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Molecular and Cellular Basis of Autoimmune Diseases
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Molecular and Cellular Basis of Autoimmune Diseases

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

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 87452

Special Issue Editor

Dr. Yasmina Juarranz

E-Mail Website1 Website2
Guest Editor
Department of Cell Biology, Faculty of Biology and Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain
Interests: autoimmune diseases; rheumatoid arthritis; immune response; T helper cells; neuropeptides; vasoactive intestinal peptide
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The characteristics of autoimmune diseases make them one of the main objectives of study in the biosanitary field, since they affect a wide spectrum of the population. Genetic background, epigenetic modifications, and environmental factors are regarded as aetiological factors, and, as a consequence, an inadequate immunological tolerance towards critical self-antigens is induced, which is characteristic of all autoimmune diseases. During the whole process, a cascade of events takes place leading to a variety of molecular and cellular alterations that can be both cause or consequence of these pathologies. Recent works have examined the role of microbiota; the receptors involved in the recognition of pathogens (PRR); molecules involved in inflammation, chemotaxis or cell activation; the differentiation and plasticity of B or T lymphocytes; self-antigens; or extracellular vesicles as important mediators in these pathologies.

Therefore, this Special Issue will summarize the latest molecular and cellular mechanisms involved in autoimmune diseases, both as a consequence and as a cause of them. The use of molecular and cellular targets as potential therapies to prevent or treat the progression of these diseases will also be addressed.

We look forward to your contributions.

Dr. Yasmina Juarranz
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • autoimmune diseases
  • microbiota
  • pattern recognition receptor
  • inflammation
  • chemotaxis
  • T lymphocytes
  • B lymphocytes
  • extracellular vesicles
  • biomarkers
  • therapeutic targets

Published Papers (18 papers)

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Editorial

Jump to: Research, Review

7 pages, 234 KiB  
Editorial
Molecular and Cellular Basis of Autoimmune Diseases
by Yasmina Juarranz
Cells 2021, 10(2), 474; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020474 - 23 Feb 2021
Cited by 9 | Viewed by 2442
Abstract
The defense organization of our organism is found in the immune system, which has two important components, the innate and the adaptive immunity, where different molecules, cells, and organs are involved and coordinated to protect us from external and internal damage [...] Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)

