New, Old, and Shared Antibody Specificities in Autoimmune Diseases

A special issue of Antibodies (ISSN 2073-4468).

Deadline for manuscript submissions: closed (20 September 2022) | Viewed by 24917

Special Issue Editor

Special Issue Information

Dear Colleagues,

This Special Issue will review the current knowledge in the field of autoimmunity with a particular focus on old and new antibody specificities discovered in autoimmune diseases that are typically antibody-driven, but also in those autoimmune diseases that seem more linked to T-cell activation, or are considered auto-inflammatory. Autoantibodies are primarily characteristic of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) or systemic sclerosis (SSc). However, there is increasing evidence that autoantibodies can be also present in diseases that are not normally considered antibody-mediated, such as psoriasis (in which T-cells and innate immunity seem to play a major role) and atopic dermatitis (AD). In psoriasis, autoantibodies can be present occasionally, and may target LL37, an antimicrobial peptide over-expressed in psoriatic lesional skin. Interestingly, in the associated arthritis (PSA), anti-carbamylated protein antibody reactivity is present, including reactivity to native and carbamylated LL37. Antimicrobial peptides such as LL37, but also alpha-defensins (HNP1-3), can be the target of autoantibodies in SLE. Thus, a shared antibody reactivity characterizes both SLE and PSA, although they are different diseases. Likewise, anti-DNA or anti-nuclear antibodies (ANA) in general, are detectable in several autoimmune diseases. This is also true for anti-citrullinated protein antibodies, primarily studied in rheumatoid arthritis (RA), but detected also in SLE and other conditions. Therefore, to understand why some antibodies mark only specific diseases, whereas others are shared between diseases that affect different body locations, a focus on shared antibody specificities is also needed.

Further insights into the pathogenesis of autoimmune diseases can come from the study of new, old, and shared antibody-specificity, to help understand common pathways or exclude pathways that appear to be involved in the diseases but instead have no relevance. Moreover, the study of new, old, and shared antibody specificities across various autoimmune diseases, can help to identify more precise and distinct biomarkers in autoimmunity, even in less-studied autoimmune disorders.

Dr. Loredana Frasca
Guest Editor

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Keywords

  • Autoimmune diseases
  • Autoantibodies
  • New antibody specificity
  • T-cell help for autoantibody production
  • New biomarkers

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Published Papers (6 papers)

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Editorial

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7 pages, 229 KiB  
Editorial
New, Old, and Shared Antibody Specificities in Autoimmune Diseases
by Loredana Frasca, Anna Mennella and Raffaella Palazzo
Antibodies 2024, 13(1), 23; https://doi.org/10.3390/antib13010023 - 13 Mar 2024
Viewed by 1711
Abstract
Autoantibodies represent a primary characteristic of many systemic autoimmune diseases [...] Full article
(This article belongs to the Special Issue New, Old, and Shared Antibody Specificities in Autoimmune Diseases)

