Human dental mesenchymal stem cells restorate immune response in sera of pemphigus vulgaris patients.

Pemphigus is an IgG-mediated autoimmune condition characterized by autoantibodies targeting desmogleins, leading to acantholysis. Current treatments, including systemic corticosteroids and immunosuppressive drugs, are associated with significant adverse effects. Mesenchymal stem cells (MSCs) offer a promising alternative due to their immunomodulatory properties and low immunogenicity. This study evaluates the immunomodulatory effects of dental follicle mesenchymal stem cells (DF-MSCs) obtained from healthy donors on Pemphigus vulgaris (PV) patients and healthy controls by examining T-cell proliferation, apoptosis, cytokine levels, and anti-desmoglein 1/3 IgG profiles. Peripheral blood mononuclear cells (PBMCs) were isolated from twenty-one symptomatic PV patients and eleven healthy volunteers. DF-MSCs were characterized and differentiated into osteocytes, adipocytes, and chondrocytes. Peripheral blood mononuclear cells (PBMCs) were co-cultured with DF-MSCs, and various assays were conducted to evaluate T-cell proliferation, apoptosis, regulatory T cells, cytokine expression, and autoantibody levels. Results showed that DF-MSC co-cultures significantly reduced lymphocyte proliferation (43.58-16.27%), IL-4 (38.06 ng/L to 32.26 ng/L), TNF-α (32.45 ng/L to 29.41 ng/L), and DSG1 (3.29 ng/ml to 3.00 ng/ml) and DSG3 (262.40 ng/ml to 245.08 ng/ml) levels in PV patients. An increase in regulatory T cells (1.22-3.75%), IL-10 (47.46 pg/ml to 54.94 pg/ml), and IFN-γ (12.39 ng/ml to 19.70 ng/ml) was also observed. No significant changes were noted in healthy controls. These findings suggest that DF-MSCs could potentially offer a curative approach for treating pemphigus by restoring immune balance. However, further clinical trials are necessary to confirm their efficacy.

Uncommon and Unusual Variants of Autoimmune Bullous Diseases.

Background: Autoimmune blistering diseases (AIBDs) are a type of dermatosis with antibodies produced against various structural proteins of the epidermis or dermoepidermal junction. AIBDs are broadly divided into intraepidermal and subepidermal types. Apart from the common AIBDs, there is an array of uncommon AIBDs. Objective: To discuss uncommon variants of AIBDs so that the readers are updated about them. Methods: In this review, we have discussed uncommon and unusual variants like pemphigus herpetiformis, IgA pemphigus, paraneoplastic pemphigus, induced pemphigus, IgG/IgA pemphigus, oral lichenoid pigmentation in pemphigus, pemphigus acanthoma, and follicular pemphigus. Rarer variants of the pemphigoid group of disorders include anti-laminin 332 pemphigoid, mixed linear IgA/IgG pemphigoid, anti-p200 pemphigoid, Brunsting-Perry pemphigoid, IgM pemphigoid, granular C3 pemphigoid, anti-p105 pemphigoid, ORF-induced anti-laminin 332 pemphigoid, and acral purpura in dermatitis herpetiformis. Conclusion: This review will help in early diagnosis and treatment of uncommon and unusual variants of AIBDs.

Scoring Criteria for Autoimmune Bullous Diseases: Utility, Merits, and Demerits.

Background: Scoring systems play a crucial role in dermatology by providing objective measurements of disease severity, treatment efficacy, and outcome comparisons. In autoimmune blistering diseases (AIBDs), standardized scoring systems are essential for accurate evaluations; however, there is currently a lack of consensus on scoring methods. Objective: This literature review explores scoring systems in AIBDs by tracing their development, addressing challenges, and highlighting their role in defining endpoints, regulatory considerations, and clinical trials. Materials and Methods: Existing scoring systems for AIBDs, such as the Pemphigus Disease Area Index, Autoimmune Bullous Skin Disorder Intensity Score, Pemphigus Oral Lesions Intensity Score, Oral Disease Severity Score, and Pemphigus Vulgaris Activity Score, are examined for their validity, reliability, and responsiveness. The Bullous Pemphigoid Disease Area Index for bullous pemphigoid is also discussed. The concept of minimal clinically important differences is explored to determine clinically significant improvements in disease severity. Conclusion: This review provides a comprehensive understanding of the central role of scoring systems in dermatology and their implications for research and clinical practice in AIBDs.

