Glomerular diseases often result from loss of immune tolerance, leading to the production of autoantibodies by plasmablasts/plasma cells. Besides secreting antibodies, B cells contribute to T cell activation through antigen presentation and the secretion of pro-inflammatory cytokines. Standard immunosuppression works broadly but has many side effects, and many patients remain refractory. Thus, there is growing interest in therapies that more precisely target B cells and plasma cells. This review in JASN 2025 really is a very nicely done summary of the topic.
B cells develop through naïve, activated, memory, plasmablast, to plasma cell stages. Memory B cells and long-lived plasma cells are particularly important in sustaining autoantibody production.
Differential expression of surface markers (e.g. CD20 present on many B cells but lost in plasma cells) and dependency on survival signals (such as BAFF, APRIL) define what makes some cells resistant to certain therapies.
Some challenges are that some plasma cell populations are long-lived and reside in protected niches (e.g. bone marrow), making them resistant to many therapies. Risk of depleting beneficial B cell subsets (e.g. those with regulatory functions). Heterogeneity of disease: different glomerular diseases (IgA nephropathy, lupus nephritis, membranous nephropathy, vasculitis etc.) have varying dependence on B cells vs plasma cells.
Therapies targeting B cells and plasma cells have shown promise in trials for various glomerular diseases. See the table below. Novel tools (like CAR-T, bispecifics) may help overcome resistance and target plasma cells more effectively.
Lupus Nephritis has trials ongoing with BAFF inhibