Autoimmune Diseases: Molecular Mechanisms and Therapies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 33697

Special Issue Editors


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Guest Editor
Institute of Biochemistry, Medical Faculty, Justus-Liebig University of Giessen, Friedrichstrasse 24, D-35392 Giessen, Germany
Interests: lysosomal storage disorders; vesicular trafficking; endosomal sorting; lysosome biogenesis; mitochondrial diseases; autoimmune disorders
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Guest Editor
Academy for Educational Research and Teacher Training, Goethe University Frankfurt, 60629 Frankfurt am Main, Germany
Interests: mTOR; inflammation; tissue engineering; dermatology
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Special Issue Information

Dear Colleagues,

Autoimmune diseases are caused by the breakage of self-tolerance and the appearance of pathogenic antibodies against normal tissue proteins. These autoantibodies may have a direct, damaging effect on their target tissues, or the autoantibodies may stimulate and activate receptor molecules and induce aberrant downstream effects. Autoimmune diseases target various tissues, such as the epidermis, thyroid, neuromuscular junction, myelinated nerves or the pancreas. The resulting tissue damage is frequently associated with profound inflammation, and the first line of treatment has traditionally been anti-inflammatory therapy with corticosteroids. However, more targeted therapies against specific molecules, such as the CD20 surface antigen (rituximab) or the neonatal Fc receptor, have started to emerge.  

The purpose of this Special Issue is to provide an overview of the molecular mechanisms of human autoimmune diseases and their therapies. We especially welcome manuscripts addressing novel molecular mechanisms of treatments for autoimmune diseases, as well as the characterization of autoantibody effects on their target cells and cellular responses induced by autoantibodies, including signaling. We encourage submission of review articles and original research papers of any length. Our aim is to provide a comprehensive update on autoimmune diseases, their pathomechanisms and therapy options. 

Prof. Dr. Ritva Tikkanen
Prof. Dr. Claudia Bürger 
Guest Editors

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Keywords

  • autoimmune diseases
  • immunity
  • tolerance
  • epidermis
  • thyroid
  • pancreas
  • pemphigus
  • pemphigoid
  • diabetes
  • myasthenia gravis
  • multiple sclerosis
  • Sjögren syndrome
  • ITPP

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Published Papers (7 papers)