Research

Jump to: Editorial, Review

19 pages, 2795 KiB  
Article
Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice
by Rocio Flores-Fernández, Angélica Aponte-López, Mayra C. Suárez-Arriaga, Patricia Gorocica-Rosete, Alberto Pizaña-Venegas, Luis Chávez-Sanchéz, Francico Blanco-Favela, Ezequiel M. Fuentes-Pananá and Adriana K. Chávez-Rueda
Cells 2021, 10(2), 316; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020316 - 04 Feb 2021
Cited by 8 | Viewed by 2675
Abstract
Self-reactive immature B cells are eliminated through apoptosis by tolerance mechanisms, failing to eliminate these cells results in autoimmune diseases. Prolactin is known to rescue immature B cells from B cell receptor engagement-induced apoptosis in lupus-prone mice. The objective of this study was [...] Read more.
Self-reactive immature B cells are eliminated through apoptosis by tolerance mechanisms, failing to eliminate these cells results in autoimmune diseases. Prolactin is known to rescue immature B cells from B cell receptor engagement-induced apoptosis in lupus-prone mice. The objective of this study was to characterize in vitro prolactin signaling in immature B cells, using sorting, PCR array, RT-PCR, flow cytometry, and chromatin immunoprecipitation. We found that all B cell maturation stages in bone marrow express the prolactin receptor long isoform, in both wild-type and MRL/lpr mice, but its expression increased only in the immature B cells of the latter, particularly at the onset of lupus. In these cells, activation of the prolactin receptor promoted STAT3 phosphorylation and upregulation of the antiapoptotic Bcl2a1a, Bcl2l2, and Birc5 genes. STAT3 binding to the promoter region of these genes was confirmed through chromatin immunoprecipitation. Furthermore, inhibitors of prolactin signaling and STAT3 activation abolished the prolactin rescue of self-engaged MRL/lpr immature B cells. These results support a mechanism in which prolactin participates in the emergence of lupus through the rescue of self-reactive immature B cell clones from central tolerance clonal deletion through the activation of STAT3 and transcriptional regulation of a complex network of genes related to apoptosis resistance. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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21 pages, 1860 KiB  
Article
Herpesvirus Antibodies, Vitamin D and Short-Chain Fatty Acids: Their Correlation with Cell Subsets in Multiple Sclerosis Patients and Healthy Controls
by Maria Inmaculada Dominguez-Mozo, Silvia Perez-Perez, Noelia Villarrubia, Lucienne Costa-Frossard, Jose Ignacio Fernandez-Velasco, Isabel Ortega-Madueño, Maria Angel Garcia-Martinez, Estefania Garcia-Calvo, Hector Estevez, Jose Luis Luque Garcia, Maria Josefa Torrejon, Rafael Arroyo, Luisa Maria Villar and Roberto Alvarez-Lafuente
Cells 2021, 10(1), 119; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010119 - 10 Jan 2021
Cited by 12 | Viewed by 2793
Abstract
Although the etiology of multiple sclerosis (MS) is still unknown, it is commonly accepted that environmental factors could contribute to the disease. The objective of this study was to analyze the humoral response to Epstein-Barr virus, human herpesvirus 6A/B and cytomegalovirus, and the [...] Read more.
Although the etiology of multiple sclerosis (MS) is still unknown, it is commonly accepted that environmental factors could contribute to the disease. The objective of this study was to analyze the humoral response to Epstein-Barr virus, human herpesvirus 6A/B and cytomegalovirus, and the levels of 25-hydroxyvitamin D (25(OH)D) and the three main short-chain fatty acids (SCFA), propionate (PA), butyrate (BA) and acetate (AA), in MS patients and healthy controls (HC) to understand how they could contribute to the pathogenesis of the disease. With this purpose, we analyzed the correlations among them and with different clinical variables and a wide panel of cell subsets. We found statistically significant differences for most of the environmental factors analyzed when we compared MS patients and HC, supporting their possible involvement in the disease. The strongest correlations with the clinical variables and the cell subsets analyzed were found for 25(OH)D and SCFAs levels. A correlation was also found between 25(OH)D and PA/AA ratio, and the interaction between these factors negatively correlated with interleukin 17 (IL-17)-producing CD4+ and CD8+ T cells in untreated MS patients. Therapies that simultaneously increase vitamin D levels and modify the proportion of SCFA could be evaluated in the future. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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Graphical abstract

16 pages, 3176 KiB  
Article
Adaptive Immunity and Pathogenesis of Diabetes: Insights Provided by the α4–Integrin Deficient NOD Mouse
by Salim Oulghazi, Sarah K. Wegner, Gabriele Spohn, Nina Müller, Sabine Harenkamp, Albrecht Stenzinger, Thalia Papayannopoulou and Halvard Bonig
Cells 2020, 9(12), 2597; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122597 - 04 Dec 2020
Cited by 4 | Viewed by 3683
Abstract
Background: The spontaneously diabetic “non-obese diabetic” (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Methods: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of [...] Read more.
Background: The spontaneously diabetic “non-obese diabetic” (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Methods: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. Results: NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. Conclusion: α4 is a potential target for primary or secondary prevention of T1D. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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Graphical abstract

