Pemphigoid diseases are a group of well defined autoimmune disorders that are characterised by autoantibodies against structural proteins of the dermal–epidermal junction and, clinically, by tense ...blisters and erosions on skin or mucous membranes close to the skin surface. The most common of these diseases is bullous pemphigoid, which mainly affects older people and the reported incidence of which in Europe has more than doubled in the past decade. Prognosis and treatments vary substantially between the different disorders and, since clinical criteria are usually not sufficient, direct immunofluorescence microscopy of a perilesional biopsy specimen or serological tests are needed for exact diagnosis. In eight pemphigoid diseases the target antigens have been identified molecularly, which has allowed the development of standard diagnostic assays for detection of serum autoantibodies—some of which are commercially available. In this Seminar we discuss the clinical range, diagnostic criteria, diagnostic assay systems, and treatment options for this group of diseases.
The dermal‐epidermal junction consists of a network of several interacting structural proteins that strengthen adhesion and mediate signalling events. This structural network consists of ...hemidesmosomal‐anchoring filament complexes connecting the basal keratinocytes to the basement membrane. The anchoring filaments in turn interact with the anchoring fibrils to attach the basement membrane to the underlying dermis. Several of these structural proteins are recognized by autoantibodies in pemphigoid diseases, a heterogeneous group of clinically and immunopathologically diverse entities. Targeted proteins include the two intracellular plakins, plectin isoform 1a and BP230 (also called bullous pemphigoid antigen (BPAG) 1 isoform e (BPAG1e)). Plectin 1a and BP230 are connected to the intermediate filaments and to the cell surface receptor α6β4 integrin, which in turn is connected to laminin 332, a component of the anchoring filaments. Further essential adhesion proteins are BP180, a transmembrane protein, laminin γ1 and type VII collagen. Latter protein is the major constituent of the anchoring fibrils. Mutations in the corresponding genes of these adhesion molecules lead to inherited epidermolysis bullosa emphasizing the importance of these proteins for the integrity of the dermal‐epidermal junction. This review will provide an overview on the structure and function of the proteins situated in the dermal‐epidermal junction targeted by autoantibodies.
Mucous membrane pemphigoid (MMP) is an autoimmune disease characterized by the predominant blistering of mucosal surfaces and the linear deposition of complement, IgG, or IgA along the basement ...membrane detected by direct immunofluorescence (DIF) test.
To assess the impact of multiple and repeated DIF sampling on establishing the diagnosis of MMP.
We reviewed the results of DIF studies in 136 nonlesional biopsies from 78 patients who were immunologically confirmed to have MMP.
Thirty-six of 52 patients (69%) who underwent only 1 biopsy at the first workup were positive. In 13 cases, the initial single biopsy was negative, and later biopsies were positive. Twenty-two of 26 patients (85%) who underwent multiple biopsies at the initial workup showed ≥1 positive DIF test result. Simultaneously obtained biopsies yielded discordant positive and negative findings in 11 patients. Overall, 74 of 78 patients (95%) had ≥1 positive result by DIF test. In the remaining 4 cases, the diagnosis was confirmed by the detection of circulating autoantibodies against BP180.
This is a retrospective, single-center study.
Our data demonstrate that multiple and repeated biopsies increase the sensitivity of the DIF test for MMP diagnosis. Negative DIF test findings in cases clinically suggestive of MMP should prompt repeat biopsies.
Melatonin is an ubiquitous molecule with a variety of functions including potent antioxidative properties. Due to its lipophilic character, it easily crosses cellular and intracellular membranes and ...reaches all subcellular organelles. Because of its ability to scavenge free radicals, melatonin protects against oxidative stress, for example, induced by ultraviolet radiation (UVR). Here, we investigated, in a dose‐dependent (0, 10, 25, and 50 mJ/cm2) and time‐dependent (0, 4, 24, 48 hr post‐UVR) manner, whether melatonin prevents the UVR‐mediated alterations in ATP synthesis and the generation of reactive oxygen species (ROS) in normal human epidermal keratinocytes (NHEK). Additionally, we evaluated the molecular mechanism of action of melatonin with regard to activation of phase‐2 antioxidative enzymes via nuclear erythroid 2‐related factor (Nrf2). We found that (i) melatonin counteracted UVR‐induced alterations in the ATP synthesis and reduced free radical formation; (ii) melatonin induced the translocation of Nrf2 transcription factor from the cytosol into the nucleus resulting in, (iii) melatonin enhanced gene expression of phase‐2 antioxidative enzymes including γ‐glutamylcysteine synthetase (γ‐GCS), heme oxygenase‐1 (HO‐1), and NADPH: quinone dehydrogenase‐1 (NQO1) representing an elevated antioxidative response of keratinocytes. These results suggest that melatonin not only directly scavenges ROS, but also significantly induces the activation of phase‐2 antioxidative enzymes via the Nrf2 pathway uncovering a new action mechanism that supports the ability of keratinocytes to protect themselves from UVR‐mediated oxidative stress.
