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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 (15 February 2024) | Viewed by 26676

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Prof. Dr. Yves Renaudineau

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Laboratory of Immunology, CHU Purpan Toulouse, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
Interests: autoimmune diseases; immunology; infection; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Dr. Dirk Roggenbuck

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Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany
Interests: molecular diagnostics; quality management; autoimmune diseases; personalized medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This special issue, dedicated to autoimmunity, attempts to present autoimmune diseases (ADs) into a comprehensive overview of how the immune system turns against self targeting in different conditions according to a balance determined by the genetic predisposition of the host, its gender, epigenetic factors, environmental circumstances and other co-factors. Moreover current knowledge from human and animal models are welcome regarding pathogenic mechanisms of autoimmune diseases, clinical aspects of specific autoimmune diseases, as well as insights regarding biomarkers and specific therapies.

Prof. Dr. Yves Renaudineau
Dr. Dirk Roggenbuck
Guest Editors

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Editorial Board Members’ Collection Series: Autoimmune Diseases—2nd Edition in International Journal of Molecular Sciences (1 article)

Published Papers (9 papers)

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Research

Jump to: Review

8 pages, 718 KiB

Open AccessCommunication

Leucine-Rich Glioma-Inactivated 1 (LGI1) Protein Stimulates Proliferation and IL-10 Production in Peripheral Blood Mononuclear Cells of Patients with LGI1 Antibody-Mediated Autoimmune Encephalitis In Vitro

by Alexander Goihl, Dirk Reinhold, Annegret Reinhold, Burkhart Schraven and Peter Körtvelyessy

Int. J. Mol. Sci. 2024, 25(5), 2581; https://doi.org/10.3390/ijms25052581 - 23 Feb 2024

Viewed by 1243

Abstract

Limbic encephalitis (LE) due to anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies is an autoimmune disease characterized by distinct clinical features unique to LGI1 LE, such as faciobrachial dystonic seizures. However, it is unclear whether an additional disease-related LGI1 antigen-specific T cell response is involved in the pathogenesis of this disease. To address this question, we studied the effect of recombinant LGI1 on the proliferation and effector-specific cytokine production (IFN-γ, IL-5, IL-10, and IL-17) of peripheral blood mononuclear cells (PBMCs) from patients with LGI1 LE and healthy controls. We observed that recombinant LGI1 stimulated the proliferation of PBMCs from patients with LGI1 LE, but not from healthy controls. Cytokine measurement of cell culture supernatants from PBMCs incubated with recombinant LGI1 revealed a highly significant increase in IL-10 release in PBMCs from patients with LGI1 LE in comparison with healthy controls. These results suggest that LGI1-mediated stimulation of PBMCs from patients with LGI1 LE leads to the establishment of an IL-10-dominated immunosuppressive cytokine milieu, which may inhibit Th1 differentiation and support B cell proliferation, IgG production, and IgG subclass switching. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases)

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11 pages, 1965 KiB

Open AccessArticle

Synthetic Nucleic Acid Antigens in Localized Scleroderma

by Sangita Khatri, Adrian H. Bustos, Christian Damsgaard Jørgensen, Kathryn S. Torok, Lise-Mette Rahbek Gjerdrum and Kira Astakhova

Int. J. Mol. Sci. 2023, 24(24), 17507; https://doi.org/10.3390/ijms242417507 - 15 Dec 2023

Viewed by 1347

Abstract

We investigated the impact of synthetic nucleic acid antigens on the autoantibody profiles in patients with localized scleroderma, an autoimmune skin disease. Anti-DNA antibodies, including double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA), are common among autoimmune diseases, such as systemic lupus erythematosus and localized scleroderma. Based on recent studies, we hypothesized that the sequence of nucleic acid antigens has an impact on the autoimmune reactions in localized scleroderma. To test our hypothesis, we synthesized a panel of DNA and RNA antigens and used them for autoantibody profiling of 70 children with localized scleroderma compared with the healthy controls and patients with pediatric systemic lupus erythematosus (as a disease control). Among the tested antigens, dsD4, which contains the sequence of the human oncogene BRAF, showed a particularly strong presence in localized scleroderma but not systemic lupus erythematosus. Disease activity in patients was significantly associated with dsD4 autoantibody levels. We confirmed this result in vivo by using a bleomycin-induced mouse model of localized scleroderma. When administered intraperitoneally, dsD4 promoted an active polyclonal response in the mouse model. Our study highlights sequence specificity for nucleic acid antigens in localized scleroderma that could potentially lead to developing novel early-stage diagnostic tools. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases)

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19 pages, 1524 KiB

Open AccessArticle

Disrupted Neural Regeneration in Dry Eye Secondary to Ankylosing Spondylitis—With a Theoretical Link between Piezo2 Channelopathy and Gateway Reflex, WDR Neurons, and Flare-Ups

by Balázs Sonkodi, László Marsovszky, Anita Csorba, Attila Balog, Bence Kopper, Anikó Keller-Pintér, Zoltán Zsolt Nagy and Miklós D. Resch

