(searched for: Oral Lichen Planus Genetics Update)
European Journal of Dental and Oral Health, Volume 3, pp 1-5; https://doi.org/10.24018/ejdent.2022.3.4.205
Lichen planus is a chronic autoimmune multi-factorial inflammatory condition of the mucocutaneous skin that mainly interests the skin and oral mucosa. Oral Lichen Planus (OLP) affects 0.5 to 1% of the world's population and all human races equally. The factors that act as triggers of autoimmune processes and determine the appearance of OLP are represented by genetic predisposition, skin injuries, viral infections, contact allergies, and medications. OLP affects the oral mucosa and occurs frequently on the inside of the cheeks and less often on the edges of the tongue, gums, or lips. The condition is manifested by the appearance of painful erosions and mouth ulcers, accompanied by erythema and gingival scaling, and sometimes localized inflammation of the gums, near the amalgam fillings. There are 132 genes currently involved in the etiopathogenesis of OLP, but only a few appear to play a major role. These genes have been termed "leader genes". Thus, based on bioinformatics studies, the main genes involved in the pathogenesis of OPL are JUN, EGFR, FOS, IL2, and ITGB4. Although genetic status, immune system background, and infectious diseases are considered to be the most important incriminating and determining factors, the etiopathogenesis of OLP remains poorly known. Further genetic research is needed in order to achieve the generalizability of the findings and to strengthen the obtaining results.
Published: 1 March 2008
Minerva Gastroenterologica e Dietologica, Volume 54
An association between lichen planus (LP) and liver diseases has been reported. PubMed database has been used to extract information on hepatitis C virus (HCV) infection and LP. The results suggest that LP, mainly the oral type, is significantly associated with HCV infection in Southern Europe and Japan but not in Northern Europe. These differences may be related to genetic factors. Detection of HCV viral sequences and HCV-specific CD4+ and/or CD8+ T lymphocytes in oral samples of LP patients suggests that HCV might be involved in the development of oral lesions via an immunological pathway, characterized by an excessive production of Th1 cytokines following an uneffective antiviral immuno-response.
The Journal of Allergy and Clinical Immunology, Volume 145, pp 1049-1060; https://doi.org/10.1016/j.jaci.2019.10.015
Epigenetics has been discussed as a potential factor influencing the pathophysiology and severity of inflammatory skin diseases. In recent years, emerging evidence suggests that epigenetic mechanisms are involved in the pathophysiology of not only atopic dermatitis (AD) and psoriasis (PSO) but also lupus erythematosus and oral lichen. A systematic review of the literature was undertaken to provide an unbiased and comprehensive update on the involvement of methylation patterns in inflammatory skin disease. In addition to reviewing the contribution of epigenetic mechanisms regulating the development of inflammatory skin diseases, this review aimed to discern the overlap of epigenetic risk factors of the 2 most common inflammatory skin diseases, AD and PSO. Although AD and PSO are both inflammatory skin diseases, both show a distinct genetic profile. Herein, we give evidence that both AD and PSO share epigenetic risk factors that might contribute to disease characteristics. We identify a core subset of inflammation-associated differentially methylated genes in both AD and PSO and discuss the association in other inflammatory diseases.
Critical Reviews in Oral Biology & Medicine, Volume 9, pp 86-122; https://doi.org/10.1177/10454411980090010501
Lichen planus (LP) is a relatively common disorder of the stratified squamous epithelia, which is, in many ways, an enigma. This paper is the consensus outcome of a workshop held in Switzerland in 1995, involving a selection of clinicians and scientists with an interest in the condition and its management. The oral (OLP) eruptions usually have a distinct clinical morphology and characteristic distribution, but OLP may also present a confusing array of patterns and forms, and other disorders may clinically simulate OLP. Lesions may affect other mucosae and/or skin. Lichen planus is probably of multifactorial origin, sometimes induced by drugs or dental materials, often idiopathic, and with an immunopathogenesis involving T-cells in particular. The etiopathogenesis appears to be complex, with interactions between and among genetic, environmental, and lifestyle factors, but much has now been clarified about the mechanisms involved, and interesting new associations, such as with liver disease, have emerged. The management of lichen planus is still not totally satisfactory, and there is as yet no definitive treatment, but there have been advances in the control of the condition. There is no curative treatment available; immunomodulation, however, can control the condition. Based on the observed increased risk of malignant development, OLP patients should be offered regular follow-up examination from two to four times annually and asked to report any changes in their lesions and/or symptoms. Follow-up may be particularly important in patients with atrophic/ulcerative/erosive affections of the tongue, the gingiva, or the buccal mucosa. Much more research is required into the genetic and environmental aspects of lichen planus, into the premalignant potential, and into the possible associations with chronic liver, and other, disorders. More clinical studies are required into the possible efficacy of immunomodulatory drugs such as pentoxifylline and thalidomide.