Tuberculosis, the leading cause of infection-related death in developing regions, is a leading cause of morbidity and mortality worldwide. Screening for, and treatment of, latent Mycobacterium ...tuberculosis infection is routine before initiation of anti-tumour necrosis factor α (anti-TNFα) agents in the management of psoriasis, Crohn's disease, and rheumatoid arthritis. By contrast, screening for latent tuberculosis before immune checkpoint inhibitor treatment in cancer is not routine, despite the increasing number of reports of primary infection with M tuberculosis or reactivation of latent M tuberculosis infection during such treatment. We present our experience with M tuberculosis screening in 70 patients who underwent immune checkpoint inhibitor therapy for metastatic skin cancer. Based on our understanding of the interaction between M tuberculosis and the immune system, we present the argument for tuberculosis screening before immune checkpoint inhibitor therapy and its use when considering anti-TNFα treatment for severe immune-related adverse events. We call for increased vigilance during immune checkpoint inhibition until its effects on tuberculosis pathophysiology are fully ascertained.
Autoimmune skin blistering diseases (AIBD) are characterized by autoantibodies that are directed against structural proteins in the skin and adjacent mucous membranes. Some clinical signs are typical ...for a specific AIBD, however, correct diagnosis requires the detection of tissue-bound or circulating autoantibodies. The gold standard for diagnosis of AIBD is the detection of autoantibodies or complement component 3 by direct immunofluorescence (DIF) microscopy of a perilesional biopsy. Circulating antibodies can be detected via indirect immunofluorescence (IIF) microscopy of different tissue substrates including human skin, monkey esophagus, and more recently, recombinant forms of the different target antigens. Latter are also employed in various commercial ELISA systems and by immunoblotting in in-house assays available in specialized laboratories. ELISA systems are also particularly valuable for monitoring of the disease activity during the disease course which can be helpful for treatment decisions. Exact diagnosis is essential for both treatment and prognosis, since some AIBD are associated with malign tumors such as paraneoplastic pemphigus and anti-laminin 332 mucous membrane pemphigoid. This review presents clinical and immunopathological features of AIBD for the state-of the art diagnosis of these disorders.
BackgroundPsoriasis is a chronic immune-mediated inflammatory disease. Beyond the physical dimensions, the disease has an extensive emotional and psychosocial effect on patients, influencing their ...quality of life, social life and interpersonal relationships. Thus patient-reported outcomes are a crucial instrument for the evaluation of disease burden. Navigating life in times of the COVID-19 pandemic is challenging, especially for persons suffering from chronic diseases. We here analyzed the impact of lockdown restrictions on psoriasis patients.ObjectiveTo compare the Dermatology Life Quality Index (DLQI) before and during the COVID-19 pandemic of patients with psoriasis.MethodsRetrospective longitudinal analysis in adult patients with moderate to severe psoriasis undergoing biologic treatment between January 2020 and January 2021. DLQI, patient demographics, Psoriasis Area and Severity Index (PASI), and recent biologic treatment were recorded.Results103 patients were identified, of whom 19 had additional psoriatic arthritis. Female (n = 29) and male (n = 74) patients were distributed 1 to 3. Median age of patients was 54 years (range 18-85). All patients received biologic systemic treatment: anti-IL-23 (n = 39), anti-IL-17A (n = 30), anti-IL-12/23 (n = 25), or anti-TNFα (n = 9). Comparing DLQI scores before the COVID-19 pandemic and under lockdown restriction showed improved DLQI scores over time. Further analysis displayed that patients mostly ticked "not relevant" on social activities during lockdown. Thus, the DLQI scores may be artificial improved and may not really reflect the actual disease burden.ConclusionsPsoriasis patients showed a contrary improvement of life quality despite harsh COVID-19 lockdown suggesting that DLQI should be modified when social life is restricted.
Diagnosis of autoimmune bullous diseases Beek, Nina; Zillikens, Detlef; Schmidt, Enno
Journal der Deutschen Dermatologischen Gesellschaft,
September 2018, 2018-Sep, 2018-09-00, 20180901, Letnik:
16, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Summary
Autoimmune bullous disorders (AIBDs) are a heterogeneous group of rare diseases clinically characterized by erosions and/or blisters on the skin and mucous membranes. AIBDs can be categorized ...into two groups: pemphigus diseases, characterized by intraepidermal blistering and autoantibodies against desmosomal proteins such as desmoglein (Dsg) 1, Dsg3, members of the plakin family, and subepidermal AIBDs, comprised of pemphigoid diseases and dermatitis herpetiformis. Autoantibodies in dermatitis herpetiformis target transglutaminases 2 and 3, while in pemphigoid disease, autoantibodies are directed against structural proteins of the dermal‐epidermal junction. Although analysis of a perilesional biopsy with direct immunofluorescence (IF) microscopy is still the diagnostic gold standard, several assays have become widely available that allow serological diagnosis in the majority of patients. Standard serological diagnosis includes indirect IF on monkey esophagus and salt‐split human skin. Assays to further characterize autoantibody specificity include ELISA systems based on recombinant forms of the immunodominant regions of the target antigens as well as multivariant indirect IF microscopy tests with several miniature substrates. These serological assays are complemented by various in‐house assays using immunoblotting and ELISA, which are only available in specialized laboratories. Here we review new developments in the diagnosis of AIBDs and describe state‐of‐the‐art diagnostic procedures for this group of diseases.
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