Pemphigus and Pregnancy.

Pemphigus in pregnancy is a special clinical scenario that has potential consequences on both maternal and fetal outcomes. Being an autoimmune disease with Th2 preponderance, pemphigus is expected to flare in pregnancy, especially in the first two trimesters. Fetal outcomes like stillbirth and neonatal pemphigus have been reported, the latter being a consequence of a transient transplacental transfer of autoantibodies. Management needs to be individualized keeping the risk/benefit ratios of therapies in mind while optimizing maternal and fetal health. It is crucial to have appropriate counseling regarding conception for women with pemphigus in the child-bearing period because the probability of adverse materno-fetal outcomes is higher if the disease is severe.

Updates on the Management of Autoimmune Bullous Diseases.

Background: Autoimmune bullous diseases are associated with high morbidity and mortality. Traditionally, systemic corticosteroids and conventional immunosuppressive agents have been the mainstay of treatment, but their broad immunosuppressive effects and long-term complications have prompted the exploration of newer more targeted therapies. Materials and Methods: This review explores the evolving landscape of therapeutic options for immunobullous diseases, with a particular focus on pemphigus, bullous pemphigoid (BP), and mucous membrane pemphigoid, by searching PubMed, clinicaltrials.gov, and Cochrane databases for published literature from 2014 to 2023. Results/Discussion: We discuss emerging treatments for pemphigus such as B cell modulatory drugs, anti-inflammatory drugs, those inhibiting autoantibody half-life or blister-inducing activity, and stem cell therapy, while offering insights into the level of evidence, potential benefits, and limitations of each approach. The role of biologics and novel therapies like rituximab, omalizumab, and dupilumab in reshaping the management of BP is also discussed. Conclusion: The article highlights the need for further research, clinical trials, and comparative studies to determine the most effective and safest treatment options for patients with immunobullous diseases.

Current Knowledge on Nail Involvement in Autoimmune Bullous Disorders.

Background: There are few studies, mainly case reports, on the involvement of the nail unit in autoimmune bullous disorders. Summary: Nail involvement in autoimmune bullous disorders is a significant clinical phenomenon, marked by a range of manifestations, most often not presenting with blisters like on the skin but rather with alterations of the nail unit such as paronychia, onychomadesis, or onycholysis. This involvement is particularly notable due to the unique immunological features of the nail unit, including the expression of various antigens and the presence of Langerhans cells. Conditions like pemphigus vulgaris, bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, and bullous systemic lupus erythematosus can lead to nail abnormalities. The prevalence of nail manifestations varies according to the disorder, and diagnosis often relies on histopathological and immunofluorescence testing. Nail involvement correlates with disease severity and duration, sometimes serving as a herald sign. Further research is needed to guide therapeutic approaches for nail involvement in autoimmune bullous diseases. Key Messages: Nail involvement in autoimmune bullous nail disorders may be confusing as there are almost never bullae. One should keep the diagnosis in mind when facing an atypical paronychia.

Guided Biofilm Therapy for Management of "Desquamative Gingivitis"-Clinical Cases.

Background: Desquamative gingivitis is a clinical manifestation often associated with various mucocutaneous disorders, characterized by red, painful, and friable gingiva. It is predominantly seen in middle-aged to elderly females and is typically linked to autoimmune conditions such as lichen planus, pemphigoid, and pemphigus, among others. Due to the chronic pain and difficulty in maintaining personal oral hygiene, professional care becomes crucial. Methods: This article explores the application of guided biofilm therapy as a novel, gentle approach for managing desquamative gingivitis, focusing on three clinical cases. This therapy employs erythritol-based powders for biofilm removal, offering a less abrasive and more comfortable alternative to traditional mechanical plaque removal techniques. Results: The cases demonstrate the effectiveness of guided biofilm therapy in reducing discomfort and improving clinical outcomes in desquamative gingivitis patients, particularly those suffering from mucous membrane pemphigoid, pemphigus vulgaris, and oral lichen planus. Conclusions: The guided biofilm approach underscores the importance of tailored periodontal therapy in managing nonplaque-induced gingival lesions, improving patient compliance and oral health outcomes.