18 pages, 4492 KiB  
Article
Comparative Study of Senescent Th Biomarkers in Healthy Donors and Early Arthritis Patients. Analysis of VPAC Receptors and Their Influence
by Raúl Villanueva-Romero, Amalia Lamana, Marissa Flores-Santamaría, Mar Carrión, Selene Pérez-García, Ana Triguero-Martínez, Eva Tomero, Gabriel Criado, José L. Pablos, Isidoro González-Álvaro, Carmen Martínez, Yasmina Juarranz, Rosa P. Gomariz and Irene Gutiérrez-Cañas
Cells 2020, 9(12), 2592; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122592 - 04 Dec 2020
Cited by 4 | Viewed by 2526
Abstract
Pro-inflammatory CD4+CD28− T cells are characteristic of immunosenescence, but also of several autoimmune/inflammatory diseases. Vasoactive intestinal peptide (VIP) acts as an anti-inflammatory and immunomodulatory mediator on these cells. Our objective was to study the mutual influence between senescent Th cells [...] Read more.
Pro-inflammatory CD4+CD28− T cells are characteristic of immunosenescence, but also of several autoimmune/inflammatory diseases. Vasoactive intestinal peptide (VIP) acts as an anti-inflammatory and immunomodulatory mediator on these cells. Our objective was to study the mutual influence between senescent Th cells and VIP axis in early arthritis (EA), comparing with non-EA donors. We characterized the correlation between senescent Th cells and clinic parameters of EA as well as the behavior of senescent Th biomarkers by real-time PCR. Clinical data were systematically recorded at baseline and after 6 months of follow-up. The number of CD4+CD28− T cells measured by sorting is higher in patients who initially meet ACR classification criteria for rheumatoid arthritis (RA) compared to those who were classified as undifferentiated arthritis (UA). A slight positive correlation between EA CD4+CD28− T cells and CRP or ESR and a negative correlation with bone mineral density were found. Th senescent biomarkers in EA CD4+CD28− T cells were similar to donors, however some of them increased after 6 months of follow-up. VPAC receptors were analyzed by real-time PCR and immunofluorescence, and CD4+CD28− T cells showed higher expression of VPAC2 and lower of VPAC1, VPAC2 showing a significant increased expression in EA cells. Sorted CD4+CD28− T cells were in vitro expanded in presence of VIP, wherein VIP increased senescent biomarker CD27, while it diminished CD57 or NKG2 senescent biomarkers. Our study demonstrates for the first time the existence of a link between senescent Th cells and the VIP axis. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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14 pages, 8893 KiB  
Article
Identification of Novel Molecular Markers of Human Th17 Cells
by Anna Sałkowska, Kaja Karaś, Iwona Karwaciak, Aurelia Walczak-Drzewiecka, Mariusz Krawczyk, Marta Sobalska-Kwapis, Jarosław Dastych and Marcin Ratajewski
Cells 2020, 9(7), 1611; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071611 - 03 Jul 2020
Cited by 24 | Viewed by 5094
Abstract
Th17 cells are important players in host defense against pathogens such as Staphylococcus aureus, Candida albicans, and Bacillus anthracis. Th17 cell-mediated inflammation, under certain conditions in which balance in the immune system is disrupted, is the underlying pathogenic mechanism of [...] Read more.
Th17 cells are important players in host defense against pathogens such as Staphylococcus aureus, Candida albicans, and Bacillus anthracis. Th17 cell-mediated inflammation, under certain conditions in which balance in the immune system is disrupted, is the underlying pathogenic mechanism of certain autoimmune disorders, e.g., rheumatoid arthritis, Graves’ disease, multiple sclerosis, and psoriasis. In the present study, using transcriptomic profiling, we selected genes and analyzed the expression of these genes to find potential novel markers of Th17 lymphocytes. We found that APOD (apolipoprotein D); C1QL1 (complement component 1, Q subcomponent-like protein 1); and CTSL (cathepsin L) are expressed at significantly higher mRNA and protein levels in Th17 cells than in the Th1, Th2, and Treg subtypes. Interestingly, these genes and the proteins they encode are well associated with the function of Th17 cells, as these cells produce inflammation, which is linked with atherosclerosis and angiogenesis. Furthermore, we found that high expression of these genes in Th17 cells is associated with the acetylation of H2BK12 within their promoters. Thus, our results provide new information regarding this cell type. Based on these results, we also hope to better identify pathological conditions of clinical significance caused by Th17 cells. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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14 pages, 2203 KiB  
