---
title: "Post-translational neoantigens in rheumatoid arthritis: molecular mechanisms and therapeutic impli"
id: "frontiers-in-immunology-9-molecular-basis-of-post-translational-neoantigen-generation-in-rheumatoid"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-9-molecular-basis-of-post-translational-neoantigen-generation-in-rheumatoid"
content_type: "clinical_feed_article"
specialty: "Rheumatology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1876035"
published_at: "2026-08-20T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Post-translational neoantigens in rheumatoid arthritis: molecular mechanisms and therapeutic impli
## Provenance & Clinical Metadata
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- **Specialty:** [Rheumatology](https://medichelpline.com/clinical-feed/rheumatology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1876035)
- **Published At:** 2026-08-20T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease driven by loss of immune tolerance to self-antigens, often affecting small and medium joints and producing extra-articular manifestations. Genetic susceptibility (eg, HLA-DRB1) and environmental triggers interact to induce disease. - **Post-translational modifications (PTMs)** — including **citrullination**, **carbamylation**, **glycosylation**, and glycation/AGE formation — generate altered self-proteins (neoantigens) with increased immunogenicity under conditions of inflammation and oxidative stress. - Enzymes such as peptidylarginine deiminases (PADs) and transglutaminases, reactive oxygen species (ROS), neutrophil activation and NET formation promote PTMs in synovium and mucosal tissues like lung and periodontal mucosa. - PTM-derived neoantigens are processed and presented by antigen-presenting cells via MHC class II to autoreactive CD4+ T cells, driving B-cell activation and production of autoantibodies including **ACPAs** and anti-CarP antibodies; immune complexes, complement activation and cytokines amplify synovial inflammation. - Chronic inflammation in RA associates with expansion and activation of synovial cell types (fibroblast-like synoviocytes, macrophage-like synoviocytes), ectopic germinal centers, Treg dysfunction and Th17 skewing, all facilitating epitope spreading and persistent joint damage. - Proteomic surveys and targeted mass spectrometry have directly identified multiple PTM-modified proteins in RA tissues and fluids (eg, citrullinated β-actin, vimentin; carbamylated albumin, collagen II; aberrantly glycosylated IgG), summarized in the review’s Table 1. - PTMs can create peptides absent during central tolerance, so peripheral modification can render self-Ags “nonself”; T-cell responses often recognize only the modified peptide while B-cell responses may cross-react with unmodified forms. - Recognizing PTM-derived neoantigens has diagnostic and prognostic potential and supports development of precision therapies aimed at interrupting neoantigen generation or restoring antigen-specific tolerance. - Emerging targeted approaches discussed include antigen-specific tolerogenic vaccines, tolerogenic dendritic cells, adoptive regulatory cell therapies (CAR-Tregs, antigen-specific Tregs), inhibitors of PTM enzymes (eg, PAD inhibitors), and NET-targeting strategies (eg, DNase I, CIT-013) intended to limit synovial inflammation while reducing systemic immunosuppression. - The review emphasizes that deeper molecular characterization of PTM neoantigens could refine diagnostics and enable more selective treatments, but it notes that many mechanistic details and clinical translation remain areas of active research.