Published: 1 July 2002
Journal: Refu'at ha-peh veha-shinayim (1993)
Refu'at ha-peh veha-shinayim (1993), Volume 19
Oral cancer is a major health problem in some parts of the world, especially in developing countries. Worldwide, the annual incidence exceeds 3,000,000 new cases. The main risk factors are tobacco and alcohol. However, dietary factors, viruses and possibly genetic predisposition have also been associated with oral cancer. Several oral lesions such as leukoplakia, erythroplakia and lichen planus carry an increased risk for malignant transformation in the oral cavity. Prognosis of oral cancer differs significantly between specific oral locations, with cancer of the lip for example having a much better prognosis than at the base of tongue or on the gingiva. Prognosis of intra-oral cancer is generally poor, with a five-year survival less than 50 percent. Local recurrences as well as lymph node metastases occur in a significant percentage of patients, while distant metastases are less frequent. Prognosis correlates mainly with the size of the lesion and the nodal status at the time of diagnosis, therefore early detection of small, stage-1 oral cancer can reduce mortality and morbidity. Oral lesions can be easily observed by direct visualization, however, knowledge of the differential diagnosis of oral lesions is mandatory for early diagnosis of malignant and pre-malignant lesions in the oral cavity. Use of screening and detection aids such as vital stains and Oral CDX can increase the number of cases diagnosed at an early stage, or even in the pre-malignant stage. Development of molecular markers can improve the early diagnosis and can help in predicting treatment response. New treatment modalities including tumor specific antibodies and gene therapy are emerging, giving more hope for patients with oral cancer. There is an important role for the dentist in both early diagnosis of pre-malignant and malignant lesions, and in prevention by educating the patients of the risks associated with tobacco, alcohol and dietary factors.
Frontiers in Oral Health, Volume 1; https://doi.org/10.3389/froh.2020.00003
Oral squamous cell carcinomas (OSCC), arising from surface epithelium, constitute more than 90% of all oral cancers and, in many studies, the term oral cancer is applied as synonymous of OSCC. OSCC, together with SCC from pharynx, larynx, nasal cavity, and paranasal sinuses, belongs to the group of head and neck SCC, but due to increasing knowledge of specific risk factors, different genetic mutations and epigenetic changes and, more importantly, distinct biological and clinical behaviors, tumors from those different sites must be studied separately. Other neoplasms may also arise in the oral cavity, including those derived from connective tissues, minor salivary glands, lymphoid tissues, melanocytes, and odontogenic apparatus, as well as metastasis from distant tumors. Due to their relatively low incidences, important areas of future research must include etiopathogenetic mechanisms, features allowing differential diagnosis, therapeutic strategies (particularly target-specific interventions), and prognostic markers. OSCC is one of the most prevalent cancers worldwide, with a global incidence of more than 350,000 new cases and 177,000 deaths every year, though with considerable geographic and environmental risk factor differences . The incidence of OSCC has been decreasing in some areas of the world, but the incidence has risen in some countries (mainly low-income countries) and among females [2, 3]. An alarming increase in the incidence of OSCC in the younger age group (≤45 years-old) has also been observed. While the use of all forms of tobacco and alcohol explains this increasing incidence in some countries and among females, as ~80% of the world's smokers live in developing countries and females are more exposed to tobacco and alcohol nowadays than before, they do not explain the incidence among younger cancer patients, who, in most of the cases, lack those traditional risk factors or, when present, the time of exposure is much shorter. In this sense, some specific issues regarding OSCC in the younger age group need to be addressed, including risk factors, patterns of inheritance of predisposing genetic alterations, clinical behavior, and prognosis. Furthermore, more effective programs, particularly in developing countries, to eliminate or reduce tobacco (smoking and chewing) and alcohol consumption would be of great value for reducing the incidence of OSCC and other cancers related to those traditional risk factors. Oral potentially malignant disorders (OPMD), mainly represented by leukoplakia, erythroplakia, oral submucous fibrosis, and proliferative verrucous leukoplakia (PVL), are well-recognized to precede the development of OSCC. In this group, PVL seems unique, since it does not consistently show association with classical environmental agents, its natural history seems different than any other OPMD, and the potential of malignant transformation is the highest among OPMD . The potential of other OPMD, such as oral lichen planus (OLP), remains still somewhat questionable. However, several meta-analyses published in the last 3 years showed a low, but consistent, transformation of classical OLP to oral cancer, confirming that OLP should be considered as an OPMD [5–7]. The early diagnosis and treatment of OPMD is essential to minimize or even eliminate the risk of malignant transformation. However, not all disorders are amenable to curative treatment, and the transformation