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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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pemphigus vulgaris (PV) is characterized by autoantibodies targeting keratinocyte adhesion proteins desmoglein (Dsg) 1 and 3, and by the human leukocyte antigen (HLA) predisposition allele HLA-DRB1*0402. Treatment using rituximab (RTX) combined with short-term corticosteroids (CS) allows disease control and long-lasting remission., Objectives: The principal aim of this study was to evaluate the impact of RTX on the circulating subpopulations of Dsg3-specific T lymphocytes that specifically regulate B-cell responses: follicular helper T (Tfh) and follicular regulatory T (Tfr) lymphocytes., Methods: Using the HLA-DRB1*0402 tetramer loaded with the Dsg3 immunodominant peptide, we used flow cytometry to analyse the frequency, polarization and activation status of blood Dsg3-specific follicular T-cell populations at baseline, month (M) 6 and long-term follow-up (M60-90) from patients with PV., Results: At baseline, we observed a predominance of Tfh1* and Tfh17 subsets and an underrepresentation of the Tfh2 subset among autoreactive Dsg3-specific Tfh cells compared with nonautoreactive Tfh cells. RTX treatment induced a decrease of autoreactive Tfh cells with no effect on their polarization during follow-up. In parallel, we observed the emergence of a Dsg3-specific Tfr subpopulation with a significant overexpression of the surface activation markers PD1, ICOS and CD25 that was not observed at the surface of autoreactive Tfh and nonautoreactive Tfr cells of the same patients with PV. In contrast, very few Dsg3-specific Tfr cells were observed in patients with PV who were treated with CS alone., Conclusions: Here we show that the emergence of circulating autoreactive Dsg3-specific Tfr cells is associated with the long-term efficacy of RTX in patients with PV., Competing Interests: Conflicts of interest V.H. reports administrative support was provided by the French Society for Dermatology and Pathology of Sexually Transmitted Diseases. P.J. reports a relationship with Roche SAS that includes board membership. N.F. reports financial support provided by the European Regional Development Fund, the French Society for Dermatology and Pathology of Sexually Transmitted Diseases, the National Institute of Health and Medical Research, the Agence Nationale de la Recherche (ANR) and the Occitanie Region., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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-1β, 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-1β) 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., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Vitamin D dysregulation has been recognized as a factor that may cause or aggravate autoimmunity. Vitamin D deficiency was found to be common in pemphigus vulgaris (PV) in different populations. This study aimed to investigate the vitamin D-VDR pathway in PV in the Tunisian population. A serological study was carried out to determine the vitamin D status in newly diagnosed PV patients. CYP27B1, CYP24A1 and VDR mRNA expression was assessed using quantitative real-time PCR in peripheral blood mononuclear cells (PBMC) from untreated newly diagnosed and treated PV patients. In addition, a genetic study was accomplished on VDR polymorphisms to investigate the changes in VDR gene expression. Overall, the serological study confirmed the hypovitaminosis D in newly diagnosed PV patients. Vitamin D-VDR pathway gene expression showed downregulation of CYP27B1 and CYP24A1 mRNA in first-discovery patients compared to healthy controls, while VDR mRNA was highly expressed in newly diagnosed PV patients. Moreover, CYP27B1, CYP24A1 and VDR mRNA were significantly upregulated in chronic disease severity groups compared to mild disease groups. The genetic study showed low VDR gene expression in carriers of FokI > CC genotype, which was more frequent among PV patients, and FokI > C-TaqI > C-ApaI > A-polyA > A 16 haplotype, suggesting that the VDR gene polymorphisms testing can provide useful information for PV treatment decision-making. In conclusion, our findings underline the impact of vitamin D-VDR pathway disruption in the PV pathophysiology in Tunisian patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Pemphigus vulgaris (PV) is a rare, yet serious autoimmune disorder primarily affecting the skin and mucous membranes. While the dermatological and mucosal aspects of PV are well-documented, the potential for systemic involvement, particularly cardiac complications, remains under-explored. This study aimed to investigate the serum cardiac troponin I (cTnI) level in patients with PV versus healthy controls. The relationship between serum cardiac troponin I (cTnI) levels and various demograpgics, clinical and laboratory characteristics in patients with PV was also dealt with. This cross-sectional study was conducted on 59 patients with pemphigus vulgaris and 59 age- and sex- matched healthy controls, visited at a tertiary care hospital from August 2021 to May 2023. After thorough history taking and physical examination, troponin level was measured by the ECL (Electrochemiluminescence) method. The correlation between serum cTnI level and various variables was evaluated using Pearson's correlation coefficient. The mean serum cardiac troponin I (cTnI) level in patient group was 0.104 ± 0.05 ng/mL, with a range of 0.01 to 0.25 ng/mL. Despite mean cTnI level in patients was greater than controls, this difference was not reach to the significance level (P value: 0.058). The analysis revealed a significant positive correlation (r = 0.52, p = 0.005310), suggesting that higher PDAI scores were associated with elevated cTnI level. The correlation between serum cardiac troponin I (cTnI) level and PDAI score, even without any clinical sign or risk factor for cardiovascular disease suggests a potential link between the severity of PV and subtle cardiac involvement, highlighting the importance of cardiac monitoring in these patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pemphigus is classified as a group of chronic, recurrent, and potentially fatal bullous autoimmune diseases that leads to blisters and skin lesions resulting from IgG antibodies and the loss of cellular connections in the epidermis. Human endogenous retrovirus (HERV) sequences and their products (RNA, cytosolic DNA, and proteins) can modulate the immune system and contribute to autoimmunity. The extent to which, HERV-W env copies may be involved in the pathogenesis of pemphigus remains to be elucidated., Aim: This study aimed to comparatively evaluate the relative levels of HERV-W env DNA copy numbers in the peripheral blood mononuclear cells (PBMCs) of pemphigus vulgaris patients and healthy controls., Methods: Thirty-one pemphigus patients and the corresponding age- and sex-matched healthy controls were included in the study. The relative levels of HERV-W env DNA copy numbers were then evaluated by qPCR using specific primers, in the PBMCs of the patients and controls., Results: Our results indicated that relative levels of HERV-W env DNA copy numbers in the patients were significantly higher than that in the controls (1.67±0.86 vs. 1.17±0.75; p = 0.02). There was also a significant difference between the HERV-W env copies of male and female patients (p = 0.001). Furthermore, there was no relationship between the HERV-W env copy number and disease onset (p = 0.19) . According to the obtained data, we could not find any relationship between the HERV-W env copy number and serum Dsg1(p=0.86) and Dsg3 (p=0.76) levels., Conclusion: Our results indicated a positive link between the HERV-W env copies and pathogenesis of pemphigus. The association between clinical severity score and HERVW env copies in the PBMCs as a biomarker for pemphigus needs further studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Pemphigus is an autoimmune bullous disease mediated by autoantibodies targeting epithelial cell-cell adhesion molecules. Predictors of relapse have not yet been clearly identified., Aims: To identify factors at diagnosis and during follow-up that could be predictors of relapse., Methods: Clinical and immunopathological data at diagnosis, clinical remission and first relapse from patients with pemphigus vulgaris or foliaceus and at least a 36-month follow-up were collected retrospectively. Based on the autoantibody profile at diagnosis, three serological patient subsets were devised: (i) anti-desmoglein (Dsg)1-positive and anti-Dsg3-negative; (iii) anti-Dsg1-negative and anti-Dsg3-positive; and (iii) anti-Dsg1-positive and anti-Dsg3-positive., Results: Data from 143 patients were collected. No significant differences were found between relapsers (n = 90) and nonrelapsers (n = 53) for time to remission or for anti-Dsg1 and anti-Dsg3 titres at diagnosis and remission. In the analysis of all patients, a higher risk of relapse was found for a body surface area (BSA) score of 3 compared with BSA < 3 (OR = 3.30, 95% CI 1.17-9.28; P = 0.02) and for a positive titre of either anti-Dsg1 or anti-Dsg3 autoantibodies at remission compared with both being negative (OR = 2.42, 95% CI 1.21-4.85, P = 0.01). In patients who were anti-Dsg3-positive and anti-Dsg1-negative at diagnosis, failure to achieve anti-Dsg3 negativity at clinical remission was a significant predictor of relapse (OR = 7.89, 95% CI 2.06-30.21; P < 0.01). Similarly, failure to achieve anti-Dsg1 negativity at clinical remission was a significant predictor of relapse in patients with both anti-Dsg1 and anti-Dsg3 positivity at diagnosis (OR = 5.74, 95% CI 1.15-28.61; P = 0.03), but not in those who were anti-Dsg1-positive/anti-Dsg3-negative at diagnosis (OR = 1.08, 95% CI 0.27-4.30; P = 0.91)., Conclusion: Regardless of pemphigus subtype, autoantibody titre negativity at clinical remission in patients classified based on their anti-Dsg1 and anti-Dsg3 profile at diagnosis and BSA were useful tools in predicting relapse., (© 2021 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The management of pemphigus vulgaris (PV) is challenging. This study aimed to evaluate the immunomodulating effects of metformin on PV. The study was conducted in two phases: in the first phase, patients received routine first-line treatment (prednisolone plus azathioprine) for 2 months, then in the second phase, metformin was added to this regimen for another 2 months. After addition of metformin to the first-line medications, significant reductions were seen in serum IgG1 (reduced from 534.92 ± 134.83 mg/dL to 481.58 ± 130.46 mg/dL, P < 0.001), IgG4 (51.83 ± 27.26 mg/dL to 44.50 ± 26.05 mg/dL, P < 0.001) and interferon-γ (277.99 ± 108.71 pg/mL to 45.05 ± 17.080 pg/mL, P = 0.03) concentrations. The suppressant effect of metformin was greatest on IgG4 (coefficient of variation 1.28), the dominant subclass of IgG involved in PV. Metformin could have immunomodulating effects on PV with controlling effects on steroid complications., (© 2021 British Association of Dermatologists.)

Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases., Competing Interests: Competing interest statement: N.L., T.H., and O.K. are preparing to file a patent related to the use of transglutaminase 1 autoantibodies as a diagnostic marker., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: B-cell depletion therapy was demonstrated to be a valid and safe alternative as an adjuvant in oral-pharyngeal pemphigus vulgaris (OPV) patients. We aimed to assess its effects on anti-desmoglein (Dsg) 1 and 3 and leukocytes subsets profile in these patients' population. Methods and Materials: We evaluated the immunologic profile of 10 OPV patients treated with RTX as adjuvant by using the ELISA testing for anti-Dsg-1 and -3 titers and the immunophenotyping for B and T-cell lymphocyte subpopulations and compared them with the PDAI score for clinical remission. Results: A significant difference in medians between baseline, end of RTX therapy, and 6 months after RTX therapy was observed in Dsg-3 titer ( p < 0.001), in the CD8 ( p = 0.009), and CD20 counts ( p < 0.001). Multiple comparisons after Bonferroni adjustment confirmed such significant differences mainly between baseline and the end of RTX therapy and baseline and 6 months after RTX therapy. Only the anti-Dsg-3 titer at the end of RTX therapy demonstrated a slight positive correlation with the PDAI score at baseline ( p = 0.046, r = 0.652). Conclusions: B-cell depletion adjuvant therapy in OPV patients demonstrated a significant impact on anti-Dsg-3 titer and B and T-cell lymphocyte subpopulations profile.

Materials and Methods: This cross-sectional study was performed on patients with pemphigus vulgaris referred to Faghihi Hospital and Shiraz Dental Faculty in 2017-2018. The participants included 26 women with histopathologically confirmed pemphigus vulgaris and 26 healthy age-matched controls. The serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, progesterone, testosterone, prolactin, dehydroepiandrosterone (DHEA), and dihydrotestosterone (DHT) were evaluated in both groups. Independent t -test and two-way ANOVA were used for data analysis., Results: The mean age of the patients was 49.88 ± 10.46 years and that of the control group was 49.92 ± 11.30 years. Unlike the case group, the DHEA serum level was significantly higher among nonmenopausal participants in the control group. Moreover, the levels of testosterone and DHEA were significantly lower in the case group in comparison to the control group ( p = 0.015 and p = 0.026, respectively)., Conclusion: Considering the effects of age and menopause, the serum levels of testosterone and DHEA were significantly lower in the patients with pemphigus vulgaris than in the healthy controls. Hence, these hormones might have a role in the pathogenesis of pemphigus vulgaris., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Fatemeh Lavaee et al.)