Int. J. Mol. Sci. 2023, 24(20), 15455; https://doi.org/10.3390/ijms242015455 - 22 Oct 2023

Cited by 2 | Viewed by 2374

Abstract

This study aimed at analyzing the corneal neural regeneration in ankylosing spondylitis patients using in vivo corneal confocal microscopy in correlation with Langerhans cell density, morphology, and dry eye parameters. Approximately 24 ankylosing spondylitis subjects and 35 age- and gender-matched control subjects were enrolled. Data analysis showed that all corneal nerve-fiber descriptives were lower in the ankylosing spondylitis group, implicating disrupted neural regeneration. Peripheral Langerhans cell density showed a negative correlation with nerve fiber descriptions. A negative correlation between tear film break-up time and corneal nerve fiber total branch density was detected. The potential role of somatosensory terminal Piezo2 channelopathy in the pathogenesis of dry eye disease and ankylosing spondylitis is highlighted in our study, exposing the neuroimmunological link between these diseases. We hypothesized earlier that spinal neuroimmune-induced sensitization due to this somatosensory terminal primary damage could lead to Langerhans cell activation in the cornea, in association with downregulated Piezo1 channels on these cells. This activation could lead to a Th17/Treg imbalance in dry eye secondary to ankylosing spondylitis. Hence, the corneal Piezo2 channelopathy-induced impaired Piezo2-Piezo1 crosstalk could explain the disrupted neural regeneration. Moreover, the translation of our findings highlights the link between Piezo2 channelopathy-induced gateway to pathophysiology and the gateway reflex, not to mention the potential role of spinal wide dynamic range neurons in the evolution of neuropathic pain and the flare-ups in ankylosing spondylitis and dry eye disease. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases)

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39 pages, 13145 KiB

Open AccessArticle

Clostridia and Enteroviruses as Synergistic Triggers of Type 1 Diabetes Mellitus

by Robert Root-Bernstein, Kaylie Chiles, Jack Huber, Alison Ziehl, Miah Turke and Maja Pietrowicz

Int. J. Mol. Sci. 2023, 24(9), 8336; https://doi.org/10.3390/ijms24098336 - 6 May 2023

Cited by 5 | Viewed by 2611

Abstract

What triggers type 1 diabetes mellitus (T1DM)? One common assumption is that triggers are individual microbes that mimic autoantibody targets such as insulin (INS). However, most microbes highly associated with T1DM pathogenesis, such as coxsackieviruses (COX), lack INS mimicry and have failed to induce T1DM in animal models. Using proteomic similarity search techniques, we found that COX actually mimicked the INS receptor (INSR). Clostridia were the best mimics of INS. Clostridia antibodies cross-reacted with INS in ELISA experiments, confirming mimicry. COX antibodies cross-reacted with INSR. Clostridia antibodies further bound to COX antibodies as idiotype–anti-idiotype pairs conserving INS–INSR complementarity. Ultraviolet spectrometry studies demonstrated that INS-like Clostridia peptides bound to INSR-like COX peptides. These complementary peptides were also recognized as antigens by T cell receptor sequences derived from T1DM patients. Finally, most sera from T1DM patients bound strongly to inactivated Clostridium sporogenes, while most sera from healthy individuals did not; T1DM sera also exhibited evidence of anti-idiotype antibodies against idiotypic INS, glutamic acid decarboxylase, and protein tyrosine phosphatase non-receptor (islet antigen-2) antibodies. These results suggest that T1DM is triggered by combined enterovirus-Clostridium (and possibly combined Epstein–Barr-virus-Streptococcal) infections, and the probable rate of such co-infections approximates the rate of new T1DM diagnoses. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases)

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14 pages, 1964 KiB

Open AccessArticle

Evidence of Disruption in Neural Regeneration in Dry Eye Secondary to Rheumatoid Arthritis

by Balázs Sonkodi, Anita Csorba, László Marsovszky, Attila Balog, Bence Kopper, Zoltán Zsolt Nagy and Miklós D. Resch

Int. J. Mol. Sci. 2023, 24(8), 7514; https://doi.org/10.3390/ijms24087514 - 19 Apr 2023