Article
Expression of miR-135b in Psoriatic Skin and Its Association with Disease Improvement
by Pablo Chicharro, Pedro Rodríguez-Jiménez, Mar Llamas-Velasco, Nuria Montes, Ancor Sanz-García, Danay Cibrian, Alicia Vara, Manuel J Gómez, María Jiménez-Fernández, Pedro Martínez-Fleta, Inés Sánchez-García, Marta Lozano-Prieto, Juan C Triviño, Rebeca Miñambres, Francisco Sánchez-Madrid, Hortensia de la Fuente and Esteban Dauden
Cells 2020, 9(7), 1603; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071603 - 02 Jul 2020
Cited by 8 | Viewed by 2745
Abstract
miRNAs have been associated with psoriasis since just over a decade. However, we are far from a complete understanding of their role during the development of this disease. Our objective was to characterize the cutaneous expression of miRNAs not previously described in psoriasis, [...] Read more.
miRNAs have been associated with psoriasis since just over a decade. However, we are far from a complete understanding of their role during the development of this disease. Our objective was to characterize the cutaneous expression of miRNAs not previously described in psoriasis, the changes induced following the treatment with biologicals and their association with disease improvement. Next generation sequencing was performed from five skin samples from psoriasis patients (lesional and non-lesional skin) and five controls, and from this cohort, 12 microRNAs were selected to be analyzed in skin samples from 44 patients with plaque psoriasis. In 15 patients, an additional sample was obtained after three months of biological treatment. MiR-9-5p, miR-133a-3p and miR-375 were downregulated in the lesional skin of psoriasis patients. After treatment, expression of miR-133a-3p, miR-375, miR-378a and miR-135b in residual lesions returned towards the levels observed in non-lesional skin. The decrease in miR-135b levels after treatment with biologics was associated with both the improvement of patients evaluated through Psoriasis Area and Severity Index score and the decrease in local inflammatory response. Moreover, basal expression of miR-135b along with age was associated with the improvement of psoriasis, suggesting its possible usefulness as a prognostic biomarker. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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17 pages, 2469 KiB  
Article
Folate Receptor β (FRβ) Expression in Tissue-Resident and Tumor-Associated Macrophages Associates with and Depends on the Expression of PU.1
by Rafael Samaniego, Ángeles Domínguez-Soto, Manohar Ratnam, Takami Matsuyama, Paloma Sánchez-Mateos, Ángel L. Corbí and Amaya Puig-Kröger
Cells 2020, 9(6), 1445; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061445 - 10 Jun 2020
Cited by 17 | Viewed by 5473
Abstract
As macrophages exhibit a huge functional plasticity under homeostasis and pathological conditions, they have become a therapeutic target for chronic inflammatory diseases. Hence, the identification of macrophage subset-specific markers is a requisite for the development of macrophage-directed therapeutic interventions. In this regard, the [...] Read more.
As macrophages exhibit a huge functional plasticity under homeostasis and pathological conditions, they have become a therapeutic target for chronic inflammatory diseases. Hence, the identification of macrophage subset-specific markers is a requisite for the development of macrophage-directed therapeutic interventions. In this regard, the macrophage-specific Folate Receptor β (FRβ, encoded by the FOLR2 gene) has been already validated as a target for molecular delivery in cancer as well as in macrophage-targeting therapeutic strategies for chronic inflammatory pathologies. We now show that the transcriptome of human macrophages from healthy and inflamed tissues (tumor; rheumatoid arthritis, RA) share a significant over-representation