cause. To the best of our knowledge, this study is also the first report of a DSP-related syndromic form of congenital ichthyosis in domestic animals. The results of our study enable genetic testing to avoid the unintentional occurrence of further affected cattle. The findings were added to the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002243-9913).
Topics: Alopecia; Animals; Cattle; Desmoplakins; Female; Ichthyosis; Ichthyosis, Lamellar; Mutation, Missense; Tongue
PubMed: 34996433
DOI: 10.1186/s12917-021-03113-3