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Lancet (London, England) Sep 2019Pemphigus consists of a group of rare and severe autoimmune blistering diseases mediated by pathogenic autoantibodies mainly directed against two desmosomal adhesion... (Review)
Review
Pemphigus consists of a group of rare and severe autoimmune blistering diseases mediated by pathogenic autoantibodies mainly directed against two desmosomal adhesion proteins, desmoglein (Dsg)1 and Dsg3 (also known as DG1 and DG3), which are present in the skin and surface-close mucosae. The binding of autoantibodies to Dsg proteins induces a separation of neighbouring keratinocytes, in a process known as acantholysis. The two main pemphigus variants are pemphigus vulgaris, which often originates with painful oral erosions, and pemphigus foliaceus, which is characterised by exclusive skin lesions. Pemphigus is diagnosed on the basis of either IgG or complement component 3 deposits (or both) at the keratinocyte cell membrane, detected by direct immunofluorescence microscopy of a perilesional biopsy, with serum anti-Dsg1 or anti-Dsg3 antibodies (or both) detected by ELISA. Corticosteroids are the therapeutic mainstay, which have recently been complemented by the anti-CD20 antibody rituximab in moderate and severe disease. Rituximab induces complete remission off therapy in 90% of patients, despite rapid tapering of corticosteroids, thus allowing for a major corticosteroid-sparing effect and a halved number of adverse events related to corticosteroids.
Topics: Adrenal Cortex Hormones; Azathioprine; Desmoglein 1; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin G; Immunosuppressive Agents; Pemphigus; Rituximab; Treatment Outcome
PubMed: 31498102
DOI: 10.1016/S0140-6736(19)31778-7 -
Nature Reviews. Disease Primers May 2017Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell... (Review)
Review
Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell-cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20 B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases.
Topics: Adrenal Cortex Hormones; Animals; Autoantibodies; Desmoglein 1; Desmoglein 3; Disease Models, Animal; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Mice; Pemphigus; Plasmapheresis; Treatment Outcome
PubMed: 28492232
DOI: 10.1038/nrdp.2017.26 -
Journal of the American Academy of... Oct 2020Antineoplastic agents that use the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal... (Review)
Review
Antineoplastic agents that use the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal antibodies that block cytotoxic T-lymphocyte-associated antigen-4, programmed cell death protein 1, or programmed cell death ligand 1 show improved and sustained responses in patients with cancer. However, these agents are associated with a plethora of adverse events, many manifesting in the skin. As the clinical application of cancer immunotherapies expands, understanding the clinical and histopathologic features of associated cutaneous toxicities becomes increasingly important to dermatologists, oncologists, and pathologists to ensure timely diagnosis and appropriate care. This review discusses cutaneous reactions to immune checkpoint inhibitors, focusing on histopathologic features.
Topics: Acantholysis; Alopecia; Drug Eruptions; Humans; Immune Checkpoint Inhibitors; Keratinocytes; Lichenoid Eruptions; Nevus, Pigmented; Panniculitis; Pemphigoid, Bullous; Pruritus; Psoriasis; Stevens-Johnson Syndrome; Vitiligo
PubMed: 32360716
DOI: 10.1016/j.jaad.2020.04.105 -
Annual Review of Pathology Jan 2017Chronic rhinosinusitis (CRS) is a troublesome, chronic inflammatory disease that affects over 10% of the adult population, causing decreased quality of life, lost... (Review)
Review
Chronic rhinosinusitis (CRS) is a troublesome, chronic inflammatory disease that affects over 10% of the adult population, causing decreased quality of life, lost productivity, and lost time at work and leading to more than a million surgical interventions annually worldwide. The nose, paranasal sinuses, and associated lymphoid tissues play important roles in homeostasis and immunity, and CRS significantly impairs these normal functions. Pathogenic mechanisms of CRS have recently become the focus of intense investigations worldwide, and significant progress has been made. The two main forms of CRS that have been long recognized, with and without nasal polyps, are each now known to be heterogeneous, based on underlying mechanism, geographical location, and race. Loss of the immune barrier, including increased permeability of mucosal epithelium and reduced production of important antimicrobial substances and responses, is a common feature of many forms of CRS. One form of CRS with polyps found worldwide is driven by the cytokines IL-5 and IL-13 coming from Th2 cells, type 2 innate lymphoid cells, and probably mast cells. Type 2 cytokines activate inflammatory cells that are implicated in the pathogenic mechanism, including mast cells, basophils, and eosinophils. New classes of biological drugs that block the production or action of these cytokines are making important inroads toward new treatment paradigms in polypoid CRS.
