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The Interplay between Innate and Adaptive Immunity in Autoimmune Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 20019

Special Issue Editor

Department of Paediatric Pulmonology and Rheumatology, Medical University of Lublin, 20-093 Lublin, Poland
Interests: rheumatology; immunology; autoimmune; autoinflammatory disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, advances in understanding the pathomechanisms of autoimmune diseases have led to new therapy pathways with great benefits for patients. Nevertheless, the trigger factors and mechanisms affecting the disease development, its activity, and response to therapy remain unknown.

The key mechanism of autoimmune disorder is loss of immune tolerance against self-antigens, leading to unregulated immune activation and tissue damage. These disorders affect different types of components of the immune response, including innate and adaptive immune cells, cytokines, and complements . A better understanding of the mechanisms underlying the development of autoimmune diseases is essential for the development of new diagnostic methods, markers of disease activity, and specific treatments.

The aim of this Special Issue is to present the current progress in autoimmune diseases include but not limited to rheumatic diseases. Please note that the IJMS provides a forum for the publication of molecular research in biology and chemistry, with a strong focus on molecular biology and molecular medicine.  Therefore, clinical observations should be directed to other journals.

Dr. Violetta Opoka-Winiarska
Guest Editor

Manuscript Submission Information

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Keywords

  • rheumatic diseases
  • autoimmune diseases
  • trigger factors
  • immune tolerance
  • self-antigens
  • components
  • cytokines
  • complements

Published Papers (7 papers)

