Posttranslational Modifications of Unconventional Autoantigens: Shaping Immunogenicity and Inflammatory Activity

Posttranslational modifications (PTMs) of self-antigens precipitate autoimmunity by generating neo-epitopes that breach tolerance and activate autoreactive T and B cells. This review spotlights cathelicidin LL37 and chemokine CXCL4 (PF4) in psoriatic disease (psoriasis and psoriatic arthritis, PSO and PSA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), drawing on key studies including our own. Uniquely, unlike most autoantigens, LL37 and CXCL4 exert a dual role: they are immunogenic targets for T and B cells while directly fueling innate inflammation. Through chaperone-like binding to self- and microbial DNA/RNA, they form complexes that potently stimulate plasmacytoid and myeloid dendritic cells (pDCs/mDCs) via DNA/RNA sensors, such as TLR7-9 and cGAS/STING, driving Type I interferon and cytokines storms. Strikingly, these complexes also induce B cells to become antibody-producing plasma cells, amplifying adaptive responses and likely suppressing regulation. Here, we detail the role of PTM-modified LL37 in PSO, PSA, and SLE-forming autoantigenic neutrophil extracellular traps-and CXCL4 in SSc, where it acts as biomarker and autoantibody target. Our work underscores how this dual functionality as "bifunctional autoantigens" exacerbates disease, and how PTMs modification influence these phenomena. These molecules and their PTM can be targeted to halt inflammatory cascades and restore tolerance.