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Research

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12 pages, 2213 KiB  
Article
T Regulatory Cell-Associated Tolerance Induction by High-Dose Immunoglobulins in an HLA-Transgenic Mouse Model of Pemphigus
by Christoph Hudemann, Jochen Hoffmann, Enno Schmidt, Michael Hertl and Rüdiger Eming
Cells 2023, 12(9), 1340; https://doi.org/10.3390/cells12091340 - 8 May 2023
Cited by 3 | Viewed by 2240
Abstract
Pemphigus vulgaris (PV) is a potentially lethal autoimmune bullous skin disorder caused by IgG autoantibodies against desmoglein 3 (Dsg3) and Dsg1. During the last three decades, high-dose intravenous immunoglobulins (IVIgs) have been applied as an effective and relatively safe treatment regime in severe, [...] Read more.
Pemphigus vulgaris (PV) is a potentially lethal autoimmune bullous skin disorder caused by IgG autoantibodies against desmoglein 3 (Dsg3) and Dsg1. During the last three decades, high-dose intravenous immunoglobulins (IVIgs) have been applied as an effective and relatively safe treatment regime in severe, therapy-refractory PV. This prompted us to study T- and B- cell polarization by IVIg in a human-Dsg3-dependent mouse model for PV. Using humanized mice transgenic for HLA-DRB1*04:02, which is a highly prevalent haplotype in PV, we employed IVIg in two different experimental approaches: in prevention and quasi-therapeutic settings. Our data show that intraperitoneally applied IVIg was systemically distributed for up to 42 days or longer. IVIg-treated Dsg3-immunized mice exhibited, in contrast to Dsg3-immunized mice without IVIg, significantly less Dsg3-specific IgG, and showed induction of T regulatory cells in lymphatic tissue. Ex vivo splenocyte analysis upon Dsg3-specific stimulation revealed an initial, temporarily reduced antigen-induced cell proliferation, as well as IFN-γ secretion that became less apparent over the course of time. Marginal-zone B cells were initially reduced in the preventive approach but re-expanded over time. In contrast, in the quasi-therapeutic approach, a robust down-regulation in both spleen and lymph nodes was observed. We found a significant down-regulation of the immature transitional 1 (T1) B cells in IVIg-treated mice in the quasi-therapeutic approach, while T2 and T3, representing a healthy stage of B-cell development, appeared to be up-regulated by IVIg. In summary, in two experimental settings employing an active PV mouse model, we demonstrate distinct alterations of T- and B-cell populations upon IVIg treatment, compatible with a tolerance-associated polarization in lymphatic tissue. Our data suggest that the clinical efficacy of IVIg is at least modulated by distinct alterations of T- and B-cell populations compatible with a tolerance-associated polarization in lymphatic tissue. Full article
(This article belongs to the Special Issue Autoimmune Diseases: Molecular Mechanisms and Therapies)
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14 pages, 1066 KiB  
Article
Enhanced Activity of NLRP3 Inflammasome in the Lung of Patients with Anti-Synthetase Syndrome
by Espiridión Ramos-Martinez, Angel E. Vega-Sánchez, Gloria Pérez-Rubio, Mayra Mejia, Ivette Buendía-Roldán, Montserrat I. González-Pérez, Heidegger N. Mateos-Toledo, Warrison A. Andrade, Ramcés Falfán-Valencia and Jorge Rojas-Serrano
Cells 2023, 12(1), 60; https://doi.org/10.3390/cells12010060 - 23 Dec 2022
Cited by 4 | Viewed by 2123
Abstract
Anti-synthetase syndrome (ASSD) is an autoimmune disorder characterized by inflammatory interstitial lung disease (ILD). The main objective of this work was to quantify the concentrations of cytokines and molecules associated with inflammasome activation in bronchoalveolar lavage (BAL) of patients with ASSD and a [...] Read more.
Anti-synthetase syndrome (ASSD) is an autoimmune disorder characterized by inflammatory interstitial lung disease (ILD). The main objective of this work was to quantify the concentrations of cytokines and molecules associated with inflammasome activation in bronchoalveolar lavage (BAL) of patients with ASSD and a comparison group of systemic sclerosis (SSc) patients. Cytokines and lactate dehydrogenase (LDH) were determined using the concentrated BAL protein. The activity of caspase-1 and concentration of NLRP3 with the protein purified from the cell pellet in each group of patients. We found higher caspase-1 levels in ASSD vs. SSc, 1.25 RFU vs. 0.75 RFU p = 0.003, and LDH levels at 0.15 OD vs. 0.09 OD p < 0.001. A significant difference was observed in molecules associated with inflammasome activation, IL-18: 1.42 pg/mL vs. 0.87 pg/mL p = 0.02 and IFN-γ: 0.9 pg/mL vs. 0.86 pg/mL, p = 0.01. A positive correlation was found between caspase-1 and LDH in the patients with ASSD Rho 0.58 (p = 0.008) but not in the SSc group. In patients with ASSD, greater caspase-1 and higher LDH activity were observed in BAL, suggesting cell death due to pyroptosis and activation of the inflammasome pathway. Full article
(This article belongs to the Special Issue Autoimmune Diseases: Molecular Mechanisms and Therapies)
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23 pages, 7408 KiB  
Article
Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?
by Anna Zakrzewicz, Celina Würth, Benedikt Beckert, Simon Feldhoff, Katrien Vanderheyden, Stian Foss, Jan Terje Andersen, Hans de Haard, Peter Verheesen, Vladimir Bobkov and Ritva Tikkanen
Cells 2022, 11(6), 942; https://doi.org/10.3390/cells11060942 - 10 Mar 2022
Cited by 15 | Viewed by 5493 | Correction
Abstract
Pemphigus vulgaris is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of immunoglobulin G binding on the [...] Read more.
Pemphigus vulgaris is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of immunoglobulin G binding on the neonatal Fc receptor, FcRn, results in reduced autoantibody recycling and shortens their half-life, providing a valid treatment option for PV. We have here analyzed the role of FcRn in human keratinocytes treated with antibodies isolated from pemphigus vulgaris patient or with recombinant anti-desmoglein-3 antibodies that induce pathogenic changes in desmosomes, such as loss of monolayer integrity, aberrant desmoglein-3 localization and degradation of desmoglein-3. We show that blocking IgG binding on FcRn by efgartigimod, a recombinant Fc fragment undergoing clinical studies for pemphigus, stabilizes the keratinocyte monolayer, whereas the loss of desmoglein-3 is not prevented by efgartigimod. Our data show that FcRn may play a direct role in the pathogenesis of pemphigus at the level of the autoantibody target cells, the epidermal keratinocytes. Our data suggest that in keratinocytes, FcRn may have functions different from its known function in IgG recycling. Therefore, stabilization of keratinocyte adhesion by FcRn blocking entities may provide a novel treatment paradigm for pemphigus. Full article
(This article belongs to the Special Issue Autoimmune Diseases: Molecular Mechanisms and Therapies)
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Review