of the “anti-inflammatory gene set”, which defines the gene profile of M-CSF-dependent IL-10-producing human macrophages (M-MØ). More specifically, FOLR2 expression has been found to strongly correlate with the expression of M-MØ-specific genes in tissue-resident macrophages, tumor-associated macrophages (TAM) and macrophages from inflamed synovium, and also correlates with the presence of the PU.1 transcription factor. In fact, PU.1-binding elements are found upstream of the first exon of FOLR2 and most M-MØ-specific- and TAM-specific genes. The functional relevance of PU.1 binding was demonstrated through analysis of the proximal regulatory region of the FOLR2 gene, whose activity was dependent on a cluster of PU.1-binding sequences. Further, siRNA-mediated knockdown established the importance of PU.1 for FOLR2 gene expression in myeloid cells. Therefore, we provide evidence that FRβ marks tissue-resident macrophages as well as macrophages within inflamed tissues, and its expression is dependent on PU.1. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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11 pages, 2874 KiB  
Article
Ets Family Transcription Factor Fli-1 Promotes Leukocyte Recruitment and Production of IL-17A in the MRL/Lpr Mouse Model of Lupus Nephritis
by Shuzo Sato, Xian K. Zhang, Jumpei Temmoku, Yuya Fujita, Naoki Matsuoka, Makiko Yashiro-Furuya, Tomoyuki Asano, Hiroko Kobayashi, Hiroshi Watanabe and Kiyoshi Migita
Cells 2020, 9(3), 714; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030714 - 14 Mar 2020
Cited by 13 | Viewed by 3376
Abstract
The transcription factor Friend leukemia integration 1 (Fli-1) regulates the expression of numerous cytokines and chemokines and alters the progression of lupus nephritis in humans and in the MRL/MpJ-Faslpr (MRL/lpr) mouse model. Th17-mediated immune responses are notably important as they promote [...] Read more.
The transcription factor Friend leukemia integration 1 (Fli-1) regulates the expression of numerous cytokines and chemokines and alters the progression of lupus nephritis in humans and in the MRL/MpJ-Faslpr (MRL/lpr) mouse model. Th17-mediated immune responses are notably important as they promote ongoing inflammation. The purpose of this study is to determine the impact of Fli-1 on expression of interleukin-17A (IL-17A) and the infiltration of immune cells into the kidney. IL-17A concentrations were measured by ELISA in sera collected from MRL/lpr Fli-1-heterozygotes (Fli-1+/−) and MRL/lpr Fli-1+/+ control littermates. Expression of IL-17A and related proinflammatory mediators was measured by real-time polymerase chain reaction (RT-PCR). Immunofluorescence staining was performed on renal tissue from MRL/lpr Fli-1+/− and control littermates using anti-CD3, anti-CD4, and anti-IL-17A antibodies to detect Th17 cells and anti-CCL20 and anti-CD11b antibodies to identify CCL20+ monocytes. The expression of IL-17A in renal tissue was significantly reduced; this was accompanied by decreases in expression of IL-6, signal transducer and activator of transcription 3 (STAT3), and IL-1β. Likewise, we detected fewer CD3+IL-17+ and CD4+IL-17+ cells in renal tissue of MLR/lpr Fli-1+/− mice and significantly fewer CCL20+CD11b+ monocytes. In conclusion, partial deletion of Fli-1 has a profound impact on IL-17A expression and on renal histopathology in the MRL/lpr mouse. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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24 pages, 4384 KiB  
Article
Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases
by Tiphaine C. Martin, Kristina M. Ilieva, Alessia Visconti, Michelle Beaumont, Steven J. Kiddle, Richard J. B. Dobson, Massimo Mangino, Ee Mun Lim, Marija Pezer, Claire J. Steves, Jordana T. Bell, Scott G. Wilson, Gordan Lauc, Mario Roederer, John P. Walsh, Tim D. Spector and Sophia N. Karagiannis
Cells 2020, 9(3), 665; https://doi.org/10.3390/cells9030665 - 09 Mar 2020
Cited by 20 | Viewed by 5321
Abstract
The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood [...] Read more.
The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335- CD314+ CD158b+ NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1α positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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Graphical abstract