A method for the analysis of the epitope specificity of auto-reactive antibodies to desmoglein 3 (Dsg3) using competitive ELISA has been developed. It is based on a two-stage solid-phase ELISA with initial "depletion" of auto-reactive antibodies against the studied epitope and subsequent quantitative assessment of antibodies against full-length extracellular domain Dsg3. The proposed approach for assessing the specificity of the autoimmune response in patients with pemphigus vulgaris can provide in the future the possibility to personalize the therapy using plasmapheresis by preliminary selection of the antigenic composition of the extracorporeal immunosorbent., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

The efficacy of the B-cell-depleting agent rituximab has been reported in immune diseases but relapses are frequent, suggesting the need for repeated infusions. The B-cell activating factor (BAFF) is an important factor for B cell survival, class switch recombination and selection of autoreactive B cells, as well as maintaining long-lived plasma cells. It has been hypothesized that relapses after rituximab might be due to the increase of serum BAFF levels. From the Ritux3 trial, we showed that baseline serum BAFF levels were higher in pemphigus patients than in healthy donors (308 ± 13 pg/mL versus 252 ± 28 pg/mL, p=0.037) and in patients with early relapse compared who didn't (368 ± 92 vs 297 ± 118 pg/mL, p=0.036). Rituximab and high doses of CS alone have different effects on the BAFF/BAFF-R axis. Rituximab led to an increase of BAFF levels associated to a decreased mRNA (Day 0: 12.3 ± 7.6 AU vs Month 36: 3.3 ± 4.3 AU, p=0.01) and mean fluorescence intensity of BAFF-R in non-autoreactive (Day 0: 3232 vs Month 36: 1527, mean difference: 1705, 95%CI: 624 to 2786; p=0.002) as well as on reappearing autoreactive DSG-specific B cells (Day 0: 3873 vs Month 36: 2688, mean difference: 1185, 95%CI: -380 to 2750; p=0.20). Starting high doses of corticosteroids allowed a transitory decrease of serum BAFF levels that re-increased after doses tapering whereas it did not modify BAFF-R expression in autoreactive and non-autoreactive B cells. Our results suggest that the activation of autoreactive B cells at the onset of pemphigus is likely to be related to the presence of high BAFF serum levels and that the decreased BAFF-R expression after rituximab might be responsible for the delayed generation of memory B cells, resulting in a rather long period of mild pemphigus activity after rituximab therapy. Conversely, the incomplete B cell depletion and persistent BAFF-R expression associated with high BAFF serum levels might explain the high number of relapses in patients treated with CS alone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hébert, Maho-Vaillant, Golinski, Petit, Riou, Boyer, Musette, Calbo and Joly.)

Using the recombinant second fragment of the extracellular domain (EC2) of human desmoglein type 3 (Dsg3) as an affinity ligand, an immunosorbent was obtained that selectively binds autoreactive antibodies to this domain from the immune sera of patients with pemphigus. The EC2 protein was obtained in the form of a fusion protein with the Fc-fragment of human IgG1. The production was carried out in CHO cells using the method of transient expression.

Pemphigus Vulgaris (PV) is a life-threatening autoimmune disease manifested with blisters in the skin and mucosa and caused by autoantibodies against adhesion protein desmoglein-3 (Dsg3) expressed in epithelial membrane linings of these tissues. Despite many studies, the pathogenesis of PV remains incompletely understood. Recently we have shown Dsg3 plays a role in regulating the yes-associated protein (YAP), a co-transcription factor and mechanical sensor, and constraining reactive oxygen species (ROS). This study investigated the effect of PV sera as well as the anti-Dsg3 antibody AK23 on these molecules. We detected elevated YAP steady-state protein levels in PV cells surrounding blisters and perilesional regions and in keratinocytes treated with PV sera and AK23 with concomitant transient ROS overproduction. Cells treated with hydrogen peroxide also exhibited augmented nuclear YAP accompanied by reduction of Dsg3 and α-catenin, a negative regulator of YAP. As expected, transfection of α-catenin-GFP plasmid rendered YAP export from the nucleus evoked by hydrogen peroxide. In addition, suppression of total YAP was observed in hydrogen peroxide treated cells exposed to antioxidants with enhanced cell-cell adhesion being confirmed by decreased fragmentation in the dispase assay compared to hydrogen peroxide treatment alone. On the other hand, the expression of exogenous YAP disrupted intercellular junction assembly. In contrast, YAP depletion resulted in an inverse effect with augmented expression of junction assembly proteins, including Dsg3 and α-catenin capable of abolishing the effect of AK23 on Dsg3 expression. Finally, inhibition of other kinase pathways, including p38MAPK, also demonstrated suppression of YAP induced by hydrogen peroxide. Furthermore, antioxidant treatment of keratinocytes suppressed PV sera-induced total YAP accumulation. In conclusion, this study suggests that oxidative stress coupled with YAP dysregulation attributes to PV blistering, implying antioxidants may be beneficial in the treatment of PV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Jedličková, Cai, Rehman, Gammon, Ahmad, Uttagomol, Parkinson, Fortune and Wan.)

Background: Pemphigus is a rare but life-threatening autoimmune skin disease characterized by blistering on skin and/or mucous membranes. The physiological process of blister formation involves IgG antibodies against the desmogleins (Dsgs) and desmocollins (Dscs). Additional autoAbs have also been suggested to mediate the disease heterogeneity, such as anti-thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies, the essential culprits of the immune system in autoimmune thyroid diseases., Purpose: To investigate the levels and antibody positivity of anti-TPO and anti-Tg antibodies in pemphigus patients., Methods: Antibody positivity and levels of anti-TPO and anti-Tg antibodies in pemphigus patients as compared to healthy controls were examined. A meta-analysis was conducted by reviewing six similar studies., Results: 98 Chinese pemphigus patients and 65 healthy controls were enrolled in the study. Our meta-analysis revealed a significant correlation between increased presence of positive anti-TPO and anti-Tg antibodies and pemphigus, particularly for pemphigus vulgaris (PV). Such correlation was also observed in our own hospitalized PV patients, but not in pemphigus foliaceus (PF) patients. In addition, the status of anti-TPO and anti-Tg antibodies were also compared between females and males within PV patients, PF patients or controls, as well as compared for females or males between pemphigus patients and controls. In the analysis of T cell counts, we found abnormal low CD3 + T cell counts (< 690 n/µl) were only detected in patients whose thyroid antibody levels were less than 20 IU/ml., Conclusion: Pemphigus patients showed higher levels and antibody positivity of anti-TPO and anti-Tg antibodies than healthy controls. Further investigations are needed to identify the pathogenic functions of these antibodies in pemphigus, as well as to identify the potential shared susceptibility genes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Yang, Hu, Zhang, Cai, Guo, Xiao, Chen, Gao and Qiao.)