does not occur in every single case. Although presence and intensity of dysplasia, representing the collection of changes in cellular morphology and tissue architecture at the histopathological standpoint, are considered the main parameters related to malignant transformation of OPMD, the histological assessment of the epithelial dysplasia is a source of substantial subjectivity, and in a meta-analysis, the mean overall transformation rate of OPMD with dysplasia was only 12.1% . Therefore, the characterization of biomarkers to define the magnitude of risk, the mechanisms and the period of progression for transformation is of great importance, in order to rationally schedule treatment or follow-up and to plan cost-effective oral screening programs. OSCC is considered a very aggressive tumor and the majority of patients displays a locoregionally advanced disease at diagnosis, for which multimodality therapy is required. Tumor invasion, lymph node metastasis and high rates of locoregional recurrence, besides development of second primary tumors, are the leading causes of death in OSCC patient. However, even at early stage, particularly tumors of the tongue and floor of mouth may be very aggressive, with increased tendency to invasion and metastasis. In this context, survival rates are of ~40–50% and these rates have not significantly changed over the past decades . Although our understanding about the biological processes involved in cancer development and progression is evolving and many biomarkers have been suggested to significantly impact diagnosis and prognosis of OSCC, no biomarker has yet met the stringent criteria that are needed to be used in clinical practice. Thereafter, it is of consensus among all professionals involved in the field that markers with potential clinical applications, such as early diagnosis, therapeutic targets, responsiveness to treatment, prognosis and post-therapeutic monitoring, are urgently needed to improve clinical management of OSCC. Investigations aimed to characterize OSCC biomarkers should ideally take into consideration some aspects, including prospective analyses of several markers, as a panel, in large cohorts, preferably multicenter, and application of quantitative and complementary assays to capture the impact of biomarkers in different scenarios (the vast majority of studies is based exclusively on immunohistochemistry without a standard pattern of quantification). Furthermore, authors should be aware that cancer heterogeneity is an important drawback for predictive biomarkers. Cancer generally starts as a monoclonal disease but, with its evolution, heterogeneous populations of tumor cells arise. Moreover, in the oral cavity, field cancerization is a factor that is likely to contribute to development of multiple primary tumors within the field of exposure, perhaps contributing further to heterogeneity of clinical disease. Patients harboring the same OSCC, such as location, clinical stage, and histopathological features, may contain cells with distinct patterns of mutations and epigenetic alterations, which may influence the biological behavior and result in significantly different clinical outcomes. In this setting, markers and therapeutic targets against cancer stem cells, which are drivers of self-renewal, metastasis, relapse and resistance to conventional therapy, hold great potential. The identification of genetic variants of risk, mutated genes, activated pathways and networks, and the characterization of potential coadjutants of the tumor cells such as the components of tumor microenvironment are of utmost importance to provide preclinical data to support clinically relevant advances. Indeed, the era of “omics,” such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and some others including genome-wide analysis of genetic variants, which are based on large-scale datasets, is allowing important advances to characterize the functional role of specific genes through their RNAs (including regulators such as non-coding RNAs) and proteins and to identify candidate therapeutic targets for some tumors. Many genome-wide profiling studies with OSCC samples are emerging, and it is time now to transform those promising data highlighting biomarkers and targeted therapies to change the dark scenario of survival rates. Liquid biopsy, the analysis of non-solid biological samples, particularly blood and saliva, has rapidly gained great attention as a potential tool for identification of cancer biomarkers. In those easily accessible body fluids, circulating tumor cells, tumor DNA, RNA, or specific proteins, and extracellular vesicles can be assessed. Although the potential is enormous, especially for OSCC-screening programs, we need to define the biomarker(s) in those fluids and to design clinical validation studies with long-term outcomes. Recent evidence suggests a link between chronic inflammatory disease, such as periodontitis, and oral cancer, supporting the longstanding concept that poor oral hygiene may underpin oral carcinogenesis. As the oral cavity is a reservoir for many hundreds of species of bacteria, one or more of these organisms may contribute to tumor development or progression. To date, bacteria that are associated with periodontal disease, including Prevotella intermedia, Porphyromonas gingivalis, and Fusobacterium nucleatum, have been associated with oral cancer [10, 11], although definitive mechanistic links are currently lacking. One possibility may be the ability of some oral bacteria to trigger host intracellular signaling pathways that lead to production of chemokines that are then able to deregulate host epithelial cell growth, as well as modifying the immune cell infiltrate in the local microenvironment. Therefore, understanding the role of the oral microbiome in the genesis of oral cancers is a key challenge for researchers, the answer to which might even help to explain the observations that, increasingly, oral cancers are being identified more frequently in patients lacking the traditional risk factors of tobacco and alcohol use, as mentioned above. Surgery remains the preferred treatment for OSCCs, with adjuvant radiotherapy with or without chemotherapy in cases at advanced stage. However, immunotherapy and targeted-therapy are showing very promising results. For example, the use of PD-1 and PD-L1 immune checkpoint inhibitors for treatment of recurrent/metastatic cancer has been tested in phase III randomized clinical trials, and it is now suggested that these inhibitors should be used to manage otherwise intractable lesions . PD-1 inhibitors have been shown a superior performance in patients whose disease is refractory to platinum chemotherapy, prolonging survival. Moreover, monotherapy with pembrolizumab (anti-PD-1 humanized antibody) is approved to treat recurrent/metastatic cancers that overexpress PD-L1, a PD-1 receptor ligand. Comprehensive understanding of the molecular events that drive oral tumorigenesis has provided rationale for the design and implementation of targeted therapeutic strategies to combat malignant progression . Examples include epidermal growth factor receptor (EGFR)-driven mechanisms, to which monoclonal antibodies and small molecule inhibitors are available and in use. However, major roadblocks exist, such as the lack of a robust clinical response in many cases, due at least in part to the rapid development of drug-resistant phenotypes. Furthermore, components of tumor microenvironment have shown potential role as biomarkers and an interesting alternative to traditional tumor cell-directed therapy. A major challenge for the oral cancer scientific community will be to identify and overcome these therapeutic shortfalls. The efficiency of treatments for oral cancer is not constant, whereby responses vary from patient to patient. This can cause several major problems including unnecessary side effects, overtreatment, worsening prognosis and increasing treatment costs. Therefore, an urgent need exists to develop efficient and reliable methods to test the efficacy of cancer drugs and irradiation before administered to patients. Similar to other cancer types, several in vitro and in vivo models are suggested for testing cancer drugs and irradiation on OSCC patient samples, however, the vast majority of these models does not have validation with a head-to-head comparison of patient response, making their clinical translation difficult at present. As the field of personalized medicine is rapidly growing, personalized approaches for OSCC treatment must be prioritized. OSCC patients may experience a wide range of oral dysfunctions during treatment, with some of those lasting for the live. The major sources of these dysfunctions are the surgeries and side effects of adjuvant therapy. Although many studies are focused in determining factors associated with those dysfunctions, preventive strategies and treatment options remain challenges to be overcome. The complexity of today's scientific and professional world, the fast pace of knowledge acquisition, and the nature of health problems yet to be solved or adequately addressed, are such that a team approach, involving different talents with complementary knowledge, backgrounds and skills, is required. In many cases this is not only true for the advancement of relevant knowledge, but also for the application of existing knowledge in the health care setting. The team approach allows both depth in the knowledge and stimulation of research, which are essential to our fight against oral cancer. We are glad to release the Oral Cancers section of Frontiers in Oral Health—a multidisciplinary forum for publications in those important areas of oral cancer, from basic research to clinical practice, for translation of scientific advances into novel diagnostic, therapeutic, and prognostic approaches to improve patient's outcome. This section has associate and reviewing editors with different backgrounds, who are real experts in their fields. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. 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. 1. Bray F, Ferlay J., Soerjomataram I., Siegel R. L., Torre L. A., and Jemal A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. 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Immunotherapy for head and neck cancer: recent advances and future directions. Oral Oncol. 99, 104460. doi: 10.1016/j.oraloncology.2019.104460 PubMed Abstract | CrossRef Full Text | Google Scholar 13. Shahoumi L. A., and Yeudall W. A. (2019). Targeted therapies for non-HPV-related head and neck cancer: challenges and opportunities in the context of predictive, preventive, and personalized medicine. EPMA J. 10, 291–305. doi: 10.1007/s13167-019-00177-y PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: oral squamous cell carcinoma, younger age group, biomakers, treatment, prognosis Citation: Coletta RD, Yeudall WA and Salo T (2020) Grand Challenges in Oral Cancers. Front. Oral. Health 1:3. doi: 10.3389/froh.2020.00003 Received: 27 February 2020; Accepted: 05 May 2020; Published: 09 June 2020. Edited and reviewed by: Ronell Bologna-Molina, Universidad de la República, Uruguay Copyright © 2020 Coletta, Yeudall and Salo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Ricardo D. Coletta, [email protected]