17 pages, 4633 KiB  
Article
(R)-Salbutamol Improves Imiquimod-Induced Psoriasis-Like Skin Dermatitis by Regulating the Th17/Tregs Balance and Glycerophospholipid Metabolism
by Fei Liu, Shanping Wang, Bo Liu, Yukun Wang and Wen Tan
Cells 2020, 9(2), 511; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020511 - 24 Feb 2020
Cited by 21 | Viewed by 6069
Abstract
Psoriasis is a skin disease that is characterized by a high degree of inflammation caused by immune dysfunction. (R)-salbutamol is a bronchodilator for asthma and was reported to alleviate immune system reactions in several diseases. In this study, using imiquimod (IMQ)-induced [...] Read more.
Psoriasis is a skin disease that is characterized by a high degree of inflammation caused by immune dysfunction. (R)-salbutamol is a bronchodilator for asthma and was reported to alleviate immune system reactions in several diseases. In this study, using imiquimod (IMQ)-induced mouse psoriasis-like dermatitis model, we evaluated the therapeutic effects of (R)-salbutamol in psoriasis in vivo, and explored the metabolic pathway involved. The results showed that, compared with IMQ group, (R)-salbutamol treatment significantly ameliorated psoriasis, reversed the suppressive effects of IMQ on differentiation, excessive keratinocyte proliferation, and infiltration of inflammatory cells. Enzyme-linked immunosorbent assays (ELISA) showed that (R)-salbutamol markedly reduced the plasma levels of IL-17. Cell analysis using flow cytometry showed that (R)-salbutamol decreased the proportion of CD4+ Th17+ T cells (Th17), whereas it increased the percentage of CD25+ Foxp3+ regulatory T cells (Tregs) in the spleens. (R)-salbutamol also reduced the increased weight ratio of spleen to body. Furthermore, untargeted metabolomics showed that (R)-salbutamol affected three metabolic pathways, including (i) arachidonic acid metabolism, (ii) sphingolipid metabolism, and (iii) glycerophospholipid metabolism. These results demonstrated that (R)-salbutamol can alleviate IMQ-induced psoriasis through regulating Th17/Tregs cell response and glycerophospholipid metabolism. It may provide a new use of (R)-salbutamol in the management of psoriasis. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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Review