Background: Emerging evidence indicates that several hematological markers can be used to evaluate treatment response, prediction, and early relapse detection in different inflammatory conditions. This study aimed to investigate the correlation between the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, platelet-to-neutrophil ratio, mean platelet volume, and disease activity in patients with pemphigus vulgaris., Methods: Fifty-six patients (20 men, 36 women; mean age 54 ± 14 years) diagnosed with pemphigus vulgaris were included in this retrospective study. Patients were divided into those treated and not treated with rituximab (groups 1 and 2), and into those who did and did not develop relapse (groups 3 and 4). The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, platelet-to-neutrophil ratio and mean platelet volume were evaluated at the time of diagnosis, remission, and relapse. The relationship between each marker and disease stage was analyzed using the Wilcoxon rank-sum test for pairwise comparisons., Results: The neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio showed a positive correlation with disease activity, while the platelet-to-neutrophil ratio and mean platelet volume showed a negative correlation. The neutrophil-to-lymphocyte ratio significantly decreased in remission (p < 0.001) and significantly increased in relapse (p < 0.01). The platelet-to-lymphocyte ratio significantly decreased in remission (p < 0.001) and showed no significant change in relapse. The platelet-to-neutrophil ratio significantly increased in remission (p < 0.001) and significantly decreased at relapse (p < 0.001). The mean platelet volume significantly increased in remission (p < 0.001) and decreased non-significantly at relapse. A more significant decrease in the neutrophil-to-lymphocyte ratio in remission was found in patients not treated with rituximab. No significant differences were observed between patients who developed relapse and those who did not., Conclusion: Our results suggest that the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, platelet-to-neutrophil ratio, and mean platelet volume can be useful markers for monitoring treatment response, while the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio can also assist in detecting early relapse., (© 2021 S. Karger AG, Basel.)

Background: Pemphigus is an autoimmune disease of the skin and mucous membranes. Glucocorticoids have been the most effective drug for the treatment of pemphigus; however, some patients are insensitive to glucocorticoid therapy. Cyclophosphamide has been extensively used in the treatment of pemphigus., Objectives: To observe and evaluate the efficacy and safety of high-dose glucocorticoid with weekly intravenous cyclophosphamide in the treatment of refractory pemphigus vulgaris insensitive to glucocorticoids., Methods: Clinical data of 19 patients with refractory pemphigus vulgaris (insensitive to glucocorticoid) who were treated with high-dose glucocorticoids(1.5 mg/kg/day prednisone) and weekly intravenous infusion of cyclophosphamide, and 24 patients who were sensitive to glucocorticoid therapy received a medium dose of glucocorticoid alone (1 mg/kg/day prednisone) were retrospectively analyzed., Results: By the time the disease was brought under control, the average total dose of cyclophosphamide was 2.02 g. Comparison between the glucocorticoid-insensitive and glucocorticoid-sensitive groups showed that the average time to disease control was 2.68 vs. 2 weeks, and the average daily dosage of steroid was 1.33 ± 0.53 vs. 0.90 ± 0.28 mg/kg. At the 12- and 18-month follow-ups, the recurrence rate of the glucocorticoid-insensitive group was significantly lower than that of the sensitive group (5.3 vs. 37.5%, 15.8 vs. 45.8%). No serious adverse reactions were observed., Conclusion: High-dose glucocorticoid plus weekly intravenous infusion of cyclophosphamide safely, effectively, and rapidly controlled the conditions of the patients with refractory pemphigus who were insensitive to glucocorticoids, shortened the duration of hospitalization, avoided the risk of complications that could be caused by further increasing the dose of glucocorticoids (>1.5 mg/kg/day), and lowered the recurrence rate within 18 months., (© 2020 S. Karger AG, Basel.)

Background: Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune bullous disease affecting the skin and mucous membranes. Its pathogenic mechanism is still not fully understood. Regulatory T cells (Tregs) have been reported to play a significant role in regulating immune homeostasis in autoimmune disorders, such as PV., Aim: To investigate the potential role of Tregs in the immunopathogenesis of PV., Methods: We enrolled 15 patients with PV and 15 healthy controls (HCs). Peripheral blood samples were collected from all participants before treatment. This was followed by flow cytometric, real-time reverse transcription PCR, and in vitro inhibition-based functional assays to explore the immunopathogenesis of Tregs in PV., Results: Our results showed no statistically significant differences in total CD4+CD25+ cells and CD4+CD25 high cells. In addition, expression levels of FOXP3 mRNA and the corresponding FOXP3 protein remained unchanged in the patients with PV and the HCs. However, the in vitro suppressive activity of CD4+CD25+ T cells was impaired in patients with PV compared with HCs., Conclusions: Our observations suggest that inhibition of suppressive activity of Treg cells may be involved in the pathogenesis of PV., (© 2020 British Association of Dermatologists.)

