Mapping organ-associated autoantigenic landscapes in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a remarkably broad and heterogeneous autoantigen repertoire. While epitope spreading, aberrant B-cell activation, and molecular mimicry act in concert with defective apoptotic clearance and sustained type I interferon signaling to drive systemic autoreactivity, many clinical manifestations of the disease are highly localized. The involvement of neuropsychiatric, renal, cutaneous, pulmonary, vascular, and hepatic systems appears to be shaped by tissue-specific autoantigen exposure and local microenvironments, where shared immunopathogenic pathways give rise to organ-associated autoantigenic landscapes. This review develops the concept of organ-associated autoantigenic landscapes, defined here as context-dependent configurations in which autoantibody-autoantigen interactions intersect with regional microenvironments and may contribute to inflammatory cascades, complement activation, and cellular damage. Importantly, organ association does not imply strict organ specificity, as the same circulating autoantibody may acquire distinct clinical relevance across tissues depending on antigen accessibility and local effector conditions. By illustrating how specific autoantibody-autoantigen axes may translate systemic autoimmunity into restricted clinical patterns, this framework provides a unifying model for disease heterogeneity and supports the development of precision, antigen-targeted therapeutic strategies.