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Following vaccination, 8/9 pemphigus patients and 4/4 BP patients showed a rapid increase in IgG levels against the SARS-CoV-2 spike protein antigen (Figure 1d). 1 TABLE Demographics, clinical stages and treatments of patients with pemphigus or bullous pemphigoid (BP), who received mRNA booster vaccinations against SARS-CoV-2. There is scepticism toward mRNA vaccines due to the growing number of reports linking SARS-CoV-2 mRNA vaccinations with the onset or relapse of inflammatory/autoimmune diseases such as pemphigus and bullous pemphigoid (BP).[[1]] However, there is a lack of immunological studies assessing the safety of these vaccines in these patient cohorts, since phase 3 studies with BNT162b2 or mRNA-1273 did not include patients with autoimmune or inflammatory disorders.[[3]] Clinical observation from daily practice shows that although some individuals may experience disease onset or relapse, most patients with pemphigus or BP who receive mRNA-based SARS-CoV-2 vaccines do not experience disease flares.[5] Prospective clinical and immunological data for these two patient populations on safety and efficacy of mRNA-based SARS-CoV-2 booster vaccinations are scarce. [Extracted from the article]

However, in contrast to spontaneous LP, expression of IL-12B and IL-24 was suppressed in our patient's LP lesion, which developed during anti-IL-17A blockade. Paradoxical lichen planus induced during anti-IL-17A treatment is immunologically different from spontaneously occurring lichen planus IL-17A expression is typically found in PSO skin, but not in LP skin.6,7 In agreement with other reports, the secukinumab-resistant PSO plaque showed a high expression of IL-17A.8,9 The patient's paradoxical LP lesion did not show any IL-17A expression. [Extracted from the article]

Development of severe pemphigus vulgaris following SARS-CoV-2 vaccination with BNT162b2 In patients vaccinated with BNT162b1, specific antibodies appear 14-21 days later.3 It is very likely that in our patient the vaccination with BNT162b2 boosted her T/B cell response that resulted in the unwanted onset of pemphigus. The patients in this manuscript have given written informed consent to the publication of their case details. [Extracted from the article]

Background: Anti‐laminin‐γ1 (lam‐γ1) pemphigoid, a recently described immunobullous disorder sharing immune serological features of bullous pemphigoid and epidermolysis bullosa acquisita (EBA), is characterized by the detection of serum IgG autoantibodies against the lam‐γ1 chain, a 200 kDa heterotrimeric component of the dermal‐epidermal junction (DEJ). Objective: The aim of the study was to develop an easy‐to‐perform and reliable assay for the serological detection of anti‐lam‐γ1 IgG autoantibodies. The clinical appearance alone is not sufficient to establish diagnosis of anti‐lam‐γ1 pemphigoid and rather requires immune serological evidence of (i) IgG reactivity against the dermal portion of salt‐split human skin; (ii) exclusion of IgG against other components of the DEJ; and (iii) IgG reactivity with a 200 kDa protein of dermal extracts by immunoblot analysis (IB). Methods: The sera of 55 patients with anti‐lam‐γ1 pemphigoid were tested by IB with two recombinant heterotrimers, laminin 111 (lam‐111) and laminin 421 (lam‐421), as well as with a recombinant lam‐γ1 chain monomer. Additionally, a total of 41 control sera from patients with EBA (n = 15), psoriasis vulgaris (PV; n = 14), and healthy controls (HC; n = 12) were tested. Results: Immunoblot analysis revealed a positive reactivity with lam‐111 and/or lam‐421 in 46/55 (84%) of anti‐lam‐γ1 pemphigoid sera. Moreover, 8/9 of the initially non‐reactive sera were positive with the lam‐γ1 monomer, leading to an overall sensitivity of 98.2%. Analyses of 41 control sera with the three lam‐γ1 recombinants led to a specificity of 88%. Specifically, 3/15 EBA sera, 1/14 PV serum and 1/12 HC serum reacted with the lam‐γ1 monomer while only the 3 EBA sera reacted with lam‐421. Conclusions: Here we show a novel two‐step IB assay using the two recombinant laminin trimers and lam‐γ1 chain monomer for the detection of anti‐lam‐γ1 serum IgG with high sensitivity and specificity. This assay will facilitate the diagnosis and further characterization of this disease. Linked article: This article is commented on J. Yamagami et al., p. 632 in this issue. To view this article visit https://doi.org/10.1111/jdv.15555. [ABSTRACT FROM AUTHOR]

A 27-year-old Caucasian woman with Lafora epilepsy was admitted at our department with a 3-weeks history of skin lesions. GLO:3NZ/01feb20:jdv15899-fig-0002.jpg PHOTO (COLOR): Pathology of bromoderma: (a) acanthosis associated with mixed inflammatory dermal infiltrate and leucocytoclasia (H&E; 40×); (b) details of epidermal acanthosis (H&E; 200x); (c) details of leucocytoclastic perivasculitis (H&E; 200×). gl Potassium bromide was broadly used as an antiepileptic drug before the advent of phenobarbital.[[1]] However, bromides are still in use in cases of severe epilepsy refractory to treatment with other common antiepileptic drugs. [Extracted from the article]