Background: The current standard in the serologic diagnosis of autoimmune bullous diseases (AIBD) is a multistep procedure sequentially applying different assays. In contrast, the BIOCHIP Mosaic technology combines multiple substrates for parallel analysis by indirect immunofluorescence., Methods: Sera from 749 consecutive, prospectively recruited patients with direct immunofluorescence-positive AIBD from 13 international study centers were analyzed independently and blinded by using (1) a BIOCHIP Mosaic including primate esophagus, salt-split skin, rat bladder, monkey liver, monkey liver with serosa, recombinant BP180 NC16A, and gliadin GAF3X, as well as HEK293 cells expressing recombinant desmoglein 1, desmoglein 3, type VII collagen, and BP230 C-terminus and (2) the conventional multistep approach of the Department of Dermatology, University of Lübeck., Results: In 731 of 749 sera (97.6%), specific autoantibodies could be detected with the BIOCHIP Mosaic, similar to the conventional procedure (725 cases, 96.8%). The Cohen κ for both serologic approaches ranged from 0.84 to 1.00. In 6.5% of sera, differences between the 2 approaches occurred and were mainly attributed to autoantigen fragments not present on the BIOCHIP Mosaic., Limitations: Laminin 332 and laminin γ1 are not represented on the BIOCHIP Mosaic., Conclusions: The BIOCHIP Mosaic is a standardized time- and serum-saving approach that further facilitates the serologic diagnosis of AIBD., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Pemphigus is a potentially fatal disease if left untreated. Valid scoring systems and defined cut-off values for classification of patients would help with better management through specified pharmaceutical and non-pharmaceutical treatments., Methods: In this study, pemphigus patients who were receiving immunosuppressive treatments and had recent disease relapse were recruited for examination of pemphigus disease area index(PDAI), autoimmune bullous skin disorder intensity score (ABSIS), physician global assessment (PGA), autoimmune bullous disease quality of life (ABQoL), anti-desmoglein 1 (anti-Dsg1), and anti-Dsg3 autoantibody titers from December-2017 to February-2018. Cut-off values were estimated using model-based clustering classification and the 25th and 75th percentiles approach, performed separately for the exclusive cutaneous, exclusive mucosal, and mucocutaneous groups., Results: In the 109 included patients, the 25th and 75th percentiles cut-offs were 6.2 and 27 for PDAI score, and 4 and 29.5 for ABSIS score. The model-based analysis resulted in two groups (cut-point:15) for PDAI score, and three groups (cut-points:6.4 and 31.5) for ABSIS score. The groups were significantly different for the PDAI, ABSIS, PGA, and ABQoL values. Based on anti-Dsg1 autoantibody values, the model-based analysis cut-point was 128 and the 25th and 75th percentiles cut-offs were 98 and 182. Anti-Dsg3 autoantibody values did not differentiate between pemphigus severity classes., Conclusions: Estimated cut-off values based on the anti-Dsg1 level, PDAI, and ABSIS scoring systems could be used to classify patients into different severity grades for better management and prognosis.

Although T cells are considered as the central component in immune-mediated diseases, supportive evidence has demonstrated that B cells also contribute to the progression of these diseases. B cells are divided into various subsets according to their secreted cytokines. Different B cell subsets play diverse roles in immune-mediated dermatoses. Regulatory B cells (Bregs) are defined functionally by their ability to secrete IL-10, which has been revealed to contribute to immunological tolerance. Drugs that deplete B cells, such as rituximab, are now used for the treatment of several immune-mediated dermatoses. In this review, we present and discuss the current knowledge on the roles of B cells in several immune-mediate dermatoses including psoriasis, pemphigus, bullous pemphigoid, and dermatomyositis, atopic dermatitis., (Copyright © 2020. Published by Elsevier Ltd.)

Pemphigus vulgaris (PV) is a life-threatening, autoimmune blistering disease affecting the skin and mucous membranes, exerting a detrimental effect on the quality of life (QOL). Our aim was to evaluate the psychological status and QOL of patients with PV and investigate Interleukin-6 (IL-6) as a possible contributor to the pathogenesis of pemphigus and associated depression. The study included 22 patients with PV, 21 patients with depression, and 20 normal controls. All the 63 participants were subjected to assessment of their QOL, psychiatric profile, as well as estimation of serum level of IL-6. All (100%) of the included patients with PV had a negative effect on their QOL, which was significant compared with controls (P<0.001). Among patients with PV, 13 patients (59.1%) had depression. IL-6 was non-significantly elevated in the pemphigus group when compared with the controls (P=0.057). QOL was significantly worse in the depressed pemphigus subgroup compared with the non-depressed pemphigus subgroup (P=0.006 and <0.001) respectively. However, IL-6 was non-significantly elevated in the depressed pemphigus subgroup compared with the non-depressed pemphigus subgroup (P=0.095). A marked deterioration in the QOL was observed in patients with pemphigus. More than 50%, but not all, of patients with pemphigus had depression. IL-6 was non-significantly elevated in patients with pemphigus.