Research

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11 pages, 1851 KiB  
Article
Heparin-Independent and Heparin-Dependent Anti-CXCL4 Antibodies Have a Reciprocal Expression in a Systemic Sclerosis Patients’ Cohort
by Raffaella Palazzo, Katia Stefanantoni, Marius Cadar, Alessia Butera, Valeria Riccieri, Roberto Lande and Loredana Frasca
Antibodies 2022, 11(4), 77; https://doi.org/10.3390/antib11040077 - 15 Dec 2022
Cited by 1 | Viewed by 2140
Abstract
Systemic sclerosis (SSc) is a chronic disease characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an early SSc biomarker that predicts worse disease outcome. We previously reported that CXCL4 is an autoantigen in SSc, and anti-CXCL4 [...] Read more.
Systemic sclerosis (SSc) is a chronic disease characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an early SSc biomarker that predicts worse disease outcome. We previously reported that CXCL4 is an autoantigen in SSc, and anti-CXCL4 antibodies correlated with IFN-I and were more abundant in patients with lung fibrosis. However, it is unclear whether antibodies to CXCL4 in SSc are only directed to CXCL4 or recognize complexes formed by CXCL4 and heparin. Here, by analyzing an SSc cohort, we addressed the occurrence of circulating heparin-dependent VS heparin-independent anti-CXCL4 antibodies and their relationship with a few disease parameters. We found that heparin-dependent, like the heparin-independent antibodies, are higher in SSc as compared to healthy donors; they are detectable in 24% and 30% of the SSc patients, respectively, and appear inversely correlated and mutually exclusive. Like the heparin-independent antibodies, heparin-dependent antibodies correlated with digital ulcers. However, in contrast to heparin-independent antibodies, heparin-dependent antibodies did not correlate with IFN-I, but were largely expressed in patients with pulmonary arterial hypertension. This pilot study indicates that heparin-dependent antibodies are worth studying in larger SSc cohorts to address whether they discriminate SSc sub-groups with different pathological characteristics and outcomes. Full article
(This article belongs to the Special Issue New, Old, and Shared Antibody Specificities in Autoimmune Diseases)
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12 pages, 1644 KiB  
Article
New Autoantibody Specificities in Systemic Sclerosis and Very Early Systemic Sclerosis
by Roberto Lande, Raffaella Palazzo, Anna Mennella, Immacolata Pietraforte, Marius Cadar, Katia Stefanantoni, Curdin Conrad, Valeria Riccieri and Loredana Frasca
Antibodies 2021, 10(2), 12; https://doi.org/10.3390/antib10020012 - 28 Mar 2021
Cited by 10 | Viewed by 5020
Abstract
Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker of unfavorable prognosis in Systemic Sclerosis (SSc), a potentially severe autoimmune condition, characterized by vasculitis, fibrosis and interferon (IFN)-I-signature. We recently reported that autoantibodies to CXCL4 circulate in SSc patients and correlate with IFN-α. [...] Read more.
Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker of unfavorable prognosis in Systemic Sclerosis (SSc), a potentially severe autoimmune condition, characterized by vasculitis, fibrosis and interferon (IFN)-I-signature. We recently reported that autoantibodies to CXCL4 circulate in SSc patients and correlate with IFN-α. Here, we used shorter versions of CXCL4 and CXCL4-L1, the CXCL4 non-allelic variant, to search for autoantibodies exclusively reacting to one or the other CXCL4 form. Moreover, to address whether anti-CXCL4/CXCL4-L1 antibodies were present before SSc onset and predicted SSc-progression, we longitudinally studied two VEDOSS (Very Early Diagnosis of Systemic Sclerosis) patient cohorts, separating SSc-progressors from SSc-non-progressors. We found that anti-CXCL4-specific autoantibodies were present in both SSc and VEDOSS patients (both SSc-progressors and SSc-non-progressors). Anti-CXCL4-L1-specific autoantibodies were especially detected in long-standing SSc (lsSSc). Anti-CXCL4/CXCL4-L1 antibodies correlated with IFN-α and with specific SSc-skin features but only in lsSSc and not in early SSc (eaSSc) or VEDOSS. Thus, a broader antibody response, with reactivity spreading to CXCL4-L1, is characteristic of lsSSc. The early anti-CXCL4 autoantibody response seems qualitatively different from, and likely less pathogenic than, that observed in advanced SSc. Lastly, we confirm that anti-CXCL4 autoantibodies are SSc-biomarkers and uncover that also CXCL4-L1 becomes an autoantigen in lsSSc. Full article
(This article belongs to the Special Issue New, Old, and Shared Antibody Specificities in Autoimmune Diseases)
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14 pages, 3472 KiB  
Article
Taking the Hinge off: An Approach to Effector-Less Monoclonal Antibodies
by Jamie Valeich, Dan Boyd, Manu Kanwar, Daniel Stenzel, Deblina De Ghosh, Arpa Ebrahimi, James Woo, Jenny Wang and Alexandre Ambrogelly
Antibodies 2020, 9(4), 50; https://doi.org/10.3390/antib9040050 - 23 Sep 2020
Cited by 4 | Viewed by 6808
Abstract
A variety of Fc domain engineering approaches for abrogating the effector functions of mAbs exists. To address some of the limitations of the current Fc domain silencing approaches, we are exploring a less commonly considered option which relies on the deletion of the [...] Read more.
A variety of Fc domain engineering approaches for abrogating the effector functions of mAbs exists. To address some of the limitations of the current Fc domain silencing approaches, we are exploring a less commonly considered option which relies on the deletion of the hinge. Removal of the hinge domain in humanized IgG1 and IgG4 mAbs obliterates their ability to bind to activating human Fc gamma receptors I and IIIA, while leaving their ability to engage their target antigen intact. Deletion of the hinge also reduces binding to the Fc neonatal receptor, although Fc engineering allows partial recovery of affinity. Engineering of the CH3 domain, stabilizes hinge deleted IgG4s and prevents Fab arm exchange. The faster clearing properties together with the pacified Fc make modality of the hinge deleted mAb an appealing solution for therapeutic and diagnostic applications. Full article
(This article belongs to the Special Issue New, Old, and Shared Antibody Specificities in Autoimmune Diseases)
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13 pages, 2247 KiB  
Article
CD1d Selectively Down Regulates the Expression of the Oxidized Phospholipid-Specific E06 IgM Natural Antibody in Ldlr−/− Mice
by Tapan K. Biswas, Paul A. VanderLaan, Xuchu Que, Ayelet Gonen, Paulette Krishack, Christoph J. Binder, Joseph L. Witztum, Godfrey S. Getz and Catherine A. Reardon
Antibodies 2020, 9(3), 30; https://doi.org/10.3390/antib9030030 - 3 Jul 2020
Cited by 3 | Viewed by 4654
Abstract
Natural antibodies (NAbs) are important regulators of tissue homeostasis and inflammation and are thought to have diverse protective roles in a variety of pathological states. E06 is a T15 idiotype IgM NAb exclusively produced by B-1 cells, which recognizes the phosphocholine (PC) head [...] Read more.
Natural antibodies (NAbs) are important regulators of tissue homeostasis and inflammation and are thought to have diverse protective roles in a variety of pathological states. E06 is a T15 idiotype IgM NAb exclusively produced by B-1 cells, which recognizes the phosphocholine (PC) head group in oxidized phospholipids on the surface of apoptotic cells and in oxidized LDL (OxLDL), and the PC present on the cell wall of Streptococcus pneumoniae. Here we report that titers of the E06 NAb are selectively increased several-fold in Cd1d-deficient mice, whereas total IgM and IgM antibodies recognizing other oxidation specific epitopes such as in malondialdehyde-modified LDL (MDA-LDL) and OxLDL were not increased. The high titers of E06 in Cd1d-deficient mice are not due to a global increase in IgM-secreting B-1 cells, but they are specifically due to an expansion of E06-secreting splenic B-1 cells. Thus, CD1d-mediated regulation appeared to be suppressive in nature and specific for E06 IgM-secreting cells. The CD1d-mediated regulation of the E06 NAb generation is a novel mechanism that regulates the production of this specific oxidation epitope recognizing NAb. Full article
(This article belongs to the Special Issue New, Old, and Shared Antibody Specificities in Autoimmune Diseases)
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Review