Jump to: Editorial, Research

15 pages, 987 KiB  
Review
Adipokines and Autoimmunity in Inflammatory Arthritis
by Elena Neumann, Rebecca Hasseli, Selina Ohl, Uwe Lange, Klaus W. Frommer and Ulf Müller-Ladner
Cells 2021, 10(2), 216; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020216 - 22 Jan 2021
Cited by 34 | Viewed by 3407
Abstract
Adipokines are adipose tissue-derived factors not only playing an important role in metabolism but also influencing other central processes of the body, such as inflammation. In autoimmune diseases, adipokines are involved in inflammatory pathways affecting different cell types. Many rheumatic diseases belong to [...] Read more.
Adipokines are adipose tissue-derived factors not only playing an important role in metabolism but also influencing other central processes of the body, such as inflammation. In autoimmune diseases, adipokines are involved in inflammatory pathways affecting different cell types. Many rheumatic diseases belong to the group of autoimmune diseases, for example rheumatoid arthritis (RA) and psoriatic arthritis. Due to the autoimmune responses, a chronic inflammatory milieu develops, which affects the whole body, including adipose tissue. Metabolic alterations such as obesity influence inflammatory responses in autoimmune diseases. Adipokines are bioactive mediators mainly produced by adipose tissue. Due to alterations of systemic adipokine levels, their role as biomarkers with diagnostic potential has been suggested in the context of rheumatic diseases. In the affected joints of RA patients, different synoviocytes but also osteoclasts, osteoblasts, and chondrocytes produce several adipokines, contributing to the unique inflammatory microenvironment. Adipokines have been shown to be potent modulatory effectors on different cell types of the immune system but also local cells in synovial tissue, cartilage, and bone. This review highlights the most recent findings on the role of adipokines in the pathophysiology of inflammatory arthritis with a distinct focus on RA in the quickly developing research field. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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18 pages, 723 KiB  
Review
Complement as a Therapeutic Target in Systemic Autoimmune Diseases
by María Galindo-Izquierdo and José Luis Pablos Alvarez
Cells 2021, 10(1), 148; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010148 - 13 Jan 2021
Cited by 19 | Viewed by 4881
Abstract
The complement system (CS) includes more than 50 proteins and its main function is to recognize and protect against foreign or damaged molecular components. Other homeostatic functions of CS are the elimination of apoptotic debris, neurological development, and the control of adaptive immune [...] Read more.
The complement system (CS) includes more than 50 proteins and its main function is to recognize and protect against foreign or damaged molecular components. Other homeostatic functions of CS are the elimination of apoptotic debris, neurological development, and the control of adaptive immune responses. Pathological activation plays prominent roles in the pathogenesis of most autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, dermatomyositis, and ANCA-associated vasculitis. In this review, we will review the main rheumatologic autoimmune processes in which complement plays a pathogenic role and its potential relevance as a therapeutic target. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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21 pages, 1152 KiB  
Review
The Multi-Omics Architecture of Juvenile Idiopathic Arthritis
by Xiaoyuan Hou, Huiqi Qu, Sipeng Zhang, Xiaohui Qi, Hakon Hakonarson, Qianghua Xia and Jin Li
Cells 2020, 9(10), 2301; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102301 - 15 Oct 2020
Cited by 16 | Viewed by 3371
Abstract
Juvenile idiopathic arthritis (JIA) is highly heterogeneous in terms of etiology and clinical presentation with ambiguity in JIA classification. The advance of high-throughput omics technologies in recent years has gained us significant knowledge about the molecular mechanisms of JIA. Besides a minor proportion [...] Read more.
Juvenile idiopathic arthritis (JIA) is highly heterogeneous in terms of etiology and clinical presentation with ambiguity in JIA classification. The advance of high-throughput omics technologies in recent years has gained us significant knowledge about the molecular mechanisms of JIA. Besides a minor proportion of JIA cases as monogenic, most JIA cases are polygenic disease caused by autoimmune mechanisms. A number of HLA alleles (including both HLA class I and class II genes), and 23 non-HLA genetic loci have been identified of association with different JIA subtypes. Omics technologies, i.e., transcriptome profiling and epigenomic analysis, contributed significant knowledge on the molecular mechanisms of JIA in addition to the genetic approach. New molecular knowledge on different JIA subtypes enables us to reconsider the JIA classification, but also highlights novel therapeutic targets to develop a cure for the devastating JIA. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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19 pages, 1800 KiB  
Review
Intrathymic Selection and Defects in the Thymic Epithelial Cell Development
by Javier García-Ceca, Sara Montero-Herradón and Agustín G. Zapata
Cells 2020, 9(10), 2226; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102226 - 02 Oct 2020
Cited by 5 | Viewed by 5562
Abstract
Intimate interactions between thymic epithelial cells (TECs) and thymocytes (T) have been repeatedly reported as essential for performing intrathymic T-cell education. Nevertheless, it has been described that animals exhibiting defects in these interactions were capable of a proper positive and negative T-cell selection. [...] Read more.