Pemphigus vulgaris (PV) is a regulatory T cell (Treg)-associated autoimmune disease. Treg cells maintain immunosuppression by expressing the signature transcription factor FOXP3. MicroRNAs (miRNAs) have frequently emerged as regulators in Treg-mediated immunosuppression. We previously found that miR-338-3p was overexpressed in the peripheral blood mononuclear cells of patients with PV. Herein, we explored the role of miR-338-3p in Treg-mediated immunosuppression by quantitative real-time polymerase chain reaction, analysis of public microarray data, miRNA transfection, Western blotting, flow cytometry, and luciferase reporter assays. Increased expression of miR-338-3p was detected in CD4+ T cells of active PV patients compared with those in healthy controls. Moreover, the miR-338-3p level was positively related to disease severity. Bioinformatics prediction revealed that Runt-related transcription factor 1 (RUNX1), a gene activating FOXP3 expression, was a putative target of miR-338-3p. There was a reduction of FOXP3 and RUNX1 expression in the CD4+ T cells of patients with PV, along with significant correlations with the level of miR-338-3p. MiRNA transfection, mRNA and protein analysis, and luciferase reporter assays verified that miR-338-3p attenuated FOXP3 expression by targeting RUNX1. This study suggests that excessive expression of miR-338-3p attenuates the expression of FOXP3 by targeting RUNX1, contributing to Treg dysfunction in PV., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Paraneoplastic pemphigus (PNP) is a devastating autoimmune multiorgan syndrome associated with autoantibodies against several autoantigens, including the alpha-2-macroglobulin-like-1 (A2ML1). A2ML1 is recognized by up to 70 % of PNP sera. The currently recommended techniques for serological diagnosis of PNP are inadequate to detect anti-A2ML1 antibodies., Objectives: To develop novel assays which allow to easily and reliably detect anti-A2ML1 autoantibodies in PNP sera., Methods: We produced full-length A2ML1 in fusion with enhanced green fluorescent protein (EGFP-A2ML1) in transfected human embryonic kidney 293 T cells. The recombinant protein was used as fluorescent ligand for immunoprecipitation studies. We further developed an enzyme-linked immunosorbent assay (ELISA) by immobilizing EGFP-A2ML1 on 96-well plates., Results: A2ML1-positive PNP sera were able to immunoprecipitate EGFP-A2ML1. Direct measurement of fluorescence in immunoprecipitates correlates with the relative levels of anti-A2ML1 antibodies in the PNP sera. By the novel ELISA, based on the determined best cut-off value, 61 % of the tested 36 PNP sera were A2ML1 positive with a specificity of 88.9 % and a sensitivity of 95 %. The 20 tested normal sera (NHS) were negative, while 2 (10 %) of 20 pemphigus vulgaris and 3 (15 %) of 20 bullous pemphigoid sera showed borderline values., Conclusions: Our novel immunoassays enable rapid stratification of PNP patients. The novel green fluorescent protein-based ELISA utilizing an active eukaryotic A2ML1 is highly sensitive and reliable and, hence, is useful for a better understanding of the immunological background of PNP. This approach may be easily applied for the rapid detection of antibodies to various other antigens., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Anti-desmoglein (anti-Dsg) antibodies are key players in the pathogenesis of pemphigus vulgaris (PV) disease. We aimed to evaluate the pathogenicity of anti-Dsg antibodies of PV patients using human organ culture assay and to assess the correlation between the pathogenicity and the disease score. In this cross-sectional study, sera from 37 PV patients were included. The organ culture acantholysis index (OCAI) was calculated as (width of blister/total width of the specimen) × 100. The sera were analyzed using Dsg ELISAs and ethylenediaminetetraacetic acid (EDTA) treated ELISAs. OCAI ranged from 0 to 100%, median = 50%. There was a moderate significant correlation between OCAI and the disease severity, r = 0.503, p = 0.002. There was a moderate significant correlation between OCAI and non-Ca 2+ -dependent anti-Dsg3 and anti-Dsg1 antibodies, p values were 0.01 and 0.021, respectively. The OCAI was assessed along the disease time course of four patients. The OCAI fluctuated parallel to the disease severity along the time course of the four patients. Human organ culture assay is an objective tool that detects the pathogenicity of anti-desmoglein antibodies. It can be used before stopping systemic steroids especially in patients in remission with high titer or if the Dsg ELISA is not available.

Background: Pemphigus vulgaris is a potentially fatal autoimmune epidermal blistering disease with a chronic and relapsing course. It is difficult to predict clinical relapse. Identification of clinical and immunological factors that are associated with early clinical relapse in a prospective study design may help in planning treatment for better maintenance of clinical remission., Aim: The aim of our study was to identify clinical and immunological factors associated with clinical relapse within 9 months of study inclusion in patients with pemphigus vulgaris in clinical remission., Methods: Forty consecutive consenting patients who had been diagnosed to have pemphigus vulgaris and were in clinical remission on minimal therapy or off therapy were included. The patients were followed up every 3 months until 9 months. Clinical factors considered relevant were recorded at the beginning of the study. Immunological factors such as CD19+ B-cell count and CD19+CD27+ memory B cells/plasma cell count in peripheral blood were assessed at baseline [anti-desmoglein (Dsg) 1 and 3 titers were first assessed at 3 months, not at baseline] and repeated every 3 months, until 9 months or clinical relapse whichever was earlier. Direct immunofluorescence (DIF) of skin biopsy specimen was performed at study initiation and again at the time of clinical relapse or study completion, whichever occurred earlier. All patients completed the study., Results: Of 40 patients, 11 (27.5%) experienced relapse as per definition, while 29 (72.5%) remained in complete remission. Clinical relapse during study duration was significantly more common in those who had onset of disease in oral mucosa [odds ratio (OR), 10.71; 95% confidence interval (CI) 1.21-94.86, P = 0.02], pruritus (OR 8.4; 95% CI 1.76-40.02, P = 0.01), and extensive cutaneous involvement during previous disease activity (OR 7.36; 95% CI 1.34-40.55, P = 0.03) and also pruritus during remission (P = 0.004). Immunological factors found to be significantly associated with early clinical relapse were raised CD19+ B-cell count at baseline (OR 7.84; 95% CI 1.39 - 53.41, P = 0.01), immunoglobulin G (OR 4.85; 95% CI 1.09-23.44, P = 0.04), and C3 (OR 20.33; 95% CI 3.02-199.5, P < 0.001) positivity in the intercellular space of the epidermis on DIF at study onset and rising anti-Dsg 3 antibody titers (OR 19.96; 95% CI 1.85- 310.9, P = 0.03)., Limitations: Limited sample size, short follow-up duration, and inability to perform anti-Dsg enzyme linked immunosorbent assay for all the patients at all the time points of assessment are limitations of this study., Conclusion: Immunological relapse can be determined before clinical relapse, so that treatment can be restarted/modified and clinical remission can be maintained., Competing Interests: None

Pemphigus vulgaris (PV) is a chronic autoimmune disorder with potentially fatal outcomes. The aim of this study was to investigate the effect of l-carnitine (LC) on secreted frizzled-related protein-5 (SFRP5), omentin, visfatin, and glycemic indices in PV patients under corticosteroid treatment. In this randomized, double-blind, placebo-controlled clinical trial, 52 patients with PV were divided randomly into two groups to receive 2 g of LC or a placebo for 8 weeks. Serum levels of SFRP5, omentin, visfatin, and also glycemic indices were evaluated at the baseline and end of the study. LC supplementation significantly decreased the serum level of visfatin (95% CI [-14.718, -0.877], p = .05) and increased the serum levels of SFRP5 (95%CI [1.637, 11.380], p < .006) and omentin (95% CI [9.014, 65.286], p < .01). However, LC supplementation had no significant effects on the serum levels of glycemic factors such as insulin (95% CI [-1.125, 3.056], p = .426), fasting blood sugar (95% CI [-4.743, 3.642], p = .894), homeostatic model assessment of insulin resistance (95% CI [-0.305, 0.528], p = .729), and quantitative insulin-sensitivity check index (95% CI [-0.016, -0.010], p = .81). LC supplementation decreased visfatin serum level and increased omentin-1 and SFRP5 serum levels in patients with PV. However, it has no significant effect on the serum levels of insulin and glycemic indices., (© 2019 John Wiley & Sons, Ltd.)

