Reprogramming rather than depleting immunity: Targeting the CD38–NAD + axis in antibody‐mediated autoimmunity

Autoimmune diseases are driven by aberrant immune responses, but effective immunity is also essential for host defence, immune memory and tissue homeostasis.Their treatment therefore faces a persistent dilemma: How to suppress pathogenic immunity without compromising protective immune function.Corticosteroids and conventional immunosuppressants control disease largely through broad immune inhibition, whereas B-celland plasma-cell-directed therapies provide greater cellular selectivity but still deplete immune-cell compartments that also support normal humoral immunity.1 Repeated or prolonged B-cell depletion is manifested with persistent hypogammaglobulinemia, recurrent infections, impaired vaccine responses and immunoglobulin replacement in some patients.2,3 The unmet need is therefore not simply for stronger immunosuppression but for strategies that selectively attenuate disease-driving immune functions while preserving immune competence.Because immunecell pathogenicity reflects not only cellular identity but also plastic functional states, reprogramming these states may offer an alternative to cell depletion.Immunometabolic pathways are particularly attractive in this regard, as they directly shape immune-cell activation and effector function.4 Plasma-cell depletion provided the original rationale for targeting CD38 in immune thrombocytopenia (ITP), with the expectation that eliminating antibody-secreting cells would reduce pathogenic autoantibody production.However, both our investigator-initiated study and the subsequent randomised controlled trial showed that anti-CD38 treatment induced platelet recovery within days, beginning as early as day 3. 5,6 Such rapid kinetics appeared difficult to explain solely by plasma-cell depletion and reduced autoantibody production.This temporal pattern therefore raised a broader mechanistic question: Might CD38 regulate not only the source of pathogenic antibodies but also the downstream effector phase of platelet destruction?