Cited by 5 | Viewed by 2396

Abstract

The purpose of our study was to analyze abnormal neural regeneration activity in the cornea through means of confocal microscopy in rheumatoid arthritis patients with concomitant dry eye disease. We examined 40 rheumatoid arthritis patients with variable severity and 44 volunteer age- and gender-matched healthy control subjects. We found that all examined parameters were significantly lower (p < 0.05) in rheumatoid arthritis patients as opposed to the control samples: namely, the number of fibers, the total length of the nerves, the number of branch points on the main fibers and the total nerve-fiber area. We examined further variables, such as age, sex and the duration of rheumatoid arthritis. Interestingly, we could not find a correlation between the above variables and abnormal neural structural changes in the cornea. We interpreted these findings via implementing our hypotheses. Correspondingly, one neuroimmunological link between dry eye and rheumatoid arthritis could be through the chronic Piezo2 channelopathy-induced K_2P-TASK1 signaling axis. This could accelerate neuroimmune-induced sensitization on the spinal level in this autoimmune disease, with Langerhans-cell activation in the cornea and theorized downregulated Piezo1 channels in these cells. Even more importantly, suggested principal primary-damage-associated corneal keratocyte activation could be accompanied by upregulation of Piezo1. Both activation processes on the periphery would skew the plasticity of the Th17/Treg ratio, resulting in Th17/Treg imbalance in dry eye, secondary to rheumatoid arthritis. Hence, chronic somatosensory-terminal Piezo2 channelopathy-induced impaired Piezo2–Piezo1 crosstalk could result in a mixed picture of disrupted functional regeneration but upregulated morphological regeneration activity of these somatosensory axons in the cornea, providing the demonstrated abnormal neural corneal morphology. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases)

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13 pages, 1476 KiB

Open AccessArticle

Over-Expression of LEDGF/p75 in HEp-2 Cells Enhances Autoimmune IgG Response in Patients with Benign Prostatic Hyperplasia—A Novel Diagnostic Approach with Therapeutic Consequence?

by Victoria Liedtke, Laura Rose, Rico Hiemann, Abdullah Nasser, Stefan Rödiger, Alena Bonaventura, Laura Winkler, Mandy Sowa, Michael Stöckle, Peter Schierack, Kerstin Junker and Dirk Roggenbuck

Int. J. Mol. Sci. 2023, 24(7), 6166; https://doi.org/10.3390/ijms24076166 - 24 Mar 2023

Cited by 6 | Viewed by 2205

Abstract

Lens epithelium-derived growth factor splice variant of 75 kDa (LEDGF/p75) is an autoantigen over-expressed in solid tumors and acts as a stress-related transcriptional co-activator. Participation of autoimmune responses in the pathophysiology of benign prostatic hyperplasia (PBH) and a corresponding immunosuppressive therapy by TNFalpha antagonists has been recently suggested. Thus, autoAb testing could aid in the diagnosis of BPH patients profiting from such therapy. We generated CRISPR/Cas9 modified HEp-2 LEDGF knock-out (KO) and HEp-2 LEDGF/p75 over-expressing (OE) cells and examined IgG autoantibody reactivity to LEDGF/p75 in patients with prostate cancer (PCa, n = 89), bladder cancer (BCa, n = 116), benign prostatic hyperplasia (BPH, n = 103), and blood donors (BD, n = 60) by indirect immunofluorescence assay (IFA). Surprisingly, we could not detect elevated binding of autoAbs against LEDGF/p75 in cancer patients, but autoAb reactivity to LEDGF/p75 OE cells in about 50% of patients with BPH was unexpectedly significantly increased. Furthermore, a line immunoassay enabling the detection of 18 different autoAbs revealed a significantly increased occurrence of anti-dsDNA autoAbs in 34% of BPH patients in contrast to tumor patients and BD. This finding was confirmed by anti-mitochondrial (mDNA) autoAb detection with the Crithidia luciliae immunofluorescence test, which also showed a significantly higher prevalence (34%) of anti-mDNA autoAbs in BPH. In summary, our study provided further evidence for the occurrence of autoimmune responses in BPH. Furthermore, LEDGF/p75 over-expression renders HEp-2 cells more autoantigenic and an ideal target for autoAb analysis in BPH with a potential therapy consequence. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases)

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13 pages, 648 KiB

Open AccessArticle

Epstein–Barr Virus Reactivation as a New Predictor of Achieving Remission or Lupus Low Disease Activity State in Patients with Systemic Lupus Erythematosus with Cutaneous Involvement

by Rada Miskovic, Andja Cirkovic, Danijela Miljanovic, Ivica Jeremic, Milka Grk, Milica Basaric, Ivana Lazarevic, Maja Stojanovic, Aleksandra Plavsic, Sanvila Raskovic and Ana Banko

Int. J. Mol. Sci. 2023, 24(7), 6156; https://doi.org/10.3390/ijms24076156 - 24 Mar 2023