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37 pages, 1606 KiB  
Review
Molecular Mechanisms in Autoimmune Thyroid Disease
by Hernando Vargas-Uricoechea
Cells 2023, 12(6), 918; https://doi.org/10.3390/cells12060918 - 16 Mar 2023
Cited by 37 | Viewed by 9697
Abstract
The most common cause of acquired thyroid dysfunction is autoimmune thyroid disease, which is an organ-specific autoimmune disease with two presentation phenotypes: hyperthyroidism (Graves-Basedow disease) and hypothyroidism (Hashimoto’s thyroiditis). Hashimoto’s thyroiditis is distinguished by the presence of autoantibodies against thyroid peroxidase and thyroglobulin. [...] Read more.
The most common cause of acquired thyroid dysfunction is autoimmune thyroid disease, which is an organ-specific autoimmune disease with two presentation phenotypes: hyperthyroidism (Graves-Basedow disease) and hypothyroidism (Hashimoto’s thyroiditis). Hashimoto’s thyroiditis is distinguished by the presence of autoantibodies against thyroid peroxidase and thyroglobulin. Meanwhile, autoantibodies against the TSH receptor have been found in Graves-Basedow disease. Numerous susceptibility genes, as well as epigenetic and environmental factors, contribute to the pathogenesis of both diseases. This review summarizes the most common genetic, epigenetic, and environmental mechanisms involved in autoimmune thyroid disease. Full article
(This article belongs to the Special Issue Autoimmune Diseases: Molecular Mechanisms and Therapies)
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17 pages, 697 KiB  
Review
Hashimoto Encephalopathy—Still More Questions than Answers
by Marta Waliszewska-Prosół and Maria Ejma
Cells 2022, 11(18), 2873; https://doi.org/10.3390/cells11182873 - 14 Sep 2022
Cited by 23 | Viewed by 6103
Abstract
The normal function of the nervous system is conditioned by the undisturbed function of the thyroid gland and its hormones. Comprehensive clinical manifestations, including neurological disorders in Hashimoto’s thyroiditis, have long been understood and, in recent years, attention has been paid to neurological [...] Read more.
The normal function of the nervous system is conditioned by the undisturbed function of the thyroid gland and its hormones. Comprehensive clinical manifestations, including neurological disorders in Hashimoto’s thyroiditis, have long been understood and, in recent years, attention has been paid to neurological symptoms in euthyroid patients. Hashimoto encephalopathy is a controversial and poorly understood disease entity and the pathogenesis of the condition remains unclear. We still derive our understanding of this condition from case reports, but on the basis of these, a clear clinical picture of this entity can be proposed. Based on a review of the recent literature, the authors present the current view on the subject, discuss controversies and questions that still remain unanswered, as well as ongoing research in this area and the results of our own work in patients with Hashimoto’s thyroiditis. Full article
(This article belongs to the Special Issue Autoimmune Diseases: Molecular Mechanisms and Therapies)
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Other

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2 pages, 1812 KiB  
Correction
Correction: Zakrzewicz et al. Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus? Cells 2022, 11, 942
by Anna Zakrzewicz, Celina Würth, Benedikt Beckert, Simon Feldhoff, Katrien Vanderheyden, Stian Foss, Jan Terje Andersen, Hans de Haard, Peter Verheesen, Vladimir Bobkov and Ritva Tikkanen
Cells 2022, 11(10), 1700; https://doi.org/10.3390/cells11101700 - 20 May 2022
Cited by 2 | Viewed by 1435
Abstract
The authors wish to make the following changes to their paper [...] Full article
(This article belongs to the Special Issue Autoimmune Diseases: Molecular Mechanisms and Therapies)
22 pages, 1529 KiB  
Hypothesis
Pathogenic Mechanism of Autoimmune Diabetes Mellitus in Humans: Potential Role of Streptozotocin-Induced Selective Autoimmunity against Human Islet β-Cells
by Bao Ting Zhu
Cells 2022, 11(3), 492; https://doi.org/10.3390/cells11030492 - 31 Jan 2022
Cited by 10 | Viewed by 4902
Abstract
Human type 1 diabetes mellitus is a chronic autoimmune disease characterized by the selective loss of insulin-producing β-cells in pancreatic islets of genetically susceptible individuals. In this communication, a new hypothesis is postulated which is based on the observations that streptozotocin (STZ), [...] Read more.
Human type 1 diabetes mellitus is a chronic autoimmune disease characterized by the selective loss of insulin-producing β-cells in pancreatic islets of genetically susceptible individuals. In this communication, a new hypothesis is postulated which is based on the observations that streptozotocin (STZ), a chemically reactive and cytotoxic compound produced by certain gram-positive bacteria, can be preferentially taken up into islet β-cells and induce cytotoxicity and autoimmunity. It is hypothesized that humans might be occasionally exposed to STZ through opportunistic infections with the STZ-producing bacteria and/or through ingestion of certain food products that contain STZ. In addition, the potential presence of the STZ-producing bacteria in the gut microbiota of some individuals might be another source of long-term STZ exposure. Because of the high chemical reactivity of STZ and its breakdown products, these chemicals can covalently modify certain cellular macromolecules (e.g., DNA and proteins), and the covalently modified cellular components would serve as new antigens, potentially capable of inducing both humoral and cellular autoimmune responses in the islets of certain individuals. In addition to STZ exposure, the eventual development of autoimmunity against STZ-exposed islet β-cells also depends critically on the genetic predisposition of the susceptible individuals plus the opportunistic presence of a conducive, strong environmental trigger, which often is presented as severe febrile viral infections subsequently inducing strong aberrant reactions of the body’s immune system. The proposed pathogenic hypothesis is supported by a considerable body of direct and indirect evidence from laboratory animal studies and clinical observations. Certainly, more experimental and clinical studies are needed to carefully further examine each of the key components of the proposed pathogenic hypothesis. Full article
(This article belongs to the Special Issue Autoimmune Diseases: Molecular Mechanisms and Therapies)
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