Topics: Adult; Chronic Disease; Humans; Nasal Polyps; Rhinitis; Sinusitis
PubMed: 27959637
DOI: 10.1146/annurev-pathol-052016-100401 -
Dermatology Practical & Conceptual Jul 2020Autoimmune bullous disorders are a heterogeneous spectrum of skin disorders characterized by the production of autoantibodies against adhesion molecules of the skin. The... (Review)
Review
Autoimmune bullous disorders are a heterogeneous spectrum of skin disorders characterized by the production of autoantibodies against adhesion molecules of the skin. The 2 major groups of diseases are "pemphigus diseases" and "autoimmune bullous diseases of the pemphigoid type." Pemphigus diseases are a group of autoimmune blistering diseases of the skin and mucous membranes characterized by intraepithelial cleft and acantholysis. The main subtypes of pemphigus include pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus. Diagnosis is based on clinical manifestations and confirmed with histological, immunofluorescence, and serological testing. Recently multivariant enzyme-linked immunosorbent assay systems have been developed as practical screening tools for patients with suspected autoimmune bullous dermatoses. The current first-line treatment of pemphigus is based on systemic corticosteroids that are often combined with immunosuppressive adjuvants, such as azathioprine, mycophenolate mofetil, and the anti-CD20 monoclonal antibody rituximab, usually at initiation of treatment. Rituximab efficacy is higher when it is administered early in the course of the disease. Therefore, it should be used as first-line treatment to improve efficacy and reduce cumulative doses of corticosteroids and their side effects. Treatment of bullous pemphigoid is based on disease extension. Localized and mild forms can be treated with superpotent topical corticosteroids or with nonimmunosuppressive agents. In patients with generalized disease or whose disease is resistant to the treatments described above, systemic corticosteroids are preferred and effective. Adjuvant immunosuppressants are often combined with steroids for their steroid-sparing effect.
PubMed: 32642305
DOI: 10.5826/dpc.1003a50 -
Giornale Italiano Di Dermatologia E... Jun 2018The involvement of the oral mucosa in patients affected by pemphigus vulgaris (PV), paraneoplastic, IgA pemphigus, and in some cases iatrogenic pemphigus is common and... (Review)
Review
The involvement of the oral mucosa in patients affected by pemphigus vulgaris (PV), paraneoplastic, IgA pemphigus, and in some cases iatrogenic pemphigus is common and often a prelude to skin lesions. Intraepidermal bullae are caused by acantholysis, induced by IgG autoantibodies directed against the desmosomes and the domain of numerous keratinocytes self-antigens desmogleins (namely cadherins), thus supporting the autoimmune nature of the disease. Apoptosis may contribute to the acantholysis. Oral mucosal lesions are more commonly refractory to treatment compared to skin lesions and have been associated with disease duration, disease location and possibly the presence of HSV DNA in the oral cavity. Recent publications have stressed the positive role of Rituximab in early disease treatment.
Topics: Acantholysis; Apoptosis; Autoantibodies; Humans; Immunoglobulin G; Immunologic Factors; Mouth Mucosa; Pemphigus; Rituximab
PubMed: 29512980
DOI: 10.23736/S0392-0488.18.05887-X -
Modern Pathology : An Official Journal... Jul 2023The diagnosis of oral epithelial dysplasia is based on the degree of architectural and cytologic atypia in the squamous epithelium. The conventional grading system of...
