Type 2 T-Cell Responses against Distinct Epitopes of the Desmoglein 3 Ectodomain in Pemphigus Vulgaris.

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.

Disease progression and response to therapy in pemphigus based on a registry.

BACKGROUND AND OBJECTIVES: Pemphigus diseases are potentially life-threatening and rare autoimmune bullous disorders characterized by blisters and erosions of the skin and mucous membranes. These disorders can be largely divided into two major subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). The objective of this study was to evaluate the autoantibody profile and response to therapy of PV and PF patients by analyzing the clinicopathological data from a registry for bullous autoimmune dermatoses. PATIENTS AND METHODS: In a retrospective study, data from 69 patients with PV and PF were included in the analysis. The Autoimmune Bullous Skin Intensity Score (ABSIS) was used to assess the clinical course, remissions, relapses and severity of the disease at first manifestation and throughout the observation period. ELISA was performed to assess levels of anti-desmoglein (Dsg)-1 and anti-Dsg3 IgG serum autoantibodies. RESULTS: The mean remission time in PV and PF patients was 63 weeks. PV patients with mucosal involvement showed a more favorable healing process. In PV patients with a moderate/high anti-Dsg1 IgG serum level at baseline, anti-Dsg3 IgG levels decreased during the observation period. CONCLUSIONS: Our study provides additional insights into the clinical course of patients with PV and PF, revealing that a mucosal phenotype is associated with a higher tendency towards remission.

Register-Studie zu Krankheitsentwicklung und Therapieansprechen bei Pemphigus.

HINTERGRUND UND ZIELE: Pemphigus gehört zu den seltenen, aber potentiell lebensbedrohlichen Autoimmunerkrankungen. Typisch sind Blasen und Erosionen der Haut und der Schleimhäute. Grundsätzlich unterscheiden wir zwei Subtypen: Pemphigus vulgaris (PV) und Pemphigus foliaceus (PF). In dieser Studie wurden die klinisch-pathologischen Daten aus einem Register für bullöse Autoimmundermatosen analysiert mit dem Ziel, das Autoantikörperprofil und das Therapieansprechen bei Patienten mit PV und PF genauer zu charakterisieren. PATIENTEN UND METHODEN: In einer retrospektiven Studie wurden die Daten von 69 Patienten mit PV und PF analysiert. Zur Beurteilung des klinischen Verlaufs, der Remissionen und Rezidive sowie des Schweregrads der Krankheit bei Erstmanifestation und während des gesamten Beobachtungszeitraums diente der ABSIS (Autoimmune Bullous Skin Intensity Score) (ABSIS). Mittels ELISA wurden die Spiegel von Anti-Desmoglein (Dsg)-1- und Anti-Dsg- IgG-Autoantikörpern im Serum bestimmt. ERGEBNISSE: Die mittlere Remissionszeit bei Patienten mit PV und PF betrug 63 Wochen. PV-Patienten mit Schleimhautbeteiligung zeigten eine schnellere Heilung. Bei PV-Patienten mit moderat oder stark erhöhten Anti-Dsg1-IgG-Autoantikörpern im Serum zu Beginn erfolgte im Lauf des Beobachtungszeitraums ein Absinken der Anti-Dsg3-IgG-Spiegel. SCHLUSSFOLGERUNGEN: Unsere Studie liefert neue Erkenntnisse zum Krankheitsverlauf bei Patienten mit PV und PF und offenbart, dass ein Phänotyp mit Schleimhautbeteiligung eine stärkere Neigung zur Remission aufweist.

Autoreactive Peripheral Blood T Helper Cell Responses in Bullous Pemphigoid and Elderly Patients With Pruritic Disorders.

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 (NH2- 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.

Potential Roles of Tumor Cell- and Stroma Cell-Derived Small Extracellular Vesicles in Promoting a Pro-Angiogenic Tumor Microenvironment.

Extracellular vesicles (EVs) are produced and released by all cells and are present in all body fluids. They exist in a variety of sizes, however, small extracellular vesicles (sEVs), the EV subset with a size range from 30 to 150 nm, are of current interest. They are characterized by a distinct biogenesis and complex cargo composition, which reflects the cytosolic contents and cell-surface molecules of the parent cells. This cargo consists of proteins, nucleic acids, and lipids and is competent in inducing signaling cascades in recipient cells after surface interactions or in initiating the generation of a functional protein by delivering nucleic acids. Based on these characteristics, sEVs are now considered as important mediators of intercellular communication. One hallmark of sEVs is the promotion of angiogenesis. It was shown that sEVs interact with endothelial cells (ECs) and promote an angiogenic phenotype, ultimately leading to increased vascularization of solid tumors and disease progression. It was also shown that sEVs reprogram cells in the tumor microenvironment (TME) and act in a functionally cooperative fashion to promote angiogenesis by a paracrine mechanism involving the differential expression and secretion of angiogenic factors from other cell types. In this review, we will focus on the distinct functions of tumor-cell-derived sEVs (TEX) in promotion of angiogenesis and describe their potential as a therapeutic target for anti-angiogenic therapies. Also, we will focus on non-cancer stroma-cell-derived small extracellular vesicles and their potential role in stimulating a pro-angiogenic TME.