CAR-based therapies in systemic autoimmunity: from deep immune depletion toward durable immune reset

Systemic autoimmune diseases are sustained by self-renewing networks of autoreactive B cells, antibody-secreting cells, pathogenic T-cell programs and tissue-resident inflammatory niches. Conventional immunosuppression and biologic therapy can reduce disease activity, but often fail to produce durable drug-free remission because the immune architecture that sustains autoreactivity is suppressed rather than dismantled. CAR-based therapies have introduced a different therapeutic concept: deep interruption of autoreactive immune circuits followed by immune reconstitution. Early clinical experience, particularly with CD19-directed CAR-T cells in refractory systemic lupus erythematosus, lupus nephritis, systemic sclerosis and idiopathic inflammatory myopathies, has shown profound B-cell depletion, rapid decline of disease-associated autoantibodies and clinical remission without immediate maintenance immunosuppression in selected patients. These findings support serological reset and provide early evidence for cellular reset, but they do not yet prove durable homeostatic reset. In this Review, we propose a three-tier framework for immune reset after CAR-based therapy: serological reset, cellular reset and homeostatic reset. We use this framework to examine the mechanistic and translational uncertainties now facing the field, including the long-lived plasma-cell kinetic paradox, the distinction between peripheral depletion and tissue eradication, the uncertainty of repertoire-based claims of immune renewal, persistence of autoreactive T-cell memory, the contribution of lymphodepleting conditioning and the trade-off between pathogenic depletion and protective humoral immunity. We argue that future progress will require tissue-validated, clonally resolved and functionally informed definitions of therapeutic success. Longitudinal B-cell and T-cell tracking, paired or protocol-defined tissue analyses, assessment of tertiary lymphoid structures and plasma-cell niches, and formal evaluation of vaccine responsiveness and immune competence are, in our view, important considerations for future studies. The success of CAR-based therapy in systemic autoimmunity should ultimately be judged not by depletion depth alone, but by whether it can rebuild a stable, nonpathogenic and immunologically competent immune system.