## Clinical Analysis & Structured Key Points
Frontiers | Molecular basis of post-translational neoantigen generation in rheumatoid arthritis: breaking immunological tolerance and implications for targeted therapy REVIEW article Front. Immunol. , 20 August 2026 Sec. Immunological Tolerance and Regulation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1876035 Published in Frontiers in Immunology Immunological Tolerance and Regulation 7 impact factor 11.3 citescore Part of a Research Topic Immunological tolerance at the crossroads of autoimmunity and oncology: Mechanisms, plasticity, and therapeutic frontiers Submission open 1959 views 3 articles Editor & Reviewers Edited by K K Karsten Kretschmer Reviewed by Y S Yohei Sato Y Z Yue Zhai Outline Figures and Tables Figure 1 View in article Table 1 Landscape of PTM-derived neoantigens and their tissue distribution in RA. View in article Table 2 The role of mucosal tissues in the pathophysiology of RA. View in article REVIEW article Front. Immunol. , 20 August 2026 Sec. Immunological Tolerance and Regulation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1876035 Molecular basis of post-translational neoantigen generation in rheumatoid arthritis: breaking immunological tolerance and implications for targeted therapy A P Alba Pérez Linaza 1,2 S P Sussel Picallo Díaz 3 I S Isabel Serrano García 1,2 W Y Wenjie Yi 3 Á G Álvaro Guerrero Lores 3 J M Juan Manuel Aragón González 4 F G Francisco Garcia-Cozar 2,3 C F Cecilia Fernandez-Ponce 2,3 † * R F Ricardo Fernandez-Cisnal 2,3 † * 1. Rheumatology Service, Puerta del Mar University Hospital, Cádiz, Spain 2. Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital, Cádiz, Spain 3. Department of Biomedicine, Biotechnology and Public Health, School of Medicine, University of Cádiz, Cádiz, Spain 4. Cardiology Service, Virgen del Rocío University Hospital, Seville, Spain See more Article metrics View details Abstract Autoimmune diseases are characterized by a loss of immune system tolerance to self-antigens, which can trigger an immune response capable of affecting various organs and tissues. An increase in the prevalence of these diseases has been reported in recent years. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by persistent synovial inflammation. While it predominantly targets small and medium-sized joints, its pathogenesis frequently extends to diverse extra-articular manifestations. In line with other autoimmune diseases, the presence of neoantigens derived from post-translational modifications represents a critical checkpoint in RA pathogenesis, driving the loss of self-tolerance and the subsequent perpetuation of the autoreactive immune response. The primary therapeutic goal in RA is to achieve clinical remission or, alternatively, to maintain low disease activity. Therapeutic strategies designed to reach these targets are currently available in clinical practice. However, most of these agents act systemically, potentially leading to significant adverse effects. This review article explores the molecular landscape of post-translational modifications and analyzes how these chemical alterations generate neoantigens, which contribute to the pathogenesis of RA. Furthermore, the identification of these specific molecular signatures offers a pathway toward precision medicine, moving beyond conventional treatments to targeted therapies that could potentially restore tolerance, improving patient quality of life and clinical outcomes. 1 Introduction Autoimmune diseases (ADs) are a group of conditions characterized by a loss of immune system tolerance to the individual’s own antigens (Ags), triggering specific immune responses against self-antigens (self-Ags), which can cause damage to different organs and systems ( 1 ). Although the real incidence of ADs is difficult to ascertain, estimates suggest that they may affect approximately 10% of the global population. With their prevalence having increased in recent years in industrialized countries, they have emerged as a major cause of morbidity and mortality. They affect women more often, and although they can develop at any age, some occur within specific age ranges, as is the case of rheumatoid arthritis (RA) and multiple sclerosis. The etiopathogenesis of ADs is very complex and not yet fully understood. Some individuals are genetically predisposed, or susceptible, and are affected by a series of environmental factors, including sex hormones, infections, and toxic agents, that favor the development of the disease ( 2 , 3 ). RA is a chronic, systemic autoimmune inflammatory disease characterized primarily by proliferation of the synovial membrane of the joints, with pannus formation and a tendency to destroy the articular cartilage. Joint involvement is mainly symmetrical in small and medium-sized joints, particularly those of the hands and feet. Additionally, extra-articular manifestations and systemic involvement may arise at any stage of the disease. The