Case report: A novel high-dose intravenous immunoglobulin preparation for the treatment of severe pemphigus vulgaris failing standard therapy.

Pemphigus vulgaris (PV) is a severe autoimmune bullous dermatosis that is characterized by autoantibodies against epidermal adhesion proteins causing painful mucosal and skin blistering. Standard treatments for PV include corticosteroids, steroid-sparing immunosuppressants, or intravenous monoclonal anti-CD20-antibody therapy. The European guidelines suggest high-dose intravenous immunoglobulin (IVIg) therapy as a promising approach for severe or treatment-resistant cases. We report on a 65-year-old woman with severe and recurrent disease who achieved long-term disease stabilization with IVIg treatment. Because of recurrent fatigue and headache, the patient was switched to an alternative IVIg preparation with a novel manufacturing process, thus ensuring high purity and better tolerability. We observed excellent efficacy, yet side effects remained largely unchanged. Further studies are necessary to evaluate the long-term efficacy and tolerability of this new IVIg preparation.

Effect of opioid receptor antagonist on mitigating tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-induced apoptolysis in pemphigus pathogenesis.

Pemphigus is a severe autoimmune blistering disease characterized by acantholysis triggered by autoantibodies against desmoglein 1 and 3 (DSG1/3). Apoptosis plays a pivotal role in facilitating acantholysis, yet the precise underlying mechanism remains obscure. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to promote apoptosis and disrupt cell junctions, although its involvement in pemphigus pathogenesis remains ambiguous. Our study observed decreased DSG1/3 expression alongside increased TWEAK/fibroblast growth factor-inducible 14 (Fn14) expression and keratinocyte apoptosis in both lesional and perilesional skin. In vitro experiments revealed that TWEAK-stimulated keratinocytes exhibited enhanced apoptosis, STAT1 phosphorylation, and reduced intercellular DSG1/3 expression. Notably, bulk-RNA sequencing unveiled that CASPASE-3 was responsible for mediating the DSG1/3 depletion, as confirmed by direct interaction with DSG1/3 in a co-immunoprecipitation assay. Naloxone, known for preserving cellular adhesion and preventing cell death, effectively reduced apoptosis and restored DSG1/3 levels in TWEAK-stimulated keratinocytes. The anti-apoptotic properties of naloxone were further validated in a murine pemphigus model. Our findings elucidate that TWEAK facilitates keratinocyte apoptosis by augmenting caspase-3 activity, leading to DSG1/3 depletion and apoptosis in pemphigus. Importantly, naloxone can counter TWEAK-induced apoptosis in pemphigus pathogenesis, offering a potential therapeutic intervention.

New complex cell junctions in and around the intervertebral discs discovered using autoantibodies from patients affected by endemic pemphigus foliaceus in El Bagre, Colombia, South America.

BACKGROUND: Traditionally, the intervertebral disks' (IVD) nucleus pulposus (NP) and annulus fibrosus (AF) are considered to have few cellular components and cell junctions. Patients affected by a new variant of endemic pemphigus foliaceus in El Bagre, Colombia, experience back pain in the spinal areas of the lower and upper back. Here, we investigate the reactivity of the patient's autoantibodies to structures in and around the IVDs at the cellular level. METHODS: We first administered a questionnaire and performed a medical examination. We then tested for autoreactivity against IVDs by indirect immunofluorescence, confocal microscopy, and reflectance confocal microscopy using bovine and human tissues as antigen sources. We tested 45 sera from patients affected by the disease and 45 control sera from the endemic area matched by age, gender, demographics, and work activity. RESULTS: Most of the patient sera revealed polyclonal antibodies against newly discovered cell junctions in the NP and AF, including their translamellar cross-bridges. Additional reactivities were detected against cell junctions in the spinal cord neurons, paraspinal nerves, blood vessels, anterior and posterior longitudinal ligaments, and paraspinal skeletal muscles. The reactivities of the patient's autoantibodies co-localized with those of commercially available antibodies to desmoplakins I-II, armadillo repeat gene deleted in velo-cardio-facial syndrome, plakophilin-4, and myocardium-enriched zonula occludens-1-associated protein (p < 0.001). CONCLUSIONS: We discovered novel complex cell junctions in the IVDs using patients' autoantibodies. These discoveries open a new chapter in the knowledge of IVD, representing a breakthrough pertinent to many diseases.