Intimate interactions between thymic epithelial cells (TECs) and thymocytes (T) have been repeatedly reported as essential for performing intrathymic T-cell education. Nevertheless, it has been described that animals exhibiting defects in these interactions were capable of a proper positive and negative T-cell selection. In the current review, we first examined distinct types of TECs and their possible role in the immune surveillance. However, EphB-deficient thymi that exhibit profound thymic epithelial (TE) alterations do not exhibit important immunological defects. Eph and their ligands, the ephrins, are implicated in cell attachment/detachment and govern, therefore, TEC–T interactions. On this basis, we hypothesized that a few normal TE areas could be enough for a proper phenotypical and functional maturation of T lymphocytes. Then, we evaluated in vivo how many TECs would be necessary for supporting a normal T-cell differentiation, concluding that a significantly low number of TEC are still capable of supporting normal T lymphocyte maturation, whereas with fewer numbers, T-cell maturation is not possible. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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21 pages, 919 KiB  
Review
Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19
by Magdalena Massalska, Wlodzimierz Maslinski and Marzena Ciechomska
Cells 2020, 9(8), 1876; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081876 - 11 Aug 2020
Cited by 27 | Viewed by 8382
Abstract
The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, [...] Read more.
The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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21 pages, 1415 KiB  
Review
Mesenchymal Stem/Stromal Cells for Rheumatoid Arthritis Treatment: An Update on Clinical Applications
by Mercedes Lopez-Santalla, Raquel Fernandez-Perez and Marina I. Garin
Cells 2020, 9(8), 1852; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081852 - 07 Aug 2020
Cited by 77 | Viewed by 6143
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects the lining of the synovial joints leading to stiffness, pain, inflammation, loss of mobility, and erosion of joints. Its pathogenesis is related to aberrant immune responses against the synovium. Dysfunction of innate [...] Read more.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects the lining of the synovial joints leading to stiffness, pain, inflammation, loss of mobility, and erosion of joints. Its pathogenesis is related to aberrant immune responses against the synovium. Dysfunction of innate and adaptive immunity, including dysregulated cytokine networks and immune complex-mediated complement activation, are involved in the progression of RA. At present, drug treatments, including corticosteroids, antirheumatic drugs, and biological agents, are used in order to modulate the altered immune responses. Chronic use of these drugs may cause adverse effects to a significant number of RA patients. Additionally, some RA patients are resistant to these therapies. In recent years, mesenchymal stem/stromal cell (MSCs)-based therapies have been largely proposed as a novel and promising stem cell therapeutic approach in the treatment of RA. MSCs are multipotent progenitor cells that have immunomodulatory properties and can be obtained and expanded easily. Today, nearly one hundred studies in preclinical models of RA have shown promising trends for clinical application. Proof-of-concept clinical studies have demonstrated satisfactory safety profile of MSC therapy in RA patients. The present review discusses MSC-based therapy approaches with a focus on published clinical data, as well as on clinical trials, for treatment of RA that are currently underway. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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31 pages, 2408 KiB  
Review
Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis–From Research to Clinical Practice
by Tomasz Wysocki, Marzena Olesińska and Agnieszka Paradowska-Gorycka
Cells 2020, 9(5), 1127; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9051127 - 02 May 2020
Cited by 45 | Viewed by 11496
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease with an unclear pathogenic mechanism. However, it has been proven that the key underlying risk factor is a genetic predisposition. Association studies of the HLA-DRB1 gene clearly indicate its importance in RA morbidity. This review presents [...] Read more.
Rheumatoid arthritis (RA) is an autoimmune disease with an unclear pathogenic mechanism. However, it has been proven that the key underlying risk factor is a genetic predisposition. Association studies of the HLA-DRB1 gene clearly indicate its importance in RA morbidity. This review presents the current state of knowledge on the impact of HLA-DRB1 gene, functioning both as a component of the patient’s genome and as an environmental risk factor. The impact of known HLA-DRB1 risk variants on the specific structure of the polymorphic HLA-DR molecule, and epitope binding affinity, is presented. The issues of the potential influence of HLA-DRB1 on the occurrence of non-articular disease manifestations and response to treatment are also discussed. A deeper understanding of the role of the HLA-DRB1 gene is essential to explore the complex nature of RA, which is a result of multiple contributing factors, including genetic, epigenetic and environmental factors. It also creates new opportunities to develop modern and personalized forms of therapy. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Autoimmune Diseases)
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