Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disorder marked by persistent synovial inflammation, pannus formation and progressive joint damage. Genetic predisposition (for example HLA-DRB1 alleles) together with environmental exposures contribute to disease onset. A key pathogenic checkpoint in RA is the emergence of neoantigens generated by post-translational modifications (PTMs) of self-proteins, which can break immunological tolerance and sustain autoreactive immune responses.
In genetically susceptible individuals, environmental factors such as smoking, microbiome dysbiosis or infections promote chronic inflammation and oxidative stress. These processes increase reactive oxygen species (ROS), drive neutrophil activation with neutrophil extracellular trap (NET) formation, and upregulate protein-modifying enzymes including peptidylarginine deiminases (PADs) and transglutaminases. The inflammatory microenvironment in synovium favors PTM accumulation, recruitment and activation of adaptive immune cells, and establishment of ectopic lymphoid structures in a subset of patients.
PTMs are chemical changes occurring after protein synthesis that can be either enzymatic or non-enzymatic. Under physiological conditions PTMs regulate protein function; under inflammation and oxidative stress they can generate modified proteoforms absent during central tolerance induction. These altered self-antigens can be processed and presented as novel peptides by MHC molecules, perceived as “nonself,” and elicit T- and B-cell responses. PTM-driven neoantigen formation is mechanistically distinct from other neoantigen sources (eg, somatic mutations, splicing variants) but similarly increases proteomic diversity and potential autoantigenicity.
Glycosylation attaches carbohydrate moieties to proteins (N- or O-glycosylation). Aberrant glycosylation alters peptide presentation and modulates immunoglobulin function. In RA, altered IgG glycosylation patterns (for example, changes at Asn297) have been documented and influence immune effector functions. Such glycosylation defects may affect immune recognition and contribute to loss of tolerance.
Citrullination, catalyzed by PAD enzymes, converts arginine residues to citrulline and is a prominent PTM implicated in RA. Inflamed synovium and other tissues show a citrullinome with multiple citrullinated proteins identified by mass spectrometry. Citrullinated peptides are efficiently processed and presented to CD4+ T cells, promoting B-cell activation and production of anti-citrullinated protein antibodies (ACPAs). T-cell responses to citrullinated neoepitopes are often specific for the modified peptide form.
Carbamylation and non-enzymatic glycation leading to advanced glycation end-products (AGEs) generate additional modified self-proteins detectable in serum, synovial fluid and tissues. Antibodies directed against carbamylated proteins (anti-CarP) have been described. Mass-spectrometry studies have identified carbamylated peptides in joint tissues and fluids, indicating that carbamylation contributes to the repertoire of RA neoantigens.
The lung and periodontal mucosa are important extranodal sites where environmental triggers can induce PTMs. Local inflammation, infection or dysbiosis at mucosal surfaces supports protein modification, generating neoantigens that may prime systemic autoreactivity prior to clinically apparent joint disease. The review highlights mucosal-origin mechanisms as part of preclinical RA pathogenesis.
PTM-modified proteins are taken up by antigen-presenting cells and presented on MHC class II to autoreactive CD4+ T cells, which in turn help B cells to produce autoantibodies. Autoantibodies, immune complex deposition, complement activation and cytokine release amplify synovial inflammation. Chronic inflammatory conditions impair regulatory T-cell (Treg) suppressive function and favor Th17 differentiation, limiting peripheral tolerance and promoting epitope spreading. B-cell responses can sometimes recognize both modified and unmodified epitopes, widening the autoimmune repertoire.
Direct proteomic approaches, including LC–MS/MS and targeted affinity techniques, have confirmed PTM-modified proteins in RA samples. Examples with direct evidence include citrullinated β-actin and vimentin in synovial fluid, carbamylated albumin and collagen peptides in joint tissues, and aberrantly glycosylated IgG in serum and synovial fluid. The review’s Table 1 collates experimentally validated PTM-derived neoantigens, their tissue distribution and detection methods.
Persistent antigen presentation and chronic inflammation promote epitope spreading—immune responses that extend from the initial epitope to intra- and intermolecular determinants—thereby sustaining and expanding autoreactivity. In the synovium, activated fibroblast-like synoviocytes and infiltrating immune cells form a self-perpetuating inflammatory niche (pannus) that drives cartilage and bone destruction. Loss of Treg function in this milieu prevents adequate control of autoreactive cells.
Identification of PTM-derived neoantigens opens avenues for more selective, antigen-focused therapies intended to restore immune tolerance or block neoantigen generation. The review outlines several emerging strategies aimed at interrupting the pathogenic cascade while limiting broad immunosuppression: antigen-specific tolerogenic vaccines, tolerogenic dendritic cells, adoptive regulatory-cell approaches (including CAR-Tregs and antigen-specific Tregs), inhibitors of PTM enzymes (for example PAD inhibitors), and NET-targeting approaches such as DNase I or agents like CIT-013. These strategies are presented as potential ways to reduce chronic synovial inflammation and prevent progressive joint damage.
PTM-derived neoantigens are central to RA pathogenesis by enabling the immune system to recognize modified self-proteins as foreign and perpetuate autoimmunity. Proteomic identification of these neoantigens enhances diagnostic precision and suggests routes toward precision medicine. The review underscores that detailed molecular characterization and translation of targeted tolerance-restoring therapies remain active areas of research; specific clinical outcomes and long-term efficacy of the emerging approaches described require continued investigation and were not exhaustively reported in the source.