For two decades, B-cell depletion has meant anti-CD20 — and that choice was deliberate. In a Paradigms and Perspectives piece in JACI, Rivière and colleagues trace how the field is now moving to CD19, and why going deeper can produce durable remission where rituximab falls short — at a greater immune cost.
Why CD20 came first. CD20 was the cautious target: it is expressed on mature B cells but spares stem cells and plasma cells, so depletion is substantial yet reversible, and antibody production is partly preserved. That safety margin made rituximab the workhorse of B-cell depletion in autoimmunity.
Where CD20 falls short. The same sparing is its limit. Tissue-resident B cells, plasmablasts, and long-lived plasma cells can survive anti-CD20 therapy and keep driving disease — a plausible explanation for relapses and for refractory SLE, NMOSD, autoimmune encephalitis, and ITP that do not remit on rituximab.
What CD19 adds. CD19 is expressed more broadly across B-cell development, including on plasmablasts. CD19-directed antibodies, bispecifics, and CAR-T cells therefore deplete a deeper and wider compartment, and in refractory autoimmune disease that deeper depletion can reset the B-cell repertoire and produce durable, drug-free remission.
The cost — and the next step. Deeper is not free: hypogammaglobulinemia, blunted vaccine responses, and infection, plus cytokine release syndrome and neurotoxicity with CAR-T approaches. The authors' conclusion is that the future is smarter, not just deeper, depletion — matching the depth of depletion to the disease, and preserving protective immunity wherever possible.
References:
Rivière E, et al. From CD20 to CD19: The shift from cautious to deeper B-cell depletion in autoimmune diseases. J Allergy Clin Immunol. 2026;158(4):951-953.