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.627565
Editorial on the Research TopicSkin Autoimmunity According to the revised Witebsky’s criteria by Rose and Bona, a disease is considered of autoimmune origin if (i) it can be transferred by pathogenic T cells or autoantibodies, (ii) it can be induced in experimental animals, or if (iii) autoimmunity is suggested by circumstantial evidence from clinical clues (1). Rather new aspects are the iatrogenic induction of autoimmune side effects or the emergence of cutaneous side effects by new immunomodulating therapies (2, 3). According to the “classical definition”, skin autoimmune diseases include pemphigus and pemphigoid diseases (4, 5). In pemphigus and pemphigoid, autoantibodies bind to specific structural proteins of the skin and either directly or indirectly (through activation of the immune system) induce skin pathology (6). Within this Research Topic, several review articles provide an excellent overview of several pemphigus and pemphigoid diseases. More specifically, paraneoplastic pemphigus, bullous pemphigoid, anti-p200 pemphigoid and lichen planus pemphigoides are reviewed in detail. Within this editorial, we aim to provide an overview of the 68 articles of the Research Topic. Each article of the Research Topic can be directly assessed by the kinks provided in the blue font. To guide the reading, we have classified the articles into the following subheadings: ● “Emerging” autoimmune diseases ● Novel insights into the pathogenesis of skin autoimmune diseases ● New diagnostic approaches in skin autoimmune diseases ● Comorbidity in skin autoimmune diseases ● Epidemiology of skin autoimmune diseases ● Novel treatment targets and therapeutic approaches for skin autoimmune diseases ● Characterization of patient biomaterials and model systems of skin autoimmune diseases In contrast to these more “classical” autoimmune diseases, fulfilling the revised Witebsky’s criteria, there is an increasing evidence for a role of autoreactive T- and/or B-cells in chronic inflammatory skin diseases that have not been considered autoimmune so far (7). As reviewed by Boehncke and Brembilla autoreactive T cells are present in several chronic skin inflammatory diseases that are (so far) not considered to be caused by an aberrant immune response to self-antigens. Among others, autoreactive T cells have been identified in psoriasis and atopic dermatitis (8–10). Overall, these are very intriguing findings, but before fully considering autoimmunity as a significant contributing factor to psoriasis or atopic dermatitis, these findings require functional validation. In addition to T cell-mediated autoimmunity in “non-autoimmune” chronic inflammatory skin diseases, presence of autoantibodies has been described in chronic spontaneous urticaria (CSU), as well as in morphea. Yet, again, these findings await functional validation in vivo. The induction of systemic sclerosis, which shares pathogenic features of morphea, in mice immunized with type V collagen (11), however, provides strong evidence for a pathogenic contribution of autoantibodies in morphea and/or systemic sclerosis. In light of the increasing importance of pathogenetic networks of innate and adaptive immune responses (12, 13), this and other observations are highlighted in the review by Schön, where in psoriasis and other autoimmune or autoinflammatory diseases, and their relation to disease pathogenies is highlighted. A complex interaction of genetics and environmental factors is one of the key underlying pathogenic mechanisms in skin autoimmune diseases. The high number of submissions reporting on genetic associations in autoimmune skin diseases underscores this. The genetics and transcriptomics in pemphigus and pemphigoid are reviewed by Olbrich et al. Targeted genetic analysis identified novel gene polymorphisms in endemic pemphigus foliaceus, namely within cell death pathways and the soluble CR1. While most genetic studies focus on the nuclear genome, few address the impact of the mitochondrial genome on complex phenotypes. This highly interesting topic has been addressed by Russlies et al., who report on polymorphisms in the mitochondrial genome that are associated with bullous pemphigoid. In addition to genetics, several articles also specifically address certain cell types in skin autoimmune diseases. Cao et al. allude to the role of regulatory immune cells in pemphigus and pemphigoid. Here, with a focus on pemphigus and pemphigoid, they review the impact of different types of regulatory T and B cells. Rauschenberger et al. present data on the crosstalk between skin infiltrating T cells and keratinocytes. Costa et al. focus on the contribution of mononuclear phagocyte activation in the context of psoriasis. Based on the determination of molecular markers of monocyte/phagocyte activation in inflamed skin and the serum of patients, they conclude that mononuclear phagocytes are activated in psoriasis and thus may contribute to disease pathogenesis. Interestingly, similar findings were made in patients with bullous pemphigoid by Riani et al. Neubert et al. also focus on the contribution of innate immune cells in the pathogenesis of chronic skin inflammation: Neutrophil extracellular traps (NETs) may be formed after neutrophil activation. NETs are important for host defense, but may also contribute to