The diagnosis of oral epithelial dysplasia is based on the degree of architectural and cytologic atypia in the squamous epithelium. The conventional grading system of mild, moderate, and severe dysplasia is considered by many the gold standard in predicting the risk of malignant transformation. Unfortunately, some low-grade lesions, with or without dysplasia, progress to squamous cell carcinoma (SCC) in short periods. As a result, we are proposing a new approach to characterize oral dysplastic lesions that will help identify lesions at high risk for malignant transformation. We included a total of 203 cases of oral epithelial dysplasia, proliferative verrucous leukoplakia, lichenoid, and commonly observed mucosal reactive lesions to evaluate their p53 immunohistochemical (IHC) staining patterns. We identified 4 wild-type patterns, including scattered basal, patchy basal/parabasal, null-like/basal sparing, mid-epithelial/basal sparing, and 3 abnormal p53 patterns, including overexpression basal/parabasal only, overexpression basal/parabasal to diffuse, and null. All cases of lichenoid and reactive lesions exhibited scattered basal or patchy basal/parabasal patterns, whereas human papillomavirus-associated oral epithelial dysplasia demonstrated null-like/basal sparing or mid-epithelial/basal sparing patterns. Of the oral epithelial dysplasia cases, 42.5% (51/120) demonstrated an abnormal p53 IHC pattern. p53 abnormal oral epithelial dysplasia was significantly more likely to progress to invasive SCC when compared to p53 wild-type oral epithelial dysplasia (21.6% vs 0%, P < .0001). Furthermore, p53 abnormal oral epithelial dysplasia was more likely to have dyskeratosis and/or acantholysis (98.0% vs 43.5%, P < .0001). We propose the term p53 abnormal oral epithelial dysplasia to highlight the importance of utilizing p53 IHC stain to recognize lesions that are at high risk of progression to invasive disease, irrespective of the histologic grade, and propose that these lesions should not be graded using the conventional grading system to avoid delayed management.
Topics: Humans; Tumor Suppressor Protein p53; Mouth Neoplasms; Immunohistochemistry; Leukoplakia, Oral; Carcinoma, Squamous Cell; Hyperplasia; Cell Transformation, Neoplastic
PubMed: 36906072
DOI: 10.1016/j.modpat.2023.100153 -
Dermatology Online Journal Dec 2016We present a 58-year-old woman with bipolardisorder and with a longstanding history of yellowbrown,hyperkeratotic papules in a seborrheicdistribution and nail changes....
We present a 58-year-old woman with bipolardisorder and with a longstanding history of yellowbrown,hyperkeratotic papules in a seborrheicdistribution and nail changes. Her father andpaternal grandmother had similar eruptions and alsohad psychiatric disease. Histopathologic examinationshowed acantholysis and dyskeratosis, which wasconsistent with Darier-White disease. Darier-Whitedisease is a rare, hereditary disorder that is inheritedin an autosomal dominant manner and that usuallypresents in adolescence or early adulthood dueto mutations in the SERCA2 calcium pump. Theresultant alterations in calcium homeostasis affectdesmosome assembly and lead to acantholysis andapoptosis, which creates the characteristic eruption.Genetic linkage analysis of affected families showsthat a susceptibility locus for bipolar disorder cosegregateswith genetic markers that are found inthe Darier-White disease region. Treatments, whichinclude topical emollients, mild keratolytics, andtopical or oral retinoids, are aimed at improvingthe appearance of skin, relieving symptoms, andpreventing or treating infectious complications.
Topics: Bipolar Disorder; Darier Disease; Female; Humans; Middle Aged
PubMed: 28329545
DOI: No ID Found -
Ugeskrift For Laeger May 2018Dyskeratosis follicularis (or Darier's disease) is a genetic skin disease with an autosomal dominant inheritance and a prevalence of 1:100,000-1:35,000. Mutations in the... (Review)
Review
Dyskeratosis follicularis (or Darier's disease) is a genetic skin disease with an autosomal dominant inheritance and a prevalence of 1:100,000-1:35,000. Mutations in the gene ATP2A2 encoding the Ca2+-ATPase SERCA2 in the endoplasmatic reticulum lead to acantholysis and dyskeratosis in the epidermis, nails and mucosal membranes with resultant brown-yellow coloured, often infested skin papules and nail changes. The newly established Danish database for genodermatoses is embarking on an extensive registration of all Danish patients with Darier's disease. Hopefully, the establishment of this database will lead to better research and the formation of a patient association.
Topics: Darier Disease; Databases, Factual; Humans; Retinoids
PubMed: 29761773
DOI: No ID Found