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Biomolecules
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Novel Insights into the Role of Autoantibodies in Diseases
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Novel Insights into the Role of Autoantibodies in Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biomarkers".

Deadline for manuscript submissions: closed (20 July 2023) | Viewed by 9955

Special Issue Editors

Prof. Dr. Oscar J. Cordero

E-Mail Website
Guest Editor
1. Department of Biochemistry and Molecular Biology, CIBUS Building, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
2. Gene Regulatory Control in Disease Group, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
3. Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
Interests: CD26; DPP4; immunology; cancer; biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Rubén Varela-Calvino

E-Mail Website
Guest Editor
1. Department of Biochemistry and Molecular Biology, Universidade de Santiago de Compostela, Faculty of Pharmacy, Campus Vida, 15782 Santiago de Compostela, Spain
2. Health Research Institute of Santiago de Compostela (IDIS), 15782 Santiago de Compostela, Spain
Interests: autoimmunity; cancer; T cell receptor; type 1 diabetes; rheumatoid arthritis
Dr. Iria Gómez-Touriño

E-Mail Website
Guest Editor
1. Department of Biochemistry and Molecular Biology and Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
2. Health Research Institute of Santiago de Compostela (IDIS), 15782 Santiago de Compostela, Spain
Interests: autoimmunity; small molecules; T cell receptor; type 1 diabetes; rheumatoid arthritis

Special Issue Information

Dear Colleagues, 

The detection of autoantibodies (aAbs) in blood is considered to be the result of a pathological breakdown in self-tolerance. The fact that autoimmune diseases including rheumatoid arthritis (RA), Sjögren’s syndrome, and systemic lupus erythematosis, among others, are initiated or exacerbated by aAbs against specific cellular and tissue components further supports this notion.

However, about three decades ago, the discovery of natural IgM (or IgA) antibodies against self-antigens challenged the association between autoantibody and disease. These autoantibodies are produced by B-1 cells and show reactivity profiles remarkably conserved between individuals, and highly conserved throughout evolution. As IgM autoantibodies bind to common apoptotic neo-antigens and markers of cell senescence, it was hypothesized that the function of natural IgM (or IgA) autoantibodies is to assist in the clean-up of apoptotic cellular debris and the maintenance of tissue homeostasis.

In addition, all human sera—as well as those of other mammals—contain hundreds or thousands of autoreactive IgGs. Although their total number is influenced by gender, age, or the presence of specific diseases, unique profiles of autoantibodies are relatively stable over time in an individual. Furthermore, novel lines of research have shown important roles of autoantibodies in other diseases, such as schizophrenia, Parkinson’s disease, and other neurological syndromes.

Therefore, autoantibodies constitute markers of disease as well as purposeful products of the immune system, and as such, this research field represents a renewed frontier in immunological research. It is time to describe what we know about how autoantibodies function, how they are generated and regulated, and what makes the difference between a pathological and a non-pathological autoantibody.

Prof. Dr. Oscar J. Cordero
Dr. Rubén Varela-Calvino
Dr. Iria Gómez-Touriño
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Biomolecules is an international peer-reviewed open access monthly 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

  • B cells
  • autoantibodies
  • peripheral blood
  • biomarkers
  • autoimmune diseases

Related Special Issue

Published Papers (5 papers)