the pathogenesis of several chronic inflammatory (skin) diseases, such as rheumatoid arthritis, psoriasis, or systemic lupus erythematosus (SLE). Interestingly, some of these diseases may be triggered or aggravated by light exposure. Based on these findings, the authors investigated the impact of UVA on NET formation. Another set of articles within the Research Topic focus on the role of cytokines in the pathogenesis of chronic skin inflammation: Buhl and Wenzel highlight the importance of the different isoforms IL-36, especially in psoriasis. The contribution of IL-36 in (pustular) psoriasis is underscored by the induction of pustular psoriasis in carriers of a missense mutation of the IL-36Ra. Le Jan et al. identified inflammasome activation in patients with bullous pemphigoid. Increased expression of IL-1β was induced by IL-17/-23 and led to an increased release of proteases from macrophages. Increased IL-1β expression was, however, predominantly found in patients with erythema and urticarial lesions. Thus, determination of IL-1β concentrations may allow to stratify patients in personalized treatment approaches. Further articles focused on the pathogenesis of chronic inflammatory skin diseases: Liu et al. report on the effects of TIPE2, a members of the tumor necrosis factor-α induced protein-8 family, in mouse models of psoriasis and autoimmune uveitis. Interestingly, in TIPE2-deficient mice opposing effects were observed: While TIPE2-deficiency alleviated clinical disease manifestation in Aldara-induced psoriasiform dermatitis, development of experimental autoimmune uveitis was exacerbated. In his article, Arneth performed a systematic literature search on SLE and summarizes the evidence that SLE is a disease caused by a disorder of DNA degradation and elimination. While the review by Günther covers a similar topic, she points toward the type I interferon signature in lupus as well as environmental triggers of the disease. Two articles provide insights into the pathogenesis of pemphigoid diseases: Hiroyasu et al. summarize the contribution of proteases to pemphigoid disease pathogenesis. Jegodzinski et al. investigated the impact of the G protein-coupled receptor 15 (GPR15) on experimental pemphigoid disease. Of note, they identified GPR15 as one (of the few) anti-inflammatory molecule in pemphigoid diseases. The molecular-based diagnosis of pemphigus and pemphigoid, with more detailed insights into mucous membrane pemphigoid, is also reviewed within this Research Topic. In addition to serology, novel non-invasive methods have been developed for the diagnosis of a variety of chronic inflammatory and autoimmune skin diseases. Among these are imaging systems such as optical coherence tomography, as well as non-invasive sampling methods such as plucked hairs and tape-stripping from skin. All of these are used for the diagnosis of disease. Recently, diagnostic developments have also focused on the development biomarkers to predict disease outcome and/or response to treatment (14). As an example, Nesmond et al. identified IL17RA and IL17RC expression on monocytes to be associated with disease activity in bullous pemphigoid. With the availability of (relatively) effective treatments for chronic skin inflammation (15–17), comorbid diseases, mostly metabolic and cardiovascular, now significantly contributes to the morbidity of patients with skin autoimmune diseases. For example, an increased prevalence was noted in psoriasis inpatients well over 50 years ago (18). Several decades later, an increased prevalence of coronary artery calcification and myocardial infarction in patients was demonstrated in imaging and epidemiologic studies (19, 20). Within this Research Topic Cugno et al. review the evidence for the prothrombotic state in CSU and bullous pemphigoid. Of note, inflammation and the prothrombotic state may form a vicious circle, whereby each pathway sustains and promotes the activation of the other. This has been compellingly reviewed in this Research Topic by Liu et al. In addition to the metabolic and cardiovascular comorbidity of patients with autoimmune skin diseases, a high prevalence of neurologic disease has been noted in bullous pemphigoid patients (21, 22). Mechanistically, the expression of one of the major BP autoantigens, BP180 in the brain has been linked to this clinical association (23). Herein, Wang et al. demonstrate that in patients with stroke, autoantibodies against BP180 were more prevalent compared to healthy controls. This suggests that autoantibodies against BP180 are relatively common after stroke. Consequently, clinical manifestation of bullous pemphigoid could emerge after stroke. However, epitope spreading may be needed because in multiple sclerosis and Alzheimer’s disease, which are also associated with bullous pemphigoid, recognize different epitopes of BP180 than those bound by bullous pemphigoid patients (23). During the last years, evidence has accumulated that bullous pemphigoid may be triggered by certain medications. More specifically, use of checkpoint inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4i) is significantly associated with bullous pemphigoid (24). Within the Research Topic, the association of bullous pemphigoid with DPP4i use is reviewed. This topic is also addressed in a cross-sectional study comparing the prevalence of bullous pemphigoid autoantibodies in patients with type II diabetes treated with or without DPP4i. Here, the authors demonstrated that BP180NC16A autoantibodies were more prevalent in those diabetics treated