Cited by 5 | Viewed by 4740

Abstract

Although Epstein–Barr virus (EBV) reactivation has long been associated with the pathogenesis of systemic lupus erythematosus (SLE), many aspects of this relationship remain unclear. Our objective was to investigate the association between EBV reactivation and the achievement of SLE remission and lupus low disease activity state (LLDAS) over a six-month period. Clinical, laboratory, and virological tests (anti-EBV antibodies and EBV DNA) were performed among 51 patients with the active form of SLE on two occasions six months apart. SLE remission and LLDAS achievement were assessed at the end of the follow-up period. Active EBV infection was detected in 45% of active SLE patients at baseline, and 77% transitioned to latent EBV infection at six months (p < 0.001). Multivariate regression revealed a higher titer of anti-EA(D) IgM-Abs and the presence of anti-EA(D) IgM-Abs as independent predictors of remission and LLDAS in SLE patients with mucocutaneous manifestations (p = 0.042) and rash only (p = 0.023), respectively. Since a higher C3 level was an independent predictor of transition to latent EBV infection (p = 0.027), the estimated cut-off value that could identify active SLE patients who will transition to latent EBV infection after six months was ≥0.780 g/L with a sensitivity of 70.6% and a specificity of 75.0% (AUC = 0.756, p = 0.003). EBV reactivation is common in patients with active SLE, and most of them transition to latent EBV infection after six months. Achieving remission and LLDAS in SLE patients with mucocutaneous manifestations can be predicted by a higher titer, whereas in SLE patients who have only a rash, the presence of anti-EA (D) IgM-Abs was a predictor of remission and LLDAS. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases)

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Review

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30 pages, 2669 KiB

Open AccessReview

Nonspecific Orbital Inflammation (NSOI): Unraveling the Molecular Pathogenesis, Diagnostic Modalities, and Therapeutic Interventions

by Kevin Y. Wu, Merve Kulbay, Patrick Daigle, Bich H. Nguyen and Simon D. Tran

Int. J. Mol. Sci. 2024, 25(3), 1553; https://doi.org/10.3390/ijms25031553 - 26 Jan 2024

Cited by 3 | Viewed by 5673

Abstract

Nonspecific orbital inflammation (NSOI), colloquially known as orbital pseudotumor, sometimes presents a diagnostic and therapeutic challenge in ophthalmology. This review aims to dissect NSOI through a molecular lens, offering a comprehensive overview of its pathogenesis, clinical presentation, diagnostic methods, and management strategies. The article delves into the underpinnings of NSOI, examining immunological and environmental factors alongside intricate molecular mechanisms involving signaling pathways, cytokines, and mediators. Special emphasis is placed on emerging molecular discoveries and approaches, highlighting the significance of understanding molecular mechanisms in NSOI for the development of novel diagnostic and therapeutic tools. Various diagnostic modalities are scrutinized for their utility and limitations. Therapeutic interventions encompass medical treatments with corticosteroids and immunomodulatory agents, all discussed in light of current molecular understanding. More importantly, this review offers a novel molecular perspective on NSOI, dissecting its pathogenesis and management with an emphasis on the latest molecular discoveries. It introduces an integrated approach combining advanced molecular diagnostics with current clinical assessments and explores emerging targeted therapies. By synthesizing these facets, the review aims to inform clinicians and researchers alike, paving the way for molecularly informed, precision-based strategies for managing NSOI. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases)

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20 pages, 2705 KiB

Open AccessReview

Characteristics of the (Auto)Reactive T Cells in Rheumatoid Arthritis According to the Immune Epitope Database

by Caroline Carlé, Yannick Degboe, Adeline Ruyssen-Witrand, Marina I. Arleevskaya, Cyril Clavel and Yves Renaudineau

Int. J. Mol. Sci. 2023, 24(5), 4296; https://doi.org/10.3390/ijms24054296 - 21 Feb 2023

Cited by 6 | Viewed by 2934

Abstract

T cells are known to be involved in the pathogenesis of rheumatoid arthritis (RA). Accordingly, and to better understand T cells’ contribution to RA, a comprehensive review based on an analysis of the Immune Epitope Database (IEDB) was conducted. An immune CD8+ T cell senescence response is reported in RA and inflammatory diseases, which is driven by active viral antigens from latent viruses and cryptic self-apoptotic peptides. RA-associated pro-inflammatory CD4+ T cells are selected by MHC class II and immunodominant peptides, which are derived from molecular chaperones, host extra-cellular and cellular peptides that could be post-translationally modified (PTM), and bacterial cross-reactive peptides. A large panel of techniques have been used to characterize (auto)reactive T cells and RA-associated peptides with regards to their interaction with the MHC and TCR, capacity to enter the docking site of the shared epitope (DRB1-SE), capacity to induce T cell proliferation, capacity to select T cell subsets (Th1/Th17, Treg), and clinical contribution. Among docking DRB1-SE peptides, those with PTM expand autoreactive and high-affinity CD4+ memory T cells in RA patients with an active disease. Considering original therapeutic options in RA, mutated, or altered peptide ligands (APL) have been developed and are tested in clinical trials. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases)

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