Summary: Background: Epidermolysis bullosa acquisita (EBA) is a rare, potentially devastating autoimmune disease of the skin. IgG autoantibodies directed against type VII collagen (Col7), the major component of anchoring fibrils, induce skin fragility leading to cutaneous and mucocutaneous blister formation, which is mostly of a scarring phenotype. Thus, powerful and reproducible diagnostic assays are critical to establish the diagnosis of EBA early to avoid irreversible sequelae. Objectives: The present international, retrospective multicentre study included a large cohort of patients with EBA and evaluated the diagnostic power of four different diagnostic assays for the detection of anti‐Col7 IgG autoantibodies. Methods: Overall, 95 EBA sera and 200 control sera consisting of 100 bullous pemphigoid sera, 50 pemphigus vulgaris sera and 50 sera of healthy controls were tested for anti‐Col7 IgG autoantibodies using indirect immunofluorescence (IIF), two commercial enzyme‐linked immunosorbent assay (ELISA) systems and Western blot (WB) analysis. EBA sera were taken from patients with positive direct immunofluorescence and IgG reactivity in at least one of the immunoserological assays (IIF, ELISA, WB). Results: A Col7‐NC1/NC2 ELISA (MBL, Nagoya, Japan) showed the highest sensitivity (97·9%), followed by a Col7‐NC1 ELISA (Euroimmun, Lübeck, Germany) (89·5%), WB with Col7‐NC1 (85·3%), and IIF on saline‐split human skin (74·7%). The specificities of both ELISA systems were comparable (NC1 98·7%, NC1/NC2 99·3%). Furthermore, WB was more sensitive than IIF, which was more specific. Conclusions: The two commercially available ELISA systems allow for a highly sensitive and specific diagnosis of EBA. The sensitivity of the Col7‐NC1/NC2 ELISA is significantly higher compared with the ELISA based on the Col7‐NC1 domain only. [ABSTRACT FROM AUTHOR]

Cheilitis granulomatosa (CG) is a rare granulomatous disease of the lips, which has been first described in 1945 by Miescher, and can be associated with peripheral facial nerve palsy, lingua plicata, sarcoidosis, tuberculosis and inflammatory bowel disease.[1] The aetiology of CG is still not well understood, which also hampers treatment. The patient was treated with daily 40 mg oral prednisone that led to improvement but was accompanied by pronounced treatment-induced systemic side effects that occurred shortly after starting therapy. In conclusion, while successful treatment of CG can be very challenging, lenalidomide presents an interesting therapeutic option if other commonly applied drugs show no benefit or cannot be utilized due to unwanted side effects. [Extracted from the article]

The article discusses the study conducted to diagnose basal cell carcinoma (BCC) of the scrotum in the inhabitants of Germany. It examines the risk factors associated with BCC due to ultraviolet (UV) light on skin, various chemical agents, and histopathology of the patients. It offers information on the treatment of BCC.

Background and Objectives: Oral lichen planus (OLP) is a T cell driven disorder that significantly impairs patients' quality of life. Previous reports suggest that both cellular and humoral activities against desmoglein (dsg) 1 and 3 may be involved in OLP pathogenesis. Here, we aim to analyze the frequency of occurrence and pathological significance of anti-dsg antibodies in a large cohort of OLP patients., Materials and Methods: OLP patients were screened for anti-dsg antibodies by enzyme-linked immunosorbent assay in three tertiary referral centers. OLP sera with anti-dsg antibodies were further analyzed by Western blot and dispase-based keratinocyte dissociation assay (DDA) to identify the targeted dsg ectodomains and to assess their pathogenicity., Results: Of 151-screened individuals with OLP, only four patients (2.6%) with erosive OLP showed serum IgG against dsg1/3. Western blot analysis with recombinant dsg3 ectodomains revealed preferential recognition of the extracellular domain 5. By DDA with spontaneously immortalized human keratinocytes, none of the sera from these four patients induced acantholysis., Conclusions: Activation of humoral immunity occurs prevalently in patients with erosive OLP, probably due to epitope spreading. OLP serum antibodies are unable to induce loss of intercellular adhesion in vitro, strongly suggesting that they are not disease causing but rather an epiphenomenon., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Erosive oral lichen planus (OLP) is a challenging disease. This T cell driven disorder frequently shows a treatment unresponsive course and strongly limits patients' quality of life. The disease lacks FDA or EMA approved drugs for its treatment and the efficacy of the commonly administered treatments (i.e. topical and systemic steroids, steroid sparing agents) is often only partial. Although the etiopathogenesis of the disease still needs to be fully elucidated, recent advances helped to identify interferon-ɣ (IFN-ɣ) as a pivotal cytokine in OLP pathogenesis, thus making the interference with its signalling a therapeutic target. Janus kinase (JAK) inhibitors therefore gained relevance for their inhibitory effect on IFN-ɣ signalling. While some drugs such as abrocitinib, upadacitinib, tofacitinib directly interfere with IFN-ɣ signalling through blockade of JAK1 and/or JAK2, deucravacitinib, a selective TYK-2 inhibitor indirectly interferes on IFN-ɣ activation through interference with interleukin (IL)-12, a potent promotor for Th1/IFN-ɣ responses. This mechanism of action makes deucravacitinib a candidate drug for the treatment of OLP. Here we provide initial evidence that deucravacitinib 6 mg daily has a beneficial effect in three patients with oral OLP., (© 2024 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Free fatty acids (FFA) have gained research interest owing to their functions in both local and systemic immune regulation. Changes in the serum levels of anti-inflammatory short chain fatty acids (SCFA), primarily derived from the gut microbiota, and pro-inflammatory medium (MCFA) and long (LCFA) chain fatty acids, derived from either the gut microbiota or the diet, have been associated with autoimmunity. Circulating FFA were retrospectively analysed by a gas chromatography-mass spectrometry method in the serum of 18 patients with pemphigus vulgaris (PV) at the baseline and 6 months (n = 10) after immunosuppressive treatments, and 18 healthy controls (HC). Circulating FFA were correlated with the Pemphigus Disease Area Index (PDAI) and serum concentrations of interferon-gamma (IFN-γ), Interleukin (IL)-17A, IL-5, IL-10 and IL-21. Principal Component analysis computed on FFA abundances revealed significant differences in the profile of SCFA (p = 0,012), MCFA (p = 0.00015) and LCFA (p = 0,035) between PV patients and HC, which were not significantly changed by immunosuppressive treatments. PV patients showed a significantly lower serum concentration of propionic (p < 0.0005) and butyric (p < 0.0005) acids, SCFA with anti-inflammatory functions, while hexanoic (p < 0.0005) and hexadecanoic (p = 0.0006) acids, pro-inflammatory MCFA and LCFA respectively, were over-represented. Treatments induced a significant decrease of hexanoic (p = 0.035) and a further increase of hexadecanoic (p = 0.046) acids. Positive correlations emerged between IFN-γ and acetic acid (Rho = 0.60), IFN-γ and hexanoic acid (Rho = 0.46), IL-5 and both hexadecanoic acid (Rho = 0.50) and octadecanoic acid (Rho = 0.53), butyric acid and PDAI (Rho = 0.53). PV was associated with a remarked imbalance of circulating FFA compared to HC. The serum alterations of SCFA, MCFA, and LCFA may contribute to promoting inflammation in PV. Deeper insights into the immunomodulatory functions of these molecules may pave the way for personalized dietary interventions in PV patients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Non-biologic immunosuppressive drugs, such as azathioprine, dapsone or methotrexate are fundamental treatment options for a wide range of autoimmune and chronic inflammatory skin diseases. Some of these drugs were initially used for malignancies (e.g., azathioprine or methotrexate) or infectious diseases (e.g., hydroxychloroquine or dapsone) but are nowadays mostly used for their immunosuppressive/immunomodulating action. Although dermatologists have years of clinical experience with these drugs, some of the mechanisms of action are not fully understood and are the subject of research. Although these drugs are commonly used, lack of experience or knowledge regarding their safety profiles and management leads to skepticism among physicians. Here, we summarize the mechanism of action and detailed management of adverse effects of the most commonly used immunosuppressive drugs for skin diseases. Furthermore, we discuss the management of these drugs during pregnancy and breastfeeding, as well as their interaction and handling during vaccination., (© 2024 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin and/or mucous membranes caused by IgG autoantibodies that predominantly target two transmembrane desmosomal cadherins: desmoglein (DSG)1 and DSG3. DSG-specific T cells play a central role in PV pathogenesis because they provide help to autoreactive B cells for autoantibody production. In this study, we characterized DSG3-specific peripheral T cells in a cohort of 52 patients with PV and 41 healthy controls with regard to cytokine profile and epitope specificity. By ELISpot analysis, type 2 T cells reactive with the DSG3 ectodomain were significantly increased in patients with PV compared with those in healthy controls. By dextramer analysis, CD4+ T cells specific for an epitope within the extracellular domain of DSG3, DSG3 (206-220) , were found at significantly higher frequencies in patients with PV than in HLA-matched healthy controls. T-cell recognition of two distinct DSG3 epitopes, that is, DSG3 (206-220) and DSG3 (378-392) , correlated significantly, suggesting a synergistic effect in B-cell help. Immunization of HLA-DRB1∗04:02-transgenic mice with PV with the same set of DSG3 peptides induced pathogenic DSG3-specific IgG antibodies, which induced loss of keratinocyte adhesion in vitro. Thus, DSG3 peptide-specific T cells are of particular interest as surrogate markers of disease activity and potential therapeutic targets in PV., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest the authors declare no conflicts of interest.

Pemphigus and pemphigoid are two potentially life-threatening groups of autoimmune diseases, characterized by autoantibodies targeting structural components of desmosomes or hemidesmosomes, respectively. Affected patients typically show itchy/painful plaques or blistering skin lesions and/or impairing mucosal blistering and erosions, which may strongly impact their quality of life. Since the milestone work of Walter Lever in 1953, who differentiated these two groups of diseases by histopathological analysis of the level of antibody-mediated skin cleavage, enormous progresses occurred. Achievements made in laboratory diagnostics now allow to identify antigen specific structural proteins of the skin that are targeted by pathogenic autoantibodies. These progresses were accompanied by an increased understanding of the pathogenesis of these diseases thanks to the establishment of animal models reproducing disease and on studies on skin and blood of affected individuals, which have been leading to novel and disease-specific treatments. Yet, given their phenotypical overlap with more common dermatological diseases, correct diagnosis and appropriate treatment are often delayed, in some cases leading to irreversible sequelae, including organ dysfunction (i.e., loss of vision in mucous membrane pemphigoid). Here, we provide a concise overview of the clinical appearance, diagnosis and therapeutic management of pemphigus and pemphigoid diseases., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Studies on the role of interleukins (ILs) in autoimmune and inflammatory diseases allow for the better understanding of pathologic mechanisms of disease and reshaping of treatment modalities. The development of monoclonal antibodies targeting specific ILs or IL signaling pathways (i.e., anti-IL-17/IL-23 in psoriasis or anti-IL-4/IL-13 in atopic dermatitis) is the shining example of therapeutic interventions in research. IL-21, belonging to the group of ɣc-cytokines (IL-2, IL-4, IL-7, IL-9, and IL-15), is gaining attention for its pleiotropic role in several types of immune cells as activator of various inflammatory pathways. In both health and disease, IL-21 sustains T- and B-cell activity. Together with IL-6, IL-21 helps to generate Th17 cells, promotes CXCR5 expression in T cells, and their maturation into follicular T helper cells. In B cells, IL-21 sustains their proliferation and maturation into plasma cells and promotes class switching and antigen-specific antibody production. Due to these characteristics, IL-21 is a main factor in numerous immunologic disorders, such as rheumatoid arthritis and MS. Studies in preclinical skin disease models and on human skin strongly suggest that IL-21 is crucially involved in inflammatory and autoimmune cutaneous disorders. Here, we summarize the current knowledge of IL-21 in well-known skin diseases., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Dermatomyositis (DM) is an autoimmune disorder, which belongs to a group of rare autoimmune dermatoses characterized by different skin features and variable muscle involvement. We recognize four main variants of DM: classic DM, clinically amyopathic DM, paraneoplastic DM, and juvenile DM. Clinically, patients show several skin features, but heliotrope rash, and violaceous papules located at the interphalangeal or metacarpophalangeal joints (Gottron's papules) are the most frequently observed. Together with skin features, patients show muscle involvement, most commonly with symmetrical weakness of the proximal muscles. DM belongs to the facultative paraneoplastic dermatoses and a wide range of solid or hematologic malignancies can be detected in DM patients. Serologically, a wide range of autoantibodies can be detected in patients with DM. Indeed, distinct serotypes can be related to specific phenotypes with specific clinical features, carrying a different risk for systemic involvement and for malignancies. Systemic corticosteroids are still considered the first-line approach, but several steroid-sparing agents, such as methotrexate, azathioprine or mycophenolate mofetil, have been reported as effective in treating DM. Furthermore, new class of drugs, such as monoclonal antibodies, purified immunoglobulins or Janus kinase inhibitors are becoming more relevant in the clinical practice or are currently under investigation. In this work, we aim to offer a clinical overview of the diagnostic workout, the characteristics of DM variants, the role of autoantibodies in DM, and the management of this life-threatening systemic disorder.

The treatment of geriatric burn patients represents a major challenge in burn care. The objective of this study was to evaluate the efficacy of enzymatic debridement (ED) in geriatric burn patients. Adult patients who received ED for treatment of mixed pattern and full thickness burns (August 2017-October 2022) were included in this study and grouped in the younger (18-65 years) and geriatric (≥65 years) groups. Primary outcome was a necessity of surgery subsequent to ED. Both groups (patient characteristics, surgical and non-surgical treatment) were compared. Multiple logistic and linear regression models were used to identify the effect of age on the outcomes. A total of 169 patients were included (younger group: 135 patients, geriatric group: 34 patients). The burn size as indicated by %TBSA (24.2 ± 20.4% vs. 26.8 ± 17.1%, p = 0.499) was similar in both groups. The ASA (2.5 ± 1.1 vs. 3.4 ± 1.1, p < 0.001) and ABSI scores (6.1 ± 2.8 vs. 8.6 ± 2.3, p < 0.001) were significantly higher in the geriatric group. The %TBSA treated with ED (5.4 ± 5.0% vs. 4.4 ± 4.3%, p = 0.245) were similar in both groups. The necessity of additional surgical interventions (63.0 % vs. 58.8 %, p = 0.763) and the wound size debrided and grafted (2.9 ± 3.5% vs. 2.2 ± 2.1%; p = 0.301) were similar in both groups. Regression models yielded that age did not have an effect on efficacy of ED. We showed that ED is reliable and safe to use in geriatric patients. Age did not have a significant influence on the surgical outcomes of ED. In both groups, the size of the grafted area was reduced and, in many patients, surgery was avoided completely.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease, characterized by severe pruritus and skin blistering. The loss of tolerance against Collagen XVII, also referred to as BP180, is the main pathogenic event of BP, leading to production of IgG autoantibodies which mainly target the juxtamembranous extracellular non-collagenous 16th A (NC16A) domain of BP180. A complex inflammatory network is activated upon autoantibody binding to the basement membrane zone; this inflammatory loop involves the complement cascade and the release of several inflammatory cytokines, chemokines and proteases from keratinocytes, lymphocytes, mast cells and granulocytes. Collectively, these events disrupt the integrity of the dermal-epidermal junction, leading to subepidermal blistering. Recent advances have led to identify novel therapeutic targets for BP, whose management is mainly based on the long-term use of topical and systemic corticosteroids. As an example, targeting type-2 T-helper cell-associated cytokines, such as Interleukin-4 and interleukin-13 has shown meaningful clinical efficacy in case series and studies; targeting IL-17 and IL-23 has also been tried, owing to an important role of these cytokines in the chronic maintenance phase of BP. In this review article, we discuss the complex cytokine milieu that characterized BP inflammation, highlighting molecules, which are currently investigated as present and future therapeutic targets for this life-threatening disease., 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 © 2023 Maglie, Solimani, Didona, Pipitò, Antiga and Di Zenzo.)

Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies against components of the cutaneous basement membrane zone. Autoantibodies lead to complement-dependent and -independent inflammation and blistering. Blister fluid is a valuable biologic resource, as it provides insight into both systemic and local microenvironment responses. Here, we utilized liquid chromatography with tandem mass spectrometry to characterize the bullous pemphigoid blister fluid proteome. We then depleted exosomes to better understand the exosomal versus non-exosomal proteome. We identified 339 proteins in the blister fluid of bullous pemphigoid patients. Gene ontology demonstrated enrichment of several key biologic processes including innate immune response, neutrophil degranulation, platelet degranulation, and complement activation. Exosome depletion resulted in a significant decrease in normalized reporter intensities of 192 proteins, consistent with our observation of a large number of exosomal proteins found in the blister fluid. We then compared the bullous pemphigoid blister fluid proteome to prior proteomic datasets in suction blister fluid, snake bites, and thermal burns, identifying 76 proteins unique to bullous pemphigoid. These include major basic protein, eosinophil peroxidase, galectin-10, and the immunoglobulin epsilon heavy constant region, consistent with tissue eosinophilia. We lastly validated several previously reported blister fluid exosomal components. Blister fluid in bullous pemphigoid contains a mixture of numerous biologic processes. While many of these processes are shared with blistering from alternative causes, we have identified several notable features unique to bullous pemphigoid., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa. Several clinical subtypes of OLP have been reported, including the reticular and erosive one. On the one hand, reticular OLP is usually asymptomatic and is characterized by white streaks surrounded by well-defined erythematous borders. On the other hand, erosive OLP shows ulcerations and erosions surrounded by erythematous mucosa. While reticular OLP is relatively easy to control, erosive OLP is extremely painful and refractory to therapies, limiting the quality of life of the patients. In addition, treating erosive OLP is extremely tricky, and a gold standard treatment has not yet been established. However, several therapeutic approaches have been reported as effective, including systemic corticosteroids, systemic retinoids, and anti-interleukin (IL)-17/anti-IL-23 drugs. Indeed, our group and other several authors reported the effectiveness of anti-IL17, anti-IL12/23, and anti-IL23 agents in refractory OLP, highlighting the urgency of clinical studies on the use of anti-IL agents in OLP patients. In this paper, we reviewed the English- and German-language literature about therapeutic strategies for treating OLP, focusing on new systemic therapies for erosive OLP., Competing Interests: Author MH has received honoraria from Novartis, Sanofi, Celgene and unrestricted grants from Biotest, Janssen Cilag, and Topas during the last 3 years. The remaining 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 © 2022 Didona, Caposiena Caro, Sequeira Santos, Solimani and Hertl.)

Analysis of T lymphocyte proliferation and activation after antigenic or mitogenic stimulation is a vital parameter used in the diagnosis of various immuno-deficiencies and during the monitoring of treatment responses. Most applied techniques are based on the incorporation of tritiated thymidine ( 3 H-TdR) or ELISPOT analysis, both rely on rather time-consuming/-intensive ex vivo protocols or encompass inherent drawbacks such as the inability to distinguish specific cell populations ( 3 H-TdR, ELISPOT) or focus on a single cytokine (ELISPOT). Here we aimed at characterizing the rapid expression of intracellular CD154 (CD40L) as a marker for rare antigen-specific CD4+ T cells in pemphigus vulgaris (PV). Upon stimulation with human desmoglein (Dsg) 3, the major autoantigen in PV, the expression of CD154 was significantly increased in PV patients compared to healthy controls (HC) and correlated with anti-Dsg3 IgG titers. Patients with active disease showed higher numbers of Dsg3-reactive CD4+ T cells in CXCR5+ T follicular helper cells. In remittent PV and HC, CXCR5+CD4+ T cells remained largely unaffected by Dsg3. IL-17 and IL-21 expression were significantly induced only in CD154+CD4+ T cells from PV patients, lending themselves as potential novel treatment targets. Additionally, stimulation with immunodominant Dsg3-derived epitopes strongly induced a CD4+ T cell response via CD40-CD154 interaction similar to the human Dsg3 protein. We here established a rapid ex vivo assay allowing the detection of Dsg3-reactive CD4+ T cells from activated systemically available PBMCs, which further supports the crucial concept of antigen-specific T cells in the pathogenesis of PV., Competing Interests: MH is a recipient of an unrestricted grant from TOPAS Therapeutics relating to a collaboration aimed at inducing therapeutic T cell tolerance in pemphigus. The remaining 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 © 2022 Polakova, Kauter, Ismagambetova, Didona, Solimani, Ghoreschi, Hertl, Möbs and Hudemann.)

Laminin-332 pemphigoid is a rare and severe autoimmune blistering disease, caused by IgG autoantibodies targeting laminin-332 in the dermal-epidermal basement zone. Laminin-332 pemphigoid is characterized by variable inflammatory infiltrate and the predominance of non-complement-fixing antibodies. Given these findings, we hypothesized that IgG autoantibodies to laminin-332 directly resulted in keratinocyte expression of inflammatory factors. We performed RNA-seq on primary human keratinocytes treated with IgG from patients with laminin-332 pemphigoid. Genes for numerous cytokines and chemokines were upregulated, including CSF2, CSF3, CXCL1, CXCL5, CXCL3, CXCL8, CXCL10, CXCL1, IL6, IL7, IL15, IL23, IL32, IL37, TGFB2 as well as metalloproteases. Considering the pro-inflammatory and proteolytic effect of autoantibodies from patients with laminin-332 pemphigoid identified in our initial experiment, we next questioned whether the reactivity against specific laminin subunits dictates the inflammatory and proteolytic keratinocyte response. Then, we treated keratinocytes with IgG from a separate cohort of patients with reactivity against individual subunits of laminin-332. We identified upregulation of IL-1α, IL-6, IL-8, CXCL1, MMP9, TSLP, and GM-CSF at the protein level, most notably in keratinocytes treated with IgG from laminin β3-reactive patients. We for the first time demonstrated a pro-inflammatory response, similar to that described in keratinocytes treated with IgG autoantibodies from patients with bullous pemphigoid, providing novel insight into the pathogenesis of laminin-332 pemphigoid and laminin-332 biology., 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 Bao, Li, Solimani, Didona, Patel, Li, Qian, Ishii, Hashimoto, Hertl and Amber.)

Lichen planus (LP) is a chronic lichenoid inflammatory disorder of the skin, mucosa and of the appendages. LP is classically characterized by the presence of a rich infiltration of inflammatory T cells, which migrate in the upper part of the dermis, arranged in a band-like pattern. Different sub types of the disease have been so far described. Albeit LP is clinically well defined, the disease still represents a therapeutic enigma. Especially with regard to mucosal or scalp affecting LP types, which often present a recalcitrant and treatment unresponsive course, efficacious therapeutic options are still lacking. Thus, LP represents a disease with a high psychosocial burden. Yet, development in the deciphering of LP pathogenesis reveals possible new druggable targets, thus paving the way for future therapeutic options. In this clinical guide, we summarize the current clinical knowledge and therapeutic standards and discuss the future perspective for the management of LP., (© 2021 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Background: T H 2 cells were thought to be a pivotal factor for initiation of the autoimmune blistering disease pemphigus. However, the role of other T-cell subsets in pemphigus pathogenesis remained unclear., Objective: We aimed to characterize the exact phenotype of T cells responsible for the development of pemphigus., Methods: Whole transcriptome shotgun sequencing was performed to determine differential gene expression in pemphigus lesions and skin of healthy individuals. The cutaneous cytokine signature was further evaluated by real-time quantitative PCR. In peripheral blood, the distribution of T H cell and folliclular helper (T FH ) cell subsets was analyzed by flow cytometry. Finally, the capacity of T H and T FH cell subsets to induce desmoglein (Dsg)-specific autoantibodies by memory B cells was evaluated in coculture experiments., Results: Transcriptome analysis of skin samples identified an IL-17A-dominated immune signature in patients with pemphigus, and Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the dominance of the IL-17A signaling pathway. Increased expression of IL17A and associated cytokines was also detected by real-time quantitative PCR comparing lesional with perilesional or healthy skin. Interestingly, utilization of flow cytometry showed that patients with active pemphigus had elevated levels of circulating IL-17 + , T H 17, T FH 17, and T FH 17.1 cells. Notably, levels of T H 17 and T FH 17 cells correlated with levels of Dsg-specific CD19 + CD27 + memory B cells, and patients with acute pemphigus showed higher levels of Dsg3-autoreactive T FH 17 cells. Coculture experiments revealed T FH 17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells., Conclusion: Our findings show that T FH 17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which are characterized by their capability to suppress T-cell responses. While MDSCs have been traditionally associated with cancer diseases, their role as regulators of autoimmune diseases is emerging. Pemphigus is a chronic autoimmune blistering skin disease characterized by dysregulated T-cell responses and autoantibody production. The role of MDSCs in pemphigus disease has not been defined yet. The aim of this study was to characterize MDSCs in pemphigus patients and to dissect their relationship with CD4 + T-cell subsets and clinical disease assessments. For this purpose, we performed a cross-sectional analysis of 20 patients with pemphigus. Our results indicate that a population of CD66b + CD11b + polymorphonuclear-like MDSCs (PMN-MDSCs) is expanded in the peripheral blood mononuclear cell fraction of pemphigus patients compared to age-matched healthy donors. These PMN-MDSCs have the capability of suppressing allogeneic T-cell proliferation in vitro and show increased expression of characteristic effector molecules such as arginase I and interleukin-10. We further demonstrate that PMN-MDSCs are especially expanded in patients with active pemphigus, but not in patients in remission. Moreover, MDSC frequencies correlate with an increased Th2/Th1 cell ratio. In conclusion, the identification of a functional PMN-MDSC population suggests a possible role of these cells as regulators of Th cell responses in pemphigus., (© 2021 The Authors. Experimental Dermatology published by John Wiley & Sons.)

Cytokine signaling, especially interferon (IFN) signaling is closely linked to several aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During initial SARS-CoV-2 infection, symptomatic patients present with impaired type I/III IFN-mediated antiviral responses. Interestingly, IFNs regulate the cellular entry receptor for SARS-CoV-2 on epithelial and endothelial cells. As reported recently, critically ill COVID-19 patients show genetic polymorphisms in one IFN receptor gene (IFNRA2) and in a gene locus near the Janus kinase (JAK) TYK2, which is key for IFN, interleukin (IL)-12 and IL-23 signaling, and T helper (Th) 1/Th17 cell-mediated antiviral immune responses. In the advanced stage of the disease, critically ill COVID-19 patients develop a cytokine storm where many inflammatory mediators using the JAK/STAT signaling pathway such as IL-6, IFN-γ, the granulocyte colony-stimulating factor (G-CSF) or IL-2, and chemokines result in an influx of macrophages and neutrophils damaging the lung tissue. The knowledge on the cytokine and JAK/STAT signaling pathways in severe COVID-19 disease explains the promising first results with JAK inhibitors like baricitinib, which not only dampen the inflammation but in the case of baricitinib also affect virus replication and endocytosis in target cells. Here, we summarize the current immunological associations of SARS-CoV-2 infection with cytokine signaling, the JAK/STAT pathway, and the current clinical stage of JAK inhibitors for improving severe COVID-19 disease., (© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Pemphigus is a rare autoimmune blistering disease which manifests with painful erosions and blisters of the skin and mucosa. This disorder is caused by autoantibodies attacking desmosomal proteins, necessary for cell-cell contact stability and epidermal integrity. Desmoglein (Dsg) 1 and Dsg3 are the two major target antigens in pemphigus. Yet, many other target proteins, which have been described over the years, seem to be involved in the loss of epidermal integrity. Clinical examination, combined to serological advances and detection of targeted antigens, permitted to differentiate among several pemphigus subtypes, in which pemphigus vulgaris and pemphigus foliaceus are the most common. Nowadays, serological analysis in pemphigus is a fundamental step of the diagnostic algorithm. This is based on analysis of clinical symptoms, histopathological examination of lesional skin, detection of tissue bound and circulating antibodies by direct and indirect immunofluorescence, and determination of target antigens either by enzyme-linked immunosorbent essay (ELISA) or by western blot analysis. A correct and exhaustive diagnostic algorithm is fundamental to characterize pemphigus subtypes, which lastly permits to adopt a correct treatment approach. Moreover, quality and quantity of circulating antibodies in patient's sera deliver important information regarding clinical course, disease severity and treatment response; thus, relevantly affecting physician's decision. To facilitate this process, "easy-to-perform" diagnostic kits with high sensitivity and specificity are being commercialized. In this review, we focus on available methods and established assays to correctly detect circulating autoantibodies in pemphigus. Moreover, we discuss subtype specific serological peculiarities in the five most relevant subtypes (pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, paraneoplastic pemphigus and intercellular IgA dermatosis (also called as IgA pemphigus).

Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against components of the basal membrane zone that lead to sub-epidermal loss of adhesion. Pruritus may be indicative of a pre-clinical stage of BP, since a subset of these patients shows serum IgG autoantibodies against BP230 and/or BP180 while chronic pruritus is increasingly common in the elderly population and is associated with a variety of dermatoses. Clinical and experimental evidence further suggests that pruritus of the elderly may be linked to autoimmunity with loss of self-tolerance against cutaneous autoantigens. Thus, the objective of this study was to determine autoreactive T cell responses against BP180 in elderly patients in comparison to patients with BP. A total of 22 elderly patients with pruritic disorders, 34 patients with bullous or non-bullous BP and 34 age-matched healthy controls were included in this study. The level of anti-BP180 and anti-BP230 IgG serum autoantibodies, Bullous Pemphigoid Disease Area Index (BPDAI), and pruritus severity were assessed for all patients and controls. For characterization of the autoreactive T cell response, peripheral blood mononuclear cells were stimulated ex vivo with recombinant BP180 proteins (NH 2 - and COOH-terminal domains) and the frequencies of BP180-specific T cells producing interferon-γ, interleukin (IL)-5 or IL-17 were subsequently determined by ELISpot assay. Patients with BP showed a mixed Th1/Th2 response against BP180 while autoreactive Th1 cells were identified in a minor subset of elderly patients with pruritic disorders. Furthermore, our T cell characterization revealed that therapeutic application of topical clobetasol propionate ointment in BP patients significantly reduced peripheral blood BP180-specific T cells, along with clinically improved symptoms, strongly suggesting a systemic immunosuppressive effect of this treatment., 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 Didona, Scarsella, Fehresti, Solimani, Juratli, Göbel, Mühlenbein, Holiangu, Pieper, Korff, Schmidt, Sitaru, Eming, Hertl and Pollmann.)

Cutaneous lichen planus (CLP) and psoriasis (PSO) are both common chronic inflammatory skin diseases for which development of new treatments requires the identification of key targets. While PSO is a typical Th17/IL-17-disorder, there is some evidence that Th1/IFN-ɣ dominate the inflammatory process in CLP. Nonetheless, the immunopathogenesis of CLP is not fully explained and key immunological factors still have to be recognized. In this study, we compared the immune signature of CLP lesions with the well-characterized inflammation present in PSO skin. First, we analysed the histological and immunohistological characteristics of CLP and PSO. Second, we assessed the cytokine expression (IL1A, IL1B, IL4, IL6, IL8, IL10, IL17A, IL19, IL21, IL22, IL23A, IL13, IFNG, TNF, IL12A, IL12B and IL36G) of lesional skin of CLP with PSO by qPCR. Histology revealed a similar epidermal thickness in CLP and PSO. Immunohistochemically, both diseases presented with an inflammatory infiltrate mainly composed by CD3 + CD4 + T cells rather than CD3 + CD8 + . Importantly, mRNA analysis showed a distinct cytokine signature: while levels of IL12B, IL1A, IL6 and IL23 were similar between the two groups, the characteristic PSO-associated cytokines IL8, IL17A, IL22, IL19 and IL36G were expressed at very low levels in CLP. In contrast, CLP lesional skin was dominated by the expression of IFNG, IL21, IL4, IL12A and TNF. Immunohistochemistry confirmed the dominance of IL-21, IFN-ɣ and also pSTAT1 in the dermal infiltrate of CLP, while IL-17A was more present in PSO. Collectively, this study improves our understanding of the immunological factors dominating CLP. The dominating cytokines and signalling proteins identified suggest that anti-cytokine therapeutics like JAK inhibitors may be beneficial in CLP., (© 2020 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Haematological malignancies induce important alterations of the immune system, which account for the high frequency of autoimmune complications observed in patients. Cutaneous immune-mediated diseases associated with haematological malignancies encompass a heterogeneous group of dermatoses, including, among others, neutrophilic and eosinophilic dermatoses, autoantibody-mediated skin diseases, vasculitis and granulomatous dermatoses. Some of these diseases, such as paraneoplastic pemphigus, are associated with an increased risk of death; others, such as eosinophilic dermatoses of haematological malignancies, run a benign clinical course but portend a significant negative impairment on a patient's quality of life. In rare cases, the skin eruption reflects immunological alterations associated with an unfavourable prognosis of the associated haematological disorder. Therapeutic management of immune-mediated skin diseases in patients with haematological malignancies is often challenging. Systemic corticosteroids and immunosuppressive drugs are considered frontline therapies but may considerably augment the risk of serious infections. Indeed, developing a specific targeted therapeutic approach is of crucial importance for this particularly fragile patient population. This review provides an up-to-date overview on the immune-mediated skin diseases most frequently encountered by patients with onco-haematological disorders, discussing new pathogenic advances and therapeutic options on the horizon.

Epidermolysis bullosa acquisita (EBA) is a rare subepidermal blistering dermatosis characterized by autoantibodies targeting collagen VII (COL7), an essential component of the anchoring fibrils, located in the sublamina densa of the dermal‒epidermal junction. In EBA, tissue-bound autoantibodies cause the recruitment and subsequent activation of neutrophils, which eventually lead to subepidermal blistering through the release of proteases and ROS. Thus, targeting either pathogenic IgG autoantibodies or neutrophil recruitment or activation has shown efficacy in experimental murine EBA models and patients with EBA. In this issue, Stüssel et al. demonstrate that propranolol, a nonselective β-adrenoreceptor blocker, markedly inhibits the neutrophil release of ROS induced by complexes of COL7 and/or anti-COL7 IgG in vitro and ameliorates the formation of blisters and erosions in an antibody passive-transfer model of murine EBA. These findings warrant further investigations aimed at characterizing the therapeutic efficacy of propranolol in EBA and possibly beyond., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)