with DPP4i. Analysis of different DPP4i showed that the increased prevalence of anti-BP180-NC16A was observed only for some, but not all DPP4i. Regarding checkpoint inhibitor-induced bullous pemphigoid, the Research Topic includes one interesting case report: A patient suffering from metastatic melanoma was treated with nivolumab, leading to a partial remission. After approximately 5 months, anti- thyroid peroxidase autoantibodies and hypothyroidism developed. At the same time, bullous pemphigoid was diagnosed. Relating to bullous pemphigoid, intriguingly only LAD-1 autoantibodies were detected. This case reports is in line with previous cases that, however, so far had only reported on Japanese patients presenting with LAD-1-only bullous pemphigoid. Another important, so far neglected field of research in bullous pemphigoid, are insights into demographics and clinical data from the USA. This has been addressed by Lee et al. in this article collection. They demonstrate female predominance in both bullous pemphigoid and mucous membrane pemphigoid. Furthermore, a large number of bullous pemphigoid and mucous membrane pemphigoid presented with other autoimmune diseases; most commonly thyroid disease. Another important aspect of this study is the notion of severe limitations of daily activities imposed by these diseases in the patients. A significant decrease in the quality of life and an inverse correlation with disease activity is also reported for pemphigus patients. One article addresses the impact of airborne pollution with dermatomyositis, underscoring the importance of the environment modulating the susceptibility to develop autoimmune disease (25, 26). Despite recent advances in the treatment of autoimmune skin diseases there is still a high medical need to develop new treatments that are more effective and safer, as well as induce long-term remissions. This need is for example reflected by pemphigus. Here, the combination of systemic corticosteroids with the anti-CD20 antibody rituximab is far more effective and induces dramatically less adverse events compared to treatment with systemic corticosteroids (albeit at a higher dose) alone (27). Yet, the time to remission still requires 180 days (27) and, as documented by Mohamad et al. in this Research Topic, relapses are frequent, even during tapering of the corticosteroid dose. One possible approach to meet this medical need may be the use of (modified) preparations of high dose intravenous immunoglobulins (IVIG) as highlighted by Hoffman and Enk. In bullous pemphigoid several polymorphisms in genes encoding for cytokines have been described (28), some of which have been functionally validated in pemphigoid disease animal models (29–31). Herein, polymorphisms within IL8 were observed when contrasting patients and controls. The IL8 polymorphisms also translated into an increased mRNA expression of the cytokine. Over the last years evidence has accumulated that points toward the presence of IgE autoantibodies on pemphigoid diseases (32, 33). The pathogenic relevance of IgE in pemphigoid has been demonstrated in experimental bullous pemphigoid, where the disease was induced by injecting anti-COL17 IgE into mice humanized for (parts of) COL17 and the IgE receptor (34). In clinical settings, treatment of bullous pemphigoid patients with the anti-IgE antibody omalizumab has been reported to have beneficial effects. Within the Research Topic, Jafari et al. also report on the successful treatment outcome in 2 bullous pemphigoid patients after omalizumab. They furthermore provide insights into molecular changes that are associated with clinical improvement of the disease. Of note, down-regulation of FcϵRI, as well as IgE in lesional skin and on circulating basophils were observed to be associated with clinical improvement. In addition to cytokines and potentially IgE autoantibodies, the activation of the complement system is of key importance to mediate skin inflammation and subepidermal blistering in pemphigoid diseases (35). This has already led to clinical trials investigating the safety and efficacy of complement-targeting biologics in pemphigoid diseases (36, 37). This topic is reviewed in detail in the Research Topic. In addition, Zheng et al. here provide compelling evidence that the central hub of complement activation, the C5a/C5aR1 is also critical for the pathogenesis of psoriasis. In the Aldara-induced psoriasiform dermatitis model, as well as in the IL-23-induced model of psoriasis genetic or pharmacological inhibition of the C5aR1 significantly ameliorated the onset of clinical disease. Mechanistically, this seems to be linked to the migration and differentiation of plasmacytoid dendritic cells. Lichen planus is a chronic relapsing inflammatory disorder of the skin and mucous membranes. The disease is characterized by band-like T cell infiltrates along the dermal-epidermal junction and apoptosis of basal keratinocytes (38). More recently, compelling data has emerged that documents the presence of desmogelin 3- and COL17-specific, autoreactive T cells in lichen planus. Characterization of the T cell response in lichen planus showed a polarization toward Th1 and Th17 cells. In addition, IL-17-producing cells were found to be present in the skin of lichen planus patients (39). Herein, Solimani et al. follow-up on these observations and report the treatment outcomes of 3 lichen planus patients treated with anti-IL17 (secukinumab). In all 3 patients, a favorable clinical outcome was observed, that was accompanied by a reduced dermal