Oral biopsy in mucous membrane pemphigoid and pemphigus vulgaris with gingival expression: the optimal site. A systematic review and meta-analysis.

PURPOSE: In order to diagnose mucous membrane pemphigoid (MMP) and pemphigus vulgaris (PV) with gingival expression, clinical data must be compared with immunohistochemical data obtained using direct immunofluorescence (DIF). It is therefore essential to carry out a good quality mucosal biopsy for this vital additional test. To date, no study has been able to effectively guide clinicians in their choice of oral site for biopsy to guarantee the efficient contribution of DIF to diagnosis. We propose a systematic review of the literature and a meta-analysis to clarify this issue. MATERIALS AND METHODS: Electronic databases and bibliographies of articles were searched in April 2023. The primary outcome was the rate of DIF + contribution to diagnosis according to the location of the oral site biopsied. RESULTS: 16 studies were included. Gingival biopsies showed a rate of DIF + 100% [97%-100%] p = 0.998 I2 = 0.0% with no heterogeneity for PV, and 90.2% [66.5%-100%] p < 0.001 I2 = 89.6% with high heterogeneity for MMP. For the other oral sites, this rate was 95.7% [87.4%- 100%] p = 0.011 I2 = 73.0% with moderate heterogeneity for PV, and 87.4% [70.1%- 98.7%] p < 0.001 I2 = 92.6% with high heterogeneity for MMP. In addition, meta-regression confirmed the significant association between the appearance of the biopsied mucosa and the rate of DIF + in MMP (p < 0.001), with no influence on residual heterogeneity. CONCLUSION: The nature of the oral mucosa biopsied does not influence the rate of DIF + to diagnosis. The choice of biopsy site should only take into account the characteristics of the clinical picture and the benefit/risk balance of the surgical protocol. The sample must be taken in healthy aeras as close as possible of active lesions: on the gingiva if the MMP and PV are strictly gingival, on the alveolar mucosa if the whole gingiva is altered and on any healthy mucosa if a large number of oral sites are affected. CLINICAL TRIALS: CRD42023392345.

HLA-Cw6 Polymorphism in Autoimmune Blistering Diseases.

Autoimmune blistering diseases of the pemphigus and pemphigoid groups are immune-mediated disorders due to circulating pathogenetic autoantibodies. Multiple human leukocyte antigen (HLA) genes have been associated with predisposition to these disorders. HLA-Cw6 is involved in antigen presentation processes and has been linked to psoriasis. The aim of our study was to investigate the association between the presence of the HLA-Cw6 allele and susceptibility to pemphigus vulgaris and bullous pemphigoid. A genetic study in vitro with a cross-sectional design was performed enrolling forty patients with pemphigus vulgaris and forty patients with bullous pemphigoid. The detection of HLA-Cw6 was performed through the EUROArray test on DNA obtained from whole blood samples. The polymorphism was detected in 3/40 genotypes in the pemphigus vulgaris group and in 4/40 genotypes of patients with bullous pemphigoid, unveiling a non-statistically significant different frequency in pemphigus (p = 0.6368) and in pemphigoid (p = 0.62) compared to the reference frequency from the literature of 0.086. Further research is needed to better investigate the role of HLA-Cw6 in immune-mediated diseases and to identify novel genetic markers associated with susceptibility to autoimmune blistering diseases and with disease severity and response to immunosuppressive therapies.

Localized facial pemphigus foliaceus presenting in a dermatomal distribution: A case report.

Pemphigus foliaceus is a superficial autoimmune blistering disorder of the skin. Localized forms of pemphigus foliaceus are rare. Only a few cases have been described. We report a case of an 81-year-old man with pemphigus foliaceus who initially presented with localized dermatomal facial lesions. Due to this atypical presentation, making the diagnosis was challenging. To our knowledge, this is the first case of localized pemphigus foliaceus with a dermatomal distribution to be recorded.

Comparison of serum cytokines and chemokines levels and clinical significance in patients with pemphigus vulgaris-A retrospective study.

In this study, we aimed to examine the relationship between the serum cytokine levels of patients with pemphigus vulgaris (PV) and the Pemphigus Disease Area Index (PDAI), along with the presence of anti-desmoglein (Dsg) 1 antibody, anti-Dsg3 antibody and co-infection among patients with pemphigus vulgaris. This retrospective study included 62 PV patients and 59 healthy individuals who attended the Second Affiliated Hospital of Kunming Medical University from November 2014 to November 2022. The serum concentrations of cytokines and chemokines were assessed using the Luminex 200 System (a high-throughput cytokine detection method). Additionally, anti-Dsg1 and anti-Dsg3 antibodies were determined through enzyme-linked immunosorbent assay, while disease severity was evaluated using the PDAI scoring system. The PV group exhibited elevated levels of Th1 cytokines (such as interleukin (IL)-1RA, IL-1ß, IL-2, IL-12p70, GM-CSF, TNF-α, IL-18, IFN-γ), Th2 cytokines (IL-5, IL-10, IL-13) and Th17/Th22-related cytokines (IL-17A, IL-22) compared to the healthy control group (p < 0.05). Conversely, the levels of chemokines (macrophage inflammatory protein-1 alpha (MIP-1α), stromal cell-derived factor-1 alpha (SDF-1α), interferon-inducible protein-10 (IP-10), Regulated on Activation in Normal T-Cell Expressed And Secreted (RANTES), growth-regulated on-gene-alpha (GRO-α), MIP-1ß) and Th2 (IL-31) were lower in the PV group compared to the healthy control group (p < 0.05). No significant differences were observed in other cytokines and chemokines (p > 0.05). Additionally, IL-7, IFN-γ, IL-18 and GRO-α showed positive correlations with PDAI, IL-6 correlated positively with anti-Dsg3 antibody levels, and IL-12p70, IL-18, and IFN-γ correlated positively with anti-Dsg1 antibody levels. Furthermore, IL-15 exhibited a positive association with skin infections. PV patients have elevated levels of various cytokines and chemokines, and there are different degrees of elevation in cytokines and chemokines associated with the activation of various T cell subsets. PDAI and the Dsg1 antibody levels are mainly related to the Th1-related cytokines.

A Comprehensive Review on the Intricate Interplay between COVID-19 Immunization and the New Onset of Pemphigus Foliaceus.

Autoimmune bullous diseases (AIBDs) are characterized by the formation of vesicles, bullous lesions, and mucosal erosions. The autoantibodies target the cellular anchoring structures from the surface of epidermal keratinocyte named desmosomes, leading to a loss of cellular cohesion named acantholysis. AIBDs are classified into intraepidermal or subepidermal types based on clinical features, histological characteristics, and immunofluorescence patterns. Pemphigus foliaceus (PF) is an acquired, rare, autoimmune skin condition associated with autoantibodies that specifically target desmoglein-1, leading to a clinical presentation characterized by delicate cutaneous blisters, typically sparing the mucous membranes. Several factors, including genetic predisposition, environmental triggers, malignancies, medication use, and vaccination (for influenza, hepatitis B, rabies, tetanus, and more recently, severe acute respiratory syndrome Coronavirus 2 known as SARS-CoV-2), can potentially trigger the onset of pemphigus. With the advent of vaccines playing a pivotal role in combatting the 2019 coronavirus disease (COVID-19), extensive research has been conducted globally to ascertain their efficacy and potential cutaneous adverse effects. While reports of AIBDs post-COVID-19 vaccination exist in the medical literature, instances of PF following vaccination have been less commonly reported worldwide. The disease's pathophysiology is likely attributed to the resemblance between the ribonucleic acid (RNA) antigen present in these vaccines and cellular nuclear matter. The protein produced by the BNT-162b2 messenger ribonucleic acid (mRNA) vaccine includes immunogenic epitopes that could potentially trigger autoimmune phenomena in predisposed individuals through several mechanisms, including molecular mimicry, the activation of pattern recognition receptors, the polyclonal stimulation of B cells, type I interferon production, and autoinflammation. In this review, we present a comprehensive examination of the existing literature regarding the relationship between COVID-19 and PF, delving into their intricate interactions. This exploration improves the understanding of both pemphigus and mRNA vaccine mechanisms, highlighting the importance of close monitoring for PF post-immunization.