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Research

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18 pages, 1822 KiB  
Article
Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation
by Aurélie Philippe, Gunnar Kleinau, Jason Jannis Gruner, Sumin Wu, Daniel Postpieszala, David Speck, Harald Heidecke, Simon J. Dowell, Gabriela Riemekasten, Peter W. Hildebrand, Julian Kamhieh-Milz, Rusan Catar, Michal Szczepek, Duska Dragun and Patrick Scheerer
Int. J. Mol. Sci. 2022, 23(7), 3984; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073984 - 02 Apr 2022
Cited by 5 | Viewed by 2962
Abstract
The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1R can also be activated by auto-antibodies (AT [...] Read more.
The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation, as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R signaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to potentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that Ang II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1R-Abs-induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation. Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R containing EL1 and EL3 blockwise alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface, we at least confirmed that parts of EL2 are involved in interactions between AT1R and Abs. This current study thus provides extended insights into the molecular action of AT1R-Abs and associated mechanisms of interrelated pathogenesis. Full article
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16 pages, 2065 KiB  
Article
Autoantibodies Targeting AT1- and ETA-Receptors Link Endothelial Proliferation and Coagulation via Ets-1 Transcription Factor
by Rusan Catar, Melanie Herse-Naether, Nan Zhu, Philine Wagner, Oskar Wischnewski, Angelika Kusch, Julian Kamhieh-Milz, Andreas Eisenreich, Ursula Rauch, Björn Hegner, Harald Heidecke, Angela Kill, Gabriela Riemekasten, Gunnar Kleinau, Patrick Scheerer, Duska Dragun and Aurelie Philippe
Int. J. Mol. Sci. 2022, 23(1), 244; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010244 - 27 Dec 2021
Cited by 8 | Viewed by 3295
Abstract
Scleroderma renal crisis (SRC) is an acute life-threatening manifestation of systemic sclerosis (SSc) caused by obliterative vasculopathy and thrombotic microangiopathy. Evidence suggests a pathogenic role of immunoglobulin G (IgG) targeting G-protein coupled receptors (GPCR). We therefore dissected SRC-associated vascular obliteration and investigated the [...] Read more.
Scleroderma renal crisis (SRC) is an acute life-threatening manifestation of systemic sclerosis (SSc) caused by obliterative vasculopathy and thrombotic microangiopathy. Evidence suggests a pathogenic role of immunoglobulin G (IgG) targeting G-protein coupled receptors (GPCR). We therefore dissected SRC-associated vascular obliteration and investigated the specific effects of patient-derived IgG directed against angiotensin II type 1 (AT1R) and endothelin-1 type A receptors (ETAR) on downstream signaling events and endothelial cell proliferation. SRC-IgG triggered endothelial cell proliferation via activation of the mitogen-activated protein kinase (MAPK) pathway and subsequent activation of the E26 transformation-specific-1 transcription factor (Ets-1). Either AT1R or ETAR receptor inhibitors/shRNA abrogated endothelial proliferation, confirming receptor activation and Ets-1 signaling involvement. Binding of Ets-1 to the tissue factor (TF) promoter exclusively induced TF. In addition, TF inhibition prevented endothelial cell proliferation. Thus, our data revealed a thus far unknown link between SRC-IgG-induced intracellular signaling, endothelial cell proliferation and active coagulation in the context of obliterative vasculopathy and SRC. Patients’ autoantibodies and their molecular effectors represent new therapeutic targets to address severe vascular complications in SSc. Full article
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13 pages, 4342 KiB  
Article
Toll-like Receptor Signaling Inhibitory Peptide Improves Inflammation in Animal Model and Human Systemic Lupus Erythematosus
by Wook-Young Baek, Yang-Seon Choi, Sang-Won Lee, In-Ok Son, Ki-Woong Jeon, Sang-Dun Choi and Chang-Hee Suh
Int. J. Mol. Sci. 2021, 22(23), 12764; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312764 - 25 Nov 2021
Cited by 7 | Viewed by 2474
Abstract
Toll-like receptors (TLRs) play a major role in the innate immune system. Several studies have shown the regulatory effects of TLR-mediated pathways on immune and inflammatory diseases. Dysregulated functions of TLRs within the endosomal compartment, including TLR7/9 trafficking, may cause systemic lupus erythematosus [...] Read more.
Toll-like receptors (TLRs) play a major role in the innate immune system. Several studies have shown the regulatory effects of TLR-mediated pathways on immune and inflammatory diseases. Dysregulated functions of TLRs within the endosomal compartment, including TLR7/9 trafficking, may cause systemic lupus erythematosus (SLE). TLR signaling pathways are fine-tuned by Toll/interleukin-1 receptor (TIR) domain-containing adapters, leading to interferon (IFN)-α production. This study describes a TLR inhibitor peptide 1 (TIP1) that primarily suppresses the downstream signaling mediated by TIR domain-containing adapters in an animal model of lupus and patients with SLE. The expression of most downstream proteins of the TLR7/9/myeloid differentiation factor 88 (MyD88)/IFN regulatory factor 7 signaling was downregulated in major tissues such as the kidney, spleen, and lymph nodes of treated mice. Furthermore, the pathological analysis of the kidney tissue confirmed that TIP1 could improve inflammation in MRL/lpr mice. TIP1 treatment downregulated many downstream proteins associated with TLR signaling, such as MyD88, interleukin-1 receptor-associated kinase, tumor necrosis factor receptor-associated factor 6, and IFN-α, in the peripheral blood mononuclear cells of patients with SLE. In conclusion, our data suggest that TIP1 can serve as a potential candidate for the treatment of SLE. Full article
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15 pages, 2155 KiB  
Article
Reduction of Oxidative Stress in Peripheral Blood Mononuclear Cells Attenuates the Inflammatory Response of Fibroblast-like Synoviocytes in Rheumatoid Arthritis
by Ha-Reum Lee, Su-Jin Yoo, Jinhyun Kim, Chan Keol Park and Seong Wook Kang
Int. J. Mol. Sci. 2021, 22(22), 12411; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212411 - 17 Nov 2021
Cited by 9 | Viewed by 1662
Abstract
The production and oxidation mechanism of reactive oxygen species (ROS) are out of balance in rheumatoid arthritis (RA). However, the correlation between ROS and T cell subsets in RA remains unclear. Peripheral blood mononuclear cells (PBMCs) from patients with RA (n = 40) [...] Read more.
The production and oxidation mechanism of reactive oxygen species (ROS) are out of balance in rheumatoid arthritis (RA). However, the correlation between ROS and T cell subsets in RA remains unclear. Peripheral blood mononuclear cells (PBMCs) from patients with RA (n = 40) and healthy controls (n = 10) were isolated from whole blood samples. Synovial tissues (n = 3) and synovial fluid (n = 10) were obtained from patients with RA. The repartition of T cell subsets and expression of ROS and cytokines were examined according to RA severity. Fibroblast-like synoviocytes (FLSs) from patients with RA were stimulated with PBMCs and the expression of inflammation-related molecules were measured by RT-PCR and cytokine array. Regulatory T cells from patients with moderate (5.1 > DAS28 ≥ 3.2) RA showed the highest expression of mitochondrial ROS among the groups based on disease severity. Although ROS levels steadily increased with RA severity, there was a slight decline in severe RA (DAS28 ≥ 5.1) compared with moderate RA. The expression of inflammatory cytokines in RA FLSs were significantly inhibited when FLSs were co-cultured with PBMCs treated with ROS inhibitor. These findings provide a novel approach to suppress inflammatory response of FLSs through ROS regulation in PBMCs. Full article
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20 pages, 30667 KiB  
Article
Impaired Innate Immunity in Pediatric Patients Type 1 Diabetes—Focus on Toll-like Receptors Expression
by Katarzyna Kurianowicz, Maria Klatka, Agnieszka Polak, Anna Hymos, Dominika Bębnowska, Martyna Podgajna, Rafał Hrynkiewicz, Olga Sierawska and Paulina Niedźwiedzka-Rystwej
Int. J. Mol. Sci. 2021, 22(22), 12135; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212135 - 09 Nov 2021
Cited by 4 | Viewed by 1918
Abstract
Type 1 diabetes (DM1) is classified as an autoimmune disease. An uncontrolled response of B and T lymphocytes to the body’s own tissues develops in the absence of immune tolerance. The main aim of the study was to evaluate the effect of the [...] Read more.
Type 1 diabetes (DM1) is classified as an autoimmune disease. An uncontrolled response of B and T lymphocytes to the body’s own tissues develops in the absence of immune tolerance. The main aim of the study was to evaluate the effect of the duration of type 1 diabetes in children on the expression of TLR receptors and the relationship with the parameters of glycemic control in patients. As a result, we showed significant differences in the level of TLR2, TLR4 and TLR9 expression in patients with DM1 in the early stage of the disease and treated chronically compared to the healthy group. Additionally, in this study, we found that the numbers of CD19+ B cells, CD3+ CD4+, CD3+ CD8+ T cells and NK cells are different for newly diagnosed DM1 individuals, patients receiving chronic treatment and for healthy controls, indicating an important role of these cells in killing pancreatic beta cells. Moreover, higher levels of IL-10 in patients with newly diagnosed DM1 have also been found, confirming the reports found in the literature. Full article
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Review