T cell infiltrate. In addition to targeting T cell-derived cytokines, modulation of T cell metabolism is an alternative, but promising approach to treat chronic skin inflammation. One major focus of the articles submitted to the Research Topic was inhibition of Janus kinases (JAK). Based on elaborate pre-clinical work that encompassed genetic studies, transcriptomics as well as use of pre-clinical model systems of chronic skin inflammatory diseases the JAK pathway was identified as a potential therapeutic target for several chronic inflammatory skin diseases (40, 41). In the review by Szilveszter et al., the various tyrosine kinase signaling pathways and their role in autoimmune and inflammatory skin diseases is presented in detail. The focus is on ongoing preclinical trials and clinical studies using small-molecule tyrosine kinase inhibitors in chronic inflammatory diseases. The reviews by Solimani et al. and by Howell et al. focus on the immunological basis and current stage of development of JAK inhibitors in chronic inflammatory indications in dermatology. However, as proposed by Ehrchen et al., insights into the mode of action of “old” drugs, such as glucocorticoids may lead to the identification of novel therapeutic targets. As highlighted by Zeidler et al., pruritus is a highly prevalent in chronic autoimmune diseases, and often is one of the key factors contributing to patient morbidity (42). Of note, and highlighted herein, IL-31 may be one of the key drivers of pruritus. The potential importance of targeting IL-31 to alleviate itch and certain chronic inflammatory skin diseases is highlighted by several clinical trials that have and are evaluating the safety and efficacy of anti-IL-31 treatment (43, 44). In addition to the above articles, CCR2-A in chronic cutaneous lupus erythematosus, neutrophil extracellular traps in Schnitzler’s Syndrome and the skin barrier in pemphigus and pemphigoid have emerged as potential targets and treatment approaches. Clinical and molecular characterization of patients and biomaterials, as well as model systems are an important pilar to understand pathogenetic pathways and identify novel therapeutic targets. As an example for an in-depth characterization of patient samples is the description of a protocol that allows the identification of autoreactive B cell subpopulations in the peripheral blood in patients with pemphigus. Another use of patient-derived biomaterial is its’ functional evaluation, exemplified by the Walter et al., who contrasted the signaling in keratinocytes after binding of either anti-Dsg 1 or anti-Dsg 3 IgG binding. This work demonstrates that pathogenic pathways in pemphigus differ depending on the autoantibodies. Therefore, exact determination of the autoantibody profile in pemphigus patients by the respective serological test systems (45, 46) is the key to personalized treatment approaches in pemphigus. Several articles of this Research Topic described novel animal models or provided in-depth reviews: In most pemphigus patients, autoantibodies against Dsg 1 and/or 3 are present (5), while non-Dsg autoantibodies are found in a minority of patients (47). This may be one of the main reasons, why most pemphigus animal models mirror the immune response against Dsg 1 and/or 3 (48). Only recently, Lotti et al. described a pemphigus mouse model that is based on the transfer of lymphocytes from mice immunized with desmocollin into immunodeficient mice. In addition to this novel pemphigus mouse model, new findings in scurfy mice are described, namely the development of mixed connective tissue disease, and mouse models of Sjögren’s Syndrome are reviewed. Demeyer et al. report on the development of atopic-like dermatitis in ageing MALT1-deficient mice. Given further validation, this new model of atopic dermatitis may be useful to decipher pathogenic pathways in atopic dermatitis. Overall, the field of skin autoimmunity has become a major focus, both in research and clinical practice. This is also reflected by the 68 submissions to the Research Topic that provides state-of-the art reviews, as well as novel insights into skin autoimmune diseases. Overall, each novel insight into the pathogenesis of these severe disease provides clues to better treat and diagnose affected individuals. All authors contributed to the article and approved the submitted version. This work supported the Excellence Cluster “Precision Medicine in Chronic Inflammation” (EXC 2167) from the Deutsche Forschungsgemeinschaft. KK received support from the Alexander von Humboldt Foundation (Humboldt Research Fellowship for Postdoctoral Researchers). MS has received honoraria from AbbVie, Biogen, Almirall, Leo, Novartis, UCB, Janssen, Leo. 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Front Med (2018) 5:218. doi: 10.3389/fmed.2018.00218 CrossRef Full Text | Google Scholar 48. Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, et al. Pemphigus. Nat Rev Dis Primers (2017) 3:17026. doi: 10.1038/nrdp.2017.26 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: skin, autoimmunity, pemphigus, pemphigoid, psoriasis, alopecia aerata (AA) Citation: Kridin K, Bieber K, Sadik CD, Schön MP, Wang G, Loser K and Ludwig RJ (2021) Editorial: Skin Autoimmunity. Front. Immunol. 12:627565. doi: 10.3389/fimmu.2021.627565 Received: 09 November 2020; Accepted: 01 March 2021; Published: 25 March 2021. Edited by: Reviewed by: Copyright © 2021 Kridin, Bieber, Sadik, Schön, Wang, Loser and Ludwig. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Ralf J. Ludwig, [email protected]