Impact of CD19-targeted CAR T cell therapy on B cell tolerance in SLE

The CD19-targeted CAR T-cell therapy has shown striking benefits in systemic lupus erythematosus (SLE), often coinciding with a major drop in harmful “self-reactive” antibodies. This suggests the immune system may regain tolerance after B cells are initially removed, but the reasons are unknown. It’s also unclear whether all patients benefit equally or how durable remission is; and treated patient may relapse. We propose that CAR T therapy may not stop the body from newly generating self-reactive B cells over time, which could contribute to relapse months later. Prior work with rituximab (another B-cell–depleting therapy) showed that wiping out B cells does not prevent the return of new autoreactive naïve B cells, implying early “quality control” problems persist. If true, this would limit the idea that CAR T produces a complete, permanent “immune reset.”

At the same time, the therapy may restore an important internal brake in B cells involving TLR9, which normally helps prevent autoantibody secretion and restricts autoreactive B cell activation. We have found that TLR9 responses are impaired in SLE B cells and may contribute to autoantibody production. We recently showed that CXCL4—often elevated in SLE—can block TLR9 signaling by diverting key activating material away from where TLR9 signals inside the cell. We therefore propose that CAR T therapy may normalize CXCL4 levels, restore TLR9’s tolerogenic function, and block autoantibody secretion.

This project will measure the frequency of autoreactive B cells and the strength of TLR9 “tolerance” responses in SLE patients before and after CD19-targeted CAR T therapy. We will test whether CAR T prevents the re-emergence of newly generated autoreactive B cells and whether it corrects defective TLR9 function in patient B cells. Thus, CAR T cells may not eliminate the source of autoreactive B cells but may re-establish the restraint that prevents them from becoming pathogenic in SLE.

CD19-directed CAR T-cell therapy has produced rapid, drug-free remissions in severe systemic lupus erythematosus (SLE), accompanied by profound B-cell depletion and marked reduction in pathogenic autoantibodies. Despite these striking outcomes, the mechanism of durable immune reset remains undefined, and emerging clinical experience indicates that relapse can occur, underscoring the need to identify biologic determinants of long-term remission.
A key unresolved question is whether CAR T cell therapy truly repairs early B-cell tolerance checkpoints and prevents the production of autoreactive B cells. Our prior work shows that B-cell depletion with rituximab does not correct impaired early B-cell tolerance checkpoints, and autoreactive naïve B cells continue to be newly generated after depletion like in most patients with autoimmune diseases. Consistent with this concept, our preliminary data suggest that autoreactive new emigrant/transitional and mature naïve B cells can be detected in patients with SLE months after CD19-targeted CAR T cell therapy, implying that this regimen may not prevent de novo generation of autoreactive clones once B cells reconstitute.

We propose instead that CAR T cell–mediated remission may depend on restoration of a peripheral tolerogenic checkpoint that restrains autoreactive B cells from secreting autoantibodies. TLR9 signaling in B cells is a critical brake on autoreactive humoral responses, and impaired TLR9 function in B cells has been implicated in autoantibody production. We have shown that TLR9 responses are defective in B cells from patients with SLE, likely contributing to autoantibody production and immune complex formation. A mechanistic candidate for TLR9 dysfunction in SLE is chemokine CXCL4/platelet factor 4, which can sequester TLR9 ligands and disrupt appropriate endosomal trafficking required for TLR9 signaling in B cells. Elevated CXCL4 serum concentrations in patients with SLE may therefore explain impaired B-cell TLR9 responses. We hypothesize that CD19-targeted CAR T cell therapy can normalize CXCL4-associated inhibition and restore TLR9-dependent tolerogenic function, thereby limiting autoantibody secretion even if autoreactive naïve B cells continue to emerge.

Hence, our research aims to investigate autoreactive B cell frequencies and TLR9 tolerogenic B cell responses in patients with SLE before and after CD19-targeted CAR T cell therapy. We will assess whether CD19-targeted CAR T cells prevent the production of autoreactive B cells in these patients and if this regimen restores defective TLR9 function in B cells from patients with SLE. Thus, CAR T cells may not eliminate the source of autoreactive B cells but may re-establish the restraint that prevents them from becoming pathogenic in SLE.