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17 pages, 1165 KiB  
Review
Potential Therapeutic Application of Regulatory T Cells in Diabetes Mellitus Type 1
by Iwona Ben-Skowronek, Joanna Sieniawska, Emilia Pach, Wiktoria Wrobel, Anna Skowronek, Zaklina Tomczyk and Iga Rosolowska
Int. J. Mol. Sci. 2022, 23(1), 390; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010390 - 30 Dec 2021
Cited by 5 | Viewed by 3128
Abstract
The autoimmune reaction against the beta cells of the pancreatic islets in type 1 diabetes mellitus (T1DM) patients is active in prediabetes and during the development of the clinical manifestation of T1DM, but it decreases within a few years of the clinical manifestation [...] Read more.
The autoimmune reaction against the beta cells of the pancreatic islets in type 1 diabetes mellitus (T1DM) patients is active in prediabetes and during the development of the clinical manifestation of T1DM, but it decreases within a few years of the clinical manifestation of this disease. A key role in the pathogenesis of T1DM is played by regulatory T cell (Treg) deficiency or dysfunction. Immune interventions, such as potential therapeutic applications or the induction of the Treg-cell population in T1DM, will be important in the development of new types of treatment. The aim of this study was to evaluate innovative immune interventions as treatments for T1DM. After an evaluation of full-length papers from the PubMed database from 2010 to 2021, 20 trials were included for the final analysis. The analysis led to the following conclusions: Treg cells play an important role in the limitation of the development of T1DM, the activation or application of Tregs may be more effective in the early stages of T1DM development, and the therapeutic use of Treg cells in T1DM is promising but requires long-term observation in a large group of patients. Full article
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13 pages, 1110 KiB  
Review
Pathophysiology of the Different Clinical Phenotypes of Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
by Edyta Dziadkowiak, Marta Waliszewska-Prosół, Marta Nowakowska-Kotas, Sławomir Budrewicz, Zofia Koszewicz and Magdalena Koszewicz
Int. J. Mol. Sci. 2022, 23(1), 179; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010179 - 24 Dec 2021
Cited by 10 | Viewed by 3747
Abstract
Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common form of autoimmune polyneuropathy. It is a chronic disease and may be monophasic, progressive or recurrent with exacerbations and incomplete remissions, causing accumulating disability. In recent years, there has been rapid progress in understanding [...] Read more.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common form of autoimmune polyneuropathy. It is a chronic disease and may be monophasic, progressive or recurrent with exacerbations and incomplete remissions, causing accumulating disability. In recent years, there has been rapid progress in understanding the background of CIDP, which allowed us to distinguish specific phenotypes of this disease. This in turn allowed us to better understand the mechanism of response or non-response to various forms of therapy. On the basis of a review of the relevant literature, the authors present the current state of knowledge concerning the pathophysiology of the different clinical phenotypes of CIDP as well as ongoing research in this field, with reference to key points of immune-mediated processes involved in the background of CIDP. Full article
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