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13 pages, 1115 KiB  
Review
Specific Autoantibodies and Microvascular Damage Progression Assessed by Nailfold Videocapillaroscopy in Systemic Sclerosis: Are There Peculiar Associations? An Update
by Elvis Hysa, Rosanna Campitiello, Silvia Sammorì, Emanuele Gotelli, Andrea Cere, Giampaola Pesce, Carmen Pizzorni, Sabrina Paolino, Alberto Sulli, Vanessa Smith and Maurizio Cutolo
Antibodies 2023, 12(1), 3; https://doi.org/10.3390/antib12010003 - 4 Jan 2023
Cited by 4 | Viewed by 3021
Abstract
Background: Specific autoantibodies and nailfold videocapillaroscopy (NVC) findings are serum and morphological diagnostic hallmarks of systemic sclerosis (SSc) as well as useful biomarkers which stratify the microvascular progression and prognosis of patients. Methods: The aim of our narrative review is to provide an [...] Read more.
Background: Specific autoantibodies and nailfold videocapillaroscopy (NVC) findings are serum and morphological diagnostic hallmarks of systemic sclerosis (SSc) as well as useful biomarkers which stratify the microvascular progression and prognosis of patients. Methods: The aim of our narrative review is to provide an update and overview of the link between SSc-related autoantibodies, used in clinical practice, and microvascular damage, evaluated by NVC, by exploring the interaction between these players in published studies. A narrative review was conducted by searching relevant keywords related to this field in Pubmed, Medline and EULAR/ACR conference abstracts with a focus on the findings published in the last 5 years. Results: Our search yielded 13 clinical studies and 10 pre-clinical studies. Most of the clinical studies (8/13, 61.5%) reported a significant association between SSc-related autoantibodies and NVC patterns: more specifically anti-centromere autoantibodies (ACA) were associated more often with an “Early” NVC pattern, whereas anti-topoisomerase autoantibodies (ATA) more frequently showed an “Active” or “Late” NVC pattern. Five studies, instead, did not find a significant association between specific autoantibodies and NVC findings. Among the pre-clinical studies, SSc-related autoantibodies showed different mechanisms of damage towards both endothelial cells, fibroblasts and smooth muscle vascular cells. Conclusions: The clinical and laboratory evidence on SSc-related autoantibodies and microvascular damage shows that these players are interconnected. Further clinical and demographic factors (e.g., age, sex, disease duration, treatment and comorbidities) might play an additional role in the SSc-related microvascular injury whose progression appears to be complex and multifactorial. Full article
(This article belongs to the Special Issue New, Old, and Shared Antibody Specificities in Autoimmune Diseases)
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