Autoimmune blistering dermatoses (ABDs) are characterized by autoantibodies to keratinocyte surface antigens and molecules within the dermal-epidermal junction causing disruption of skin integrity. The affinity of Fc receptors (FcRs) causing an autoimmune response in ABDs may vary based on single-nucleotide polymorphisms (SNPs) in FcRs determining the course of disease. This study aimed to explore the effects of CD16A and CD32A SNPs on the autoimmune response in several ABDs. In total, 61 ABDs patients were investigated. ELISA tests, direct immunofluorescence (DIF), TaqMan SNP Genotyping Assays, and statistical analyses were performed. The CA genotype (composed of allele C and A) of rs396991 in CD16A had a higher affinity for tissue-bound IgG1 in pemphigus and for C3 in subepithelial ABDs, showing statistical significance. The greatest relative risk (odds ratio) was reported for AA (rs396991 of CD16A ) and CC (rs1801274 of CD32A ) homozygotes. There were no statistically significant differences between certain genotypes and specific circulating autoantibodies (anti-DSG1, anti-DSG3 IgG in pemphigus; anti-BP180, anti-BP230 IgG) in subepithelial ABDs. Our findings indicated that rs396991 in CD16A may be of greater importance in ABDs development. Moreover, FcR polymorphisms appeared to have a greater impact on tissue-bound antibodies detected using DIF than circulating serum antibodies in ABDs.

Background: Red blood cell distribution width (RDW) has recently emerged as an inflammatory marker in several inflammatory diseases but has not been investigated in patients with pemphigus., Objective: We aimed to examine RDW percentage in patients with pemphigus relative to control subjects and to assess the association between this biomarker and the morphological characteristics of the disease., Methods: This case-control study included 183 pemphigus patients and 915 age- and sex-matched control subjects. RDW, hemoglobin, and mean corpuscular volume (MCV) were measured for all study participants., Results: The RDW was significantly higher in patients with pemphigus than in controls (13.7±1.3 vs. 13.4±1.1%, respectively; P =0.001). A significant association between RDW and pemphigus was demonstrated in multivariate analysis (odds ratio, 1.22; 95% confidence interval, 1.01-1.46; P =0.036). The RDW was higher in patients with pemphigus vulgaris (PV) than in pemphigus foliaceus (PF; P =0.043), and in those with mucocutaneous PV relative to those with mucosal only and cutaneous only PV. The RDW increased significantly following treatment ( P <0.001)., Conclusion: Pemphigus patients demonstrated elevated RDW as compared with healthy controls. RDW may be a feasible biomarker in patients with pemphigus. Although it clearly does not replace any of the accepted diagnostic immunopathological criteria, increased RDW may be more suggestive of PV than PF, and of mucocutaneous rather than cutaneous PV. The remarkable increase following treatment may be ascribed to the corticosteroid-induced erythropoiesis., (© 2020 by the Association of Clinical Scientists, Inc.)

Pemphigus is an organ-specific autoimmune disease that targets skin and/or mucous membranes. Our previous study showed that infiltrating lymphocytes in pemphigus vulgaris (PV) lesions produce anti-desmoglein (Dsg) 1/3 antibodies after in vitro culture. In this study, we found diffuse ectopic lymphoid-like structures (ELSs) commonly present in the lesions of both PV and pemphigus foliaceus. Notably, pemphigus lesions contained centroblasts, plasmablasts, and plasma cells, which recapitulated the different stages of B cell differentiation. Elevated mRNA expression levels of the differentiation-related transcription factors BLIMP-1, IRF4, and BCL-6 were observed in pemphigus lesions. Moreover, B cell receptor repertoire analysis revealed the clonal expansion of the lesional B cells. Lesional B cells might recirculate among lesions, lymph nodes, and peripheral blood. Increased mRNA expression levels of multiple chemokines in pemphigus lesions and elevated expression levels of chemokine receptors on lesional B cells were also observed. Collectively, these results show that the ELSs in pemphigus lesions might act as a niche, supporting in situ B cell differentiation and clonal expansion., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

A male neonate was born with blisters on the trunk to a 37-year-old primigravid woman with a past medical history of recurrent, painful, topical steroid-responsive oral blisters. The diagnosis of neonatal pemphigus was made after the neonate and mother were found to have elevated desmoglein 3 (Dsg3) antibodies in conjunction with histopathologic features of pemphigus vulgaris. Interestingly, both neonate and mother also had elevated levels of BP180 antibodies, classically seen in bullous pemphigoid. This case is unique in that it portrays neonatal pemphigus, an already rare condition, complicated by the presence of BP180 antibodies., (© 2019 Wiley Periodicals, Inc.)

Pemphigus foliaceus is an autoimmune disease that is sporadic around the world but endemic in Brazil, where it is known as fogo selvagem (FS). Characterized by autoantibodies against the desmosomal cadherin desmoglein 1, FS causes painful erosions, and crusts that may be widespread. The recognition of antigens, including exposed sugar moieties, activates the complement system. Complement receptor 1 (CR1, CD35), which is responsible for the Knops blood group on erythrocytes (York and McCoy antigens), is also expressed by antigen-presenting cells. This regulates the complement system by removing opsonized antigens, blocking the final steps of the complement cascade. Membrane-bound CR1 also fosters antigen presentation to B cells, whereas soluble CR1 has anti-inflammatory properties. CR1 gene polymorphisms have been associated with susceptibility to complex diseases. In order to investigate the association of CR1 polymorphisms with FS susceptibility, we developed a multiplex sequence-specific assay to haplotype eleven polymorphisms in up to 367 FS patients and 242 controls from an endemic area and 289 from a non-endemic area. We also measured soluble CR1 (sCR1) in the serum of 53 FS patients and 27 controls and mRNA levels in the peripheral blood mononuclear cells of 63 genotyped controls. The haplotypes CR1 * 3B2B (with the York antigen-encoded by p.1408Met) and CR1 * 3A2A (with p.1208Arg) were associated with protection against FS (OR = 0.57, P = 0.027, and OR = 0.46, P = 0.014, respectively). In contrast, the CR1 * 1 haplotype (with the McCoy antigen - encoded by p.1590Glu) was associated with FS susceptibility (OR = 4.97, P < 0.001). Heterozygote rs12034383 * A/G individuals presented higher mRNA expression than homozygotes with the G allele ( P = 0.04). The lowest sCR1 levels occurred in patients with active disease before treatment ( P = 0.036). Patients in remission had higher levels of sCR1 than did healthy controls ( P = 0.013). Among those under treatment, patients with localized lesions also presented higher sCR1 levels than those with generalized lesions ( P = 0.0073). In conclusion, the Knops blood group seems to modulate susceptibility to the disease. Furthermore, corticosteroid treatment might increase sCR1 serum levels, and higher levels may play an anti-inflammatory role in patients with FS, limiting the distribution of lesions. Based on these results, we suggest CR1 as a potential new therapeutic target for the treatment of FS., (Copyright © 2019 Oliveira, Kretzschmar, dos Santos, Camargo, Nisihara, Farias, Franke, Wittig, Schmidt, Busch, Petzl-Erler and Boldt.)

Desmoglein-3 (Dsg3), the Pemphigus Vulgaris (PV) antigen (PVA), plays an essential role in keratinocyte cell-cell adhesion and regulates various signaling pathways involved in the progression and metastasis of cancer where it is upregulated. We show here that expression of Dsg3 impacts on the expression and function of p53, a key transcription factor governing the responses to cellular stress. Dsg3 depletion increased p53 expression and activity, an effect enhanced by treating cells with UVB, mechanical stress and genotoxic drugs, whilst increased Dsg3 expression resulted in the opposite effects. Such a pathway in the negative regulation of p53 by Dsg3 was Dsg3 specific since neither E-cadherin nor desmoplakin knockdown caused similar effects. Analysis of Dsg3 -/- mouse skin also indicated an increase of p53/p21 WAF1/CIP1 and cleaved caspase-3 relative to Dsg3 +/- controls. Finally, we evaluated whether this pathway was operational in the autoimmune disease PV in which Dsg3 serves as a major antigen involved in blistering pathogenesis. We uncovered increased p53 with diffuse cytoplasmic and/or nuclear staining in the oral mucosa of patients, including cells surrounding blisters and the pre-lesional regions. This finding was verified by in vitro studies where treatment of keratinocytes with PV sera, as well as a characterized pathogenic antibody specifically targeting Dsg3, evoked pronounced p53 expression and activity accompanied by disruption of cell-cell adhesion. Collectively, our findings suggest a novel role for Dsg3 as an anti-stress protein, via suppression of p53 function, and this pathway is disrupted in PV.

The role of interleukin-17 (IL-17) in pemphigoid diseases is not fully understood. Both pemphigus vulgaris (PV) as well as pemphigus foliaceus (PF) show intralesional IL-17 positive cells. A patient with initially assumed coexisting PF and psoriasis pustulosa (PP) was treated with the anti-IL-17 antibody secukinumab. The clinical skin picture markedly improved and the level of anti-desmoglein-1 antibodies clearly decreased; however, with the prolongation of injection intervals of secukinumab, autoantibody levels started to rise again. A dose-dependent effect of secukinumab on autoantibody production in PF is suspected. Retrospectively, a neutrophilic PF can be discussed in the present case, where almost complete healing was achieved under IL-17 blockade treatment.

Background: Pemphigus vulgaris (PV) is a life-threatening autoimmune disease with no certain treatment. Anticytokine therapy is being increasingly discussed in multiple autoimmune diseases. Osteopontin (OPN) is a glycoprotein produced by a variety of immune cells. Increased OPN serum levels have been reported in several autoimmune diseases, with targeting OPN considered as a promising therapy in these diseases. However, the role of OPN in PV has not been well studied so far., Objective: To investigate whether OPN level is elevated in PV patients in the active stage of the disease and to examine its possible relationship with disease severity and anti-desmoglein (anti-Dsg) antibodies levels., Materials and Methods: This study included 53 consecutive subjects affected by PV and 38 age- and sex-matched healthy controls. Clinical characteristics and Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) were assessed. Serum OPN levels (pg/mL) and anti-Dsg antibodies were also measured., Results: The serum OPN level of the patient group proved to be statistically higher than that of the control group (11.08 ± 5.24 vs 8.47 ± 5.68; p = .02). No significant relationship were detected between the serum OPN level and anti-Dsg1 or anti-Dsg3 antibodies (r = 0.1, p = .2 and r = 0.1, p = .4), respectively. In addition, no correlation was found between serum OPN levels and severity of PV as measured by ABSIS (r = 0.08 and p = .5)., Conclusion: The growth observed in OPN levels in pemphigus patients suggests the role of OPN in pemphigus pathogenesis, but there is a need for more extensive studies to show how OPN can be associated with the PV pathogenesis and whether OPN could be used as an important therapeutic target in pemphigus disease., (© 2019 Wiley Periodicals, Inc.)

Background: More than half of patients with pemphigus experience relapse during the disease course. The risk factors and clinical and immunological characteristics of relapse remain largely unclear., Objectives: To elucidate the risk factors and clinical features of pemphigus relapse., Methods: We carried out a retrospective review of the clinical records of 42 cases of pemphigus at a single centre., Results: Sixty-two per cent of patients experienced relapse, usually when oral prednisolone was tapered to around 0·1 mg kg -1 . In mucocutaneous pemphigus vulgaris (mcPV), the initial doses (mean ± SD) of prednisolone were significantly lower in patients with relapse (0·78 ± 0·24 mg kg -1 ) than in those without relapse (1·01 ± 0·01 mg kg -1 ). At relapse, mcPV shifted to mucosal dominant PV (mPV; 40%), pemphigus foliaceus (PF) (20%) or 'other' (20%). In contrast, relapsing mPV and PF had the same clinical phenotypes as the initial phenotypes. Patients with both anti-desmoglein (Dsg)1 and anti-Dsg3 antibodies at onset had recurrence with anti-Dsg3 antibodies alone (40%), with both anti-Dsg1 and anti-Dsg3 antibodies (30%), with anti-Dsg1 antibody alone (20%) or were subthreshold (10%)., Conclusions: mcPV shows transitions in clinical phenotype and autoantibody profile at relapse. At least 1 mg kg -1 daily of prednisolone, especially for patients with mcPV, and prudent tapering around 0·1 mg kg -1 may lead to better outcomes., (© 2018 British Association of Dermatologists.)