prevalence of RA ranges from 0.5% to 1%, and, as in other ADs, its incidence is higher in women ( 4 , 5 ). It has been proposed that various genetic and environmental factors participate in the etiology of RA, in such a way that genetically predisposed or susceptible individuals are exposed to a series of environmental factors leading to an abnormal activation of the immune system characterized by a loss of tolerance to autoantigens, which trigger autoimmune responses. Thus, genetic susceptibility factors, such as the HLA system, non-HLA genes, and other epigenetic mechanisms, are not sufficient on their own to trigger the onset and development of the disease, although they may play an important role in pathogenesis, progression, and response to treatment ( Figure 1A ) ( 4 – 6 ). Figure 1 From post-translational modification of self-proteins to immune tolerance breakdown and emerging targeted therapies in rheumatoid arthritis. (A) Chronic inflammation and oxidative stress, driven by environmental factors (e.g., smoking and microbiome dysbiosis or infection) acting on a genetically susceptible background (e.g., HLA-DRB1 ), promote the generation of reactive oxygen species (ROS), neutrophil activation and neutrophil extracellular trap (NET) formation, together with the upregulation of protein-modifying enzymes such as peptidylarginine deiminases (PADs) and transglutaminases. These processes induce multiple post-translational modifications (PTMs), including citrullination, carbamylation and glycation/advanced glycation end product (AGE) formation, generating modified self-proteins with increased immunogenicity. The resulting neoepitopes are more efficiently processed and presented by antigen-presenting cells (APCs), ultimately contributing to the breakdown of immune tolerance. (B) PTM-derived neoantigens are presented to autoreactive CD4 + T cells, promoting B-cell activation and differentiation into autoantibody-producing plasma cells, including anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein (anti-CarP) antibodies. Immune complex deposition, cytokine production, complement activation and NET formation amplify chronic synovial inflammation, ultimately leading to cartilage destruction, bone erosion and persistent joint pathology. (C) Emerging therapeutic strategies aim to interrupt this pathogenic cascade by restoring antigen-specific immune tolerance or preventing PTM generation and downstream inflammatory mechanisms. These approaches include antigen-specific tolerogenic vaccines, tolerogenic dendritic cells, CAR-Tregs and antigen-specific regulatory T cells, PAD inhibitors, and NET-targeting strategies (e.g., DNase I or CIT-013), with the goal of restoring immune tolerance, limiting chronic synovial inflammation and preventing progressive joint damage while minimizing systemic immunosuppression. According to the pathogenesis of RA, in the preclinical stage of RA, different risk factors and the development of alterations of the immune system take place before joint involvement occurs. In genetically predisposed individuals, exposure to one or more environmental factors leads to post-translational modifications of self-antigens, such as citrullination, carbamylation or acetylation of proteins located in synovial membrane, and other tissues, including the lung or periodontal mucosa. These modified proteins act as neoantigens, which are recognized by the immune system and presented to CD4+ T lymphocytes via MHC class II molecules. This interaction stimulates B lymphocytes to synthesize autoantibodies. Furthermore, other stimuli such as the formation of immune complexes, alterations in microcirculation, or activation of the complement system promote cellular migration to the affected tissues and the development of synovitis ( Figures 1A, B ) ( 7 – 9 ). Some important pathogenic changes occur in the synovial membrane of patients with RA. One of them is the expansion of the intima lining due to the proliferation and activation of synoviocytes, specifically macrophage-like synoviocytes (MLSs) and fibroblast-like synoviocytes (FLSs). While MLSs serve as a primary source of pro-inflammatory cytokines, FLSs are characterized by the secretion of matrix metalloproteinases and small-molecule mediators like prostaglandins and leukotrienes. This activated FLS phenotype is further driven by specific microRNA expression patterns. Consequently, FLSs adopt an invasive behavior capable of migrating between joints to propagate the disease, while actively supporting ectopic lymphoid structure formation through interactions with adaptive immune cells. On the other hand, the synovial sublining exhibits infiltration by adaptive immune cells, especially CD4+ T lymphocytes, which either diffusely populate the tissue or aggregate into ectopic germinal centers in 15–20% of patients. Within these structures, mature B cells and plasma cells undergo local affinity maturation suggesting an immune response against native or altered peptides ( Figure 1B ) ( 8 , 9 ). It’s critical to note that the chronic inflammatory milieu characteristic of RA promotes dysfunction of regulatory T cells (Tregs) and the loss of their suppressive capacity, which prevents effective control of autoreactive T cells and favors the differentiation of Tregs into pathogenic Th17 cells ( 8 – 10 ). In addition, macrophages, follicular dendritic cells and mast cells are widely distributed throughout the synovial sublining. Thus, this cellular infiltration and its immune activity drive the formation of an inflammatory tissue called pannus at the interface between cartilage and bone, triggering progressive joint erosion and bone destruction ( Figure 1B ) ( 8 , 9 , 11 ). Unlike normal immune responses, complete resolution does not occur due to the existence of mechanisms that amplify the immune response. Furthermore, tissue damage and alterations in protein structure can result in the emergence of new epitopes, different from the original epitope that triggered the immune response, that are targeted by specific lymphocytes, promoting the exacerbation and chronicity of the disease. This phenomenon is known as epitope spreading and is crucial in perpetuating the pathology ( 12 – 14 ). In summary, the pathogenesis of this disease is due to the loss of Treg cells suppressive capacity in the affected tissues and the existence of a pro-inflammatory vicious circle caused by the presentation of antigens to B cells, which produce autoantibodies, generating immune complexes and perpetuating inflammation. This chronic inflammatory environment is sustained by the immune cells mentioned above, autoantibodies, cytokines and other inflammatory mediators, leading to progressive joint destruction ( Figure 1B ). 2 Neoantigens in RA In line with the aforementioned immunopathogenesis of RA, the generation of neoantigens plays an important role ( 6 , 14 ). Neoantigens are self-Ags that undergo changes in their original structure and can trigger an immune response when they are recognized as foreign by lymphocytes, thus breaking immune tolerance ( 15 , 16 ). Among the potential mechanisms involved in the generation of neoantigens are epigenetic changes, epitopes generated by point mutations, alternative RNA splicing, defective ribosomal products (DRiPs) or aberrant post-translational modifications ( 16 – 18 ). Despite being mechanistically distinct, these processes share a common outcome: the diversification of the cellular proteome beyond the canonical genetic sequence, resulting in the generation of previously unrecognized peptides that can be processed and presented by MHC molecules. Although the available evidence indicates that these mechanisms generate transcriptomic and proteomic diversity and may serve as potential sources of neoepitopes, their contribution to autoimmunity in RA, like in other ADs, is still an area of active research ( 19 , 20 ). Regarding the generation of neoantigens by post-translational modifications (PTMs), these are chemical changes, either spontaneous or enzyme-mediated, occurring in the structure of proteins after their synthesis. Although these changes are part of normal physiology, they can also occur under inflammatory or oxidative stress conditions, generating modified self-proteins with altered immunogenicity that may trigger an immune response ( 15 – 17 , 21 ) ( Figure 1A ). While the immune system employs several mechanisms to eliminate autoreactive lymphocytes, in the periphery, PTMs, driven by inflammation or oxidative stress, can generate novel proteoforms that are absent during central tolerance induction in primary lymphoid organs. Consequently, these modified self-Ags can be recognize as “nonself”, triggering both T and B cell-mediated autoimmune response ( 22 , 23 ). While T cell-mediated immune responses to PTM-generated neoantigens tend to be specific to the modified peptides and do not recognize unmodified self-peptides, B cells can release antibodies (Abs) that can recognize both modified and unmodified antigens ( 24 , 25 ). Furthermore, autoimmune responses triggered by self-Ags that have undergone PTMs may subsequently spread to other intra- and intermolecular determinants (epitope spreading), favoring the chronic course of the disease ( 23 , 26 ). PTM-modified self-Ags have been identified in many ADs. One such example is RA, in which the occurrence of various modifications associated with different self-Ags has also been described ( 22 , 23 , 27 – 29 ). Thus, PTM-derived neoantigens are pivotal in the pathogenesis of ADs like RA and represent potential indicators for assessing disease progression ( 15 , 23 , 30 ). A deeper insight into the nature and origin of these neoantigens could enhance diagnostic precision and promote the development of potential targeted therapies in RA and in other ADs, offering a more selective mechanism of action minimizing the systemic adverse effects associated with current treatments ( 15 , 24 ). The following sections examine PTM-derived neoantigens in RA. Table 1 details neoantigens generated by some of the PTMs discussed in this review, as well as the species and the biological sources where these neoantigens have been detected, and the methods used for their detection. Studies based solely on serological reactivity without direct antigen detection, or those reporting PTMs outside the predefined scope, were excluded. Due to the vast number of citrullinated proteins identified in RA, only the most well-characterized neoantigens with direct experimental evidence are listed. Table 1 Protein Tissue/biofluid (source) Species Evidence type PTM detected Amino acid sites where protein modification occur Method β-actin Synovial fluid (inflamed joint) Human Direct Citrullinated β-actin Arg196 Arg206 Arg210 LC–MS/MS citrullinome ( 54 ) A1AT Serum Human Direct Carbamylated A1AT Lys125 Affinity chromatography - LC-MS/MS and ELISA ( 95 ) Synovial fluid (inflamed joint; RA) Human Direct (MS) Carbamylated A1AT Lys125 Affinity chromatography - LC-MS/MS and ELISA ( 95 ) Albumin Serum Human Direct Carbamylated albumin N/A LC–MS/MS ( 91 ) Joint tissues (cartilage/synovial tissue/synovial fluid) Human Direct Carbamylated albumin peptides K257 K402 K438 Whole-proteome LC–MS/MS carbamylome ( 92 ) apoE Synovial fluid (inflamed joint) Human Direct Citrullinated apoE Arg198 LC–MS/MS citrullinome ( 54 ) COL2 Joint cartilage Human/Rat Indirect Glycosylated and de-glycosylated immunodominant COL2 Lys264 Protein purification from tissue samples followed by T-cell hybridoma assays ( 40 ) Joint tissues (cartilage/synovial tissue/synovial fluid) Human Direct Carbamylated collagen peptides K250 K620 K773 K929 Whole-proteome LC–MS/MS carbamylome ( 92 ) Fibrinogen Synovial fluid Human Indirect Citrullinated fibrinogen N/A Electrophoresis/ Western blot analysis/MALDI-TOF-MS ( 55 ) Fibronectin Synovial fluid Human Indirect Citrullinated fibronectin N/A Electrophoresis/ Western blot analysis/MALDI-TOF-MS ( 55 ) Joint tissues (cartilage/synovial tissue/synovial fluid) Human Direct Carbamylated fibronectin peptides K486 K987 K1050 Whole-proteome LC–MS/MS carbamylome ( 92 ) IgG Serum Human Direct Aberrant IgG galactosylation pattern Asn297 HPLC-based N-glycan quantification ( 35 ) Serum (prior to the onset of RA) Human Direct Aberrant ACPA/IgG1 galactosylation and fucosylation pattern Asn297 Nano-LC-MS ( 36 ) Serum Human Direct Aberrant IgG galactosylation and sialyation pattern Asn297 MALDI-TOF MS ( 37 ) Plasma and synovial fluid Human Direct ACPA IgG - Fc glycosylation N/A LC-MS ( 38 ) Serum (RA and other inflammatory arthropathies) Human Indirect IgG modified by AGE N/A ELISA ( 49 ) Serum immune complexes / serum Human Indirect AGE-modified IgG N/A PEG precipitation of immune complexes - Affinity Chromatography – immunoblotting ( 50 ) MNDA Synovial fluid (inflamed joint) Human Direct (MS) Citrullinated MNDA Arg127 Arg129 LC–MS/MS citrullinome ( 54 ) Vimentin Synovial fluid Human Direct Citrullinated vimentin N/A Electrophoresis/ Western blot analysis/MALDI-TOF MS ( 55 ) Joint tissues (cartilage/synovial tissue/synovial fluid) Human Direct Carbamylated vimentin K235 K448 Whole-proteome LC–MS/MS carbamylome ( 92 ) Landscape of PTM-derived neoantigens and their tissue distribution in RA. A1AT, Alpha-1 antitrypsin; ACPA, Anti-citrullinated protein antibodies; AGE, Advanced glycation end-products; anti-CarP, Antibodies directed against carbamylated proteins; apoE, Apolipoprotein E; COL2, Collagen type II; ELISA, Enzyme linked immunosorbent assay; IgG, Immunoglobulin G; LC-MS/MS, Liquid chromatography–mass spectrometry/ mass spectrometry; Nano-LC-MS, Nano-liquid chromatography mass spectrometry; MNDA, Myeloid cell nuclear differentiation antigen; MS, Mass spectrometry; RA, rheumatoid arthritis; N/A, Not available due to lack of specific modification site data in current literature. 3 Post-translational modifications as a mechanism of neoantigen generation in RA PTMs are chemical changes that occur in the structure of proteins after their synthesis, giving rise to neoantigens that can alter immune tolerance and favor the development of ADs, including RA ( 15 , 31 ). Selected examples of PTMs and their role in neoantigen generation in RA are summarized in Figure 1A and detailed below. 3.1 Glycosylation Glycosylation consists of the covalent attachment of carbohydrate moieties to either a nitrogen (N-glycosylation) or an oxygen (O-glycosylation) atom within the amino acid side chains of a protein. This process plays a role in epitope presentation and in the regulation of the immune response mediated by immunoglobulins (Igs). When glycosylation occurs aberrantly, it can alter antigen presentation, inducing a loss of immune tolerance, and can also modify the properties of Igs, thereby affecting the immune response ( 32 , 33 ). In patients with RA, aberrant glycosylation of IgG acts as
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