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Research

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14 pages, 2156 KiB  
Article
The Binding of the SARS-CoV-2 Spike Protein to Platelet Factor 4: A Proposed Mechanism for the Generation of Pathogenic Antibodies
by Thi-Huong Nguyen, Li-Yu Chen, Nida Zaman Khan, Annerose Lindenbauer, Van-Chien Bui, Peter F. Zipfel and Doris Heinrich
Biomolecules 2024, 14(3), 245; https://doi.org/10.3390/biom14030245 - 20 Feb 2024
Viewed by 1446
Abstract
Pathogenic platelet factor 4 (PF4) antibodies contributed to the abnormal coagulation profiles in COVID-19 and vaccinated patients. However, the mechanism of what triggers the body to produce these antibodies has not yet been clarified. Similar patterns and many comparable features between the COVID-19 [...] Read more.
Pathogenic platelet factor 4 (PF4) antibodies contributed to the abnormal coagulation profiles in COVID-19 and vaccinated patients. However, the mechanism of what triggers the body to produce these antibodies has not yet been clarified. Similar patterns and many comparable features between the COVID-19 virus and heparin-induced thrombocytopenia (HIT) have been reported. Previously, we identified a new mechanism of autoimmunity in HIT in which PF4-antibodies self-clustered PF4 and exposed binding epitopes for other pathogenic PF4/eparin antibodies. Here, we first proved that the SARS-CoV-2 spike protein (SP) also binds to PF4. The binding was evidenced by the increase in mass and optical intensity as observed through quartz crystal microbalance and immunosorbent assay, while the switching of the surface zeta potential caused by protein interactions and binding affinity of PF4-SP were evaluated by dynamic light scattering and isothermal spectral shift analysis. Based on our results, we proposed a mechanism for the generation of PF4 antibodies in COVID-19 patients. We further validated the changes in zeta potential and interaction affinity between PF4 and SP and found that their binding mechanism differs from ACE2–SP binding. Importantly, the PF4/SP complexes facilitate the binding of anti-PF4/Heparin antibodies. Our findings offer a fresh perspective on PF4 engagement with the SARS-CoV-2 SP, illuminating the role of PF4/SP complexes in severe thrombotic events. Full article
(This article belongs to the Special Issue Novel Insights into the Role of Autoantibodies in Diseases)
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14 pages, 716 KiB  
Article
Tumor-Associated and Systemic Autoimmunity in Pre-Clinical Breast Cancer among Post-Menopausal Women
by Christine G. Parks, Lauren E. Wilson, Michela Capello, Kevin D. Deane and Samir M. Hanash
Biomolecules 2023, 13(11), 1566; https://doi.org/10.3390/biom13111566 - 24 Oct 2023
Viewed by 1344
Abstract
Autoantibodies to tumor-associated antigens (anti-TAA) are potential biomarkers for breast cancer, but their relationship systemic autoimmunity as ascertained though antinuclear antibodies (ANA) is unknown and warrants consideration given the common occurrence of autoimmunity and autoimmune diseases among women. The relationship between anti-TAAs and [...] Read more.
Autoantibodies to tumor-associated antigens (anti-TAA) are potential biomarkers for breast cancer, but their relationship systemic autoimmunity as ascertained though antinuclear antibodies (ANA) is unknown and warrants consideration given the common occurrence of autoimmunity and autoimmune diseases among women. The relationship between anti-TAAs and ANA among women who were later diagnosed with breast cancer and others who remained cancer free in the Women’s Health Initiative cohort. The study sample included 145 post-menopausal women with baseline ANA data. A total of 37 ANA-positive women who developed breast cancer (i.e., cases; mean time to diagnosis 6.8 years [SE 3.9]) were matched to a random sample of 36 ANA-negative cases by age and time to diagnosis. An age-matched control sample was selected including 35 ANA-positive and 37 ANA-negative women who did not develop breast cancer (i.e., controls; follow-up time ~13 years [SE 3]). Baseline sera were assessed for Immunoglobulin G (IgG) antibodies, measured by custom microarray for 171 breast and other cancer-associated TAA. We used linear regression to estimate cross-sectional associations of ANA with log-transformed anti-TAA among cases and controls. Most anti-TAA did not vary by ANA status. Two anti-TAA were elevated in ANA-positive compared to ANA-negative cases: anti-PGM3 (p = 0.004) and anti-TTN (p = 0.005, especially in cases up to 7 years before diagnosis, p = 0.002). Anti-TAA antibodies were not generally related to ANA, a common marker of systemic autoimmunity. Associations of ANA with particular antigens inducing autoimmunity prior to breast cancer warrant further investigation. Full article
(This article belongs to the Special Issue Novel Insights into the Role of Autoantibodies in Diseases)
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17 pages, 2847 KiB  
Article
Patients with Systemic Juvenile Idiopathic Arthritis (SJIA) Show Differences in Autoantibody Signatures Based on Disease Activity
by Julie Krainer, Michaela Hendling, Sandra Siebenhandl, Sabrina Fuehner, Christoph Kessel, Emely Verweyen, Klemens Vierlinger, Dirk Foell, Silvia Schönthaler and Andreas Weinhäusel
Biomolecules 2023, 13(9), 1392; https://doi.org/10.3390/biom13091392 - 15 Sep 2023
Viewed by 2938
Abstract
Systemic juvenile idiopathic arthritis (SJIA) is a severe rheumatic disease in children. It is a subgroup of juvenile idiopathic arthritis (JIA; MIM #604302), which is the most common rheumatic disease in children. The diagnosis of SJIA often comes with a significant delay, and [...] Read more.
Systemic juvenile idiopathic arthritis (SJIA) is a severe rheumatic disease in children. It is a subgroup of juvenile idiopathic arthritis (JIA; MIM #604302), which is the most common rheumatic disease in children. The diagnosis of SJIA often comes with a significant delay, and the classification between autoinflammatory and autoimmune disease is still discussed. In this study, we analyzed the immunological responses of patients with SJIA, using human proteome arrays presenting immobilized recombinantly expressed human proteins, to analyze the involvement of autoantibodies in SJIA. Results from group comparisons show several differentially reactive antigens involved in inflammatory processes. Intriguingly, many of the identified antigens had a high reactivity against proteins involved in the NF-κB pathway, and it is also notable that many of the detected DIRAGs are described as dysregulated in rheumatoid arthritis. Our data highlight novel proteins and pathways potentially dysregulated in SJIA and offer a unique approach to unraveling the underlying disease pathogenesis in this chronic arthropathy. Full article
(This article belongs to the Special Issue Novel Insights into the Role of Autoantibodies in Diseases)
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14 pages, 3069 KiB  
Article
Anti-Citrullinated Protein Antibody Reactivity towards Neutrophil-Derived Antigens: Clonal Diversity and Inter-Individual Variation
by Alexandra Cîrciumaru, Marcelo Gomes Afonso, Heidi Wähämaa, Akilan Krishnamurthy, Monika Hansson, Linda Mathsson-Alm, Márton Keszei, Ragnhild Stålesen, Lars Ottosson, Charlotte de Vries, Miriam A. Shelef, Vivianne Malmström, Lars Klareskog, Anca I. Catrina, Caroline Grönwall, Aase Hensvold and Bence Réthi
Biomolecules 2023, 13(4), 630; https://doi.org/10.3390/biom13040630 - 31 Mar 2023
Cited by 2 | Viewed by 1964
Abstract
Background: Why the adaptive immune system turns against citrullinated antigens in rheumatoid arthritis (RA) and whether anti-citrullinated protein antibodies (ACPAs) contribute to pathogenesis are questions that have triggered intense research, but still are not fully answered. Neutrophils may be crucial in this context, [...] Read more.
Background: Why the adaptive immune system turns against citrullinated antigens in rheumatoid arthritis (RA) and whether anti-citrullinated protein antibodies (ACPAs) contribute to pathogenesis are questions that have triggered intense research, but still are not fully answered. Neutrophils may be crucial in this context, both as sources of citrullinated antigens and also as targets of ACPAs. To better understand how ACPAs and neutrophils contribute to RA, we studied the reactivity of a broad spectrum of RA patient-derived ACPA clones to activated or resting neutrophils, and we also compared neutrophil binding using polyclonal ACPAs from different patients. Methods: Neutrophils were activated by Ca2+ ionophore, PMA, nigericin, zymosan or IL-8, and ACPA binding was studied using flow cytometry and confocal microscopy. The roles of PAD2 and PAD4 were studied using PAD-deficient mice or the PAD4 inhibitor BMS-P5. Results: ACPAs broadly targeted NET-like structures, but did not bind to intact cells or influence NETosis. We observed high clonal diversity in ACPA binding to neutrophil-derived antigens. PAD2 was dispensable, but most ACPA clones required PAD4 for neutrophil binding. Using ACPA preparations from different patients, we observed high patient-to-patient variability in targeting neutrophil-derived antigens and similarly in another cellular effect of ACPAs, the stimulation of osteoclast differentiation. Conclusions: Neutrophils can be important sources of citrullinated antigens under conditions that lead to PAD4 activation, NETosis and the extrusion of intracellular material. A substantial clonal diversity in targeting neutrophils and a high variability among individuals in neutrophil binding and osteoclast stimulation suggest that ACPAs may influence RA-related symptoms with high patient-to-patient variability. Full article
(This article belongs to the Special Issue Novel Insights into the Role of Autoantibodies in Diseases)
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Review

