The lung as an autoimmune organ: From mucosal tolerance breach to AI-enabled interception.

Autoimmune diseases have traditionally been conceptualized as systemic disorders that secondarily involve the lung. This roadmap review proposes a complementary framework in which the lung is considered an autoimmune organ: a mucosal site where tolerance may be breached, a vulnerable target of systemic autoimmunity, and a sentinel from which future disease trajectories can be inferred. Across connective tissue diseases, the lung is also a major determinant of prognosis through airway disease, interstitial lung disease, progressive fibrosis, pulmonary vascular involvement and acute alveolar injury. A compelling human model for lung-first autoimmunity is rheumatoid arthritis, in which inhaled exposures, airway inflammation, citrullination, neutrophil extracellular traps, mucosal immunoglobulin A responses and anti-citrullinated protein antibodies may precede clinically apparent synovitis. We integrate these observations into a lung autoimmune continuum linking inhaled exposome, epigenetic remodeling, microbiota-redox imbalance, mitochondrial dysfunction, alarmins, local autoantibody generation, systemic immune spread and target-organ injury. We then outline a forward-looking model in which artificial intelligence supports prevention, risk prediction, treatable-trait classification, therapy-response prediction and closed-loop monitoring. Multimodal models integrating high-resolution computed tomography, pulmonary function tests, autoantibodies, omics, electronic health records, exposome data and patient-generated data may enable earlier interception of autoimmune lung trajectories. Clinical implementation will require prospective utility studies, external validation, calibration, explainability, fairness assessment, data governance and human oversight. Reframing the lung as an autoimmune organ could shift the next decade from reactive recognition of irreversible pulmonary damage to personalized interception before fibrosis, vascular remodeling or acute injury become clinically fixed.