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16 pages, 1038 KiB  
Review
Oxidative Stress as a Regulatory Checkpoint in the Production of Antiphospholipid Autoantibodies: The Protective Role of NRF2 Pathway
by Maurizio Sorice, Elisabetta Profumo, Antonella Capozzi, Serena Recalchi, Gloria Riitano, Benedetta Di Veroli, Luciano Saso and Brigitta Buttari
Biomolecules 2023, 13(8), 1221; https://doi.org/10.3390/biom13081221 - 5 Aug 2023
Cited by 1 | Viewed by 1642
Abstract
Oxidative stress is a well-known hallmark of Antiphospholipid Antibody Syndrome (APS), a systemic autoimmune disease characterized by arterial and venous thrombosis and/or pregnancy morbidity. Oxidative stress may affect various signaling pathways and biological processes, promoting dysfunctional immune responses and inflammation, inducing apoptosis, deregulating [...] Read more.
Oxidative stress is a well-known hallmark of Antiphospholipid Antibody Syndrome (APS), a systemic autoimmune disease characterized by arterial and venous thrombosis and/or pregnancy morbidity. Oxidative stress may affect various signaling pathways and biological processes, promoting dysfunctional immune responses and inflammation, inducing apoptosis, deregulating autophagy and impairing mitochondrial function. The chronic oxidative stress and the dysregulation of the immune system leads to the loss of tolerance, which drives autoantibody production and inflammation with the development of endothelial dysfunction. In particular, anti-phospholipid antibodies (aPL), which target phospholipids and/or phospholipid binding proteins, mainly β-glycoprotein I (β-GPI), play a functional role in the cell signal transduction pathway(s), thus contributing to oxidative stress and thrombotic events. An oxidation–antioxidant imbalance may be detected in the blood of patients with APS as a reflection of disease progression. This review focuses on functional evidence highlighting the role of oxidative stress in the initiation and progression of APS. The protective role of food supplements and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) activators in APS patients will be summarized to point out the potential of these therapeutic approaches to reduce APS-related clinical complications. Full article
(This article belongs to the Special Issue Novel Insights into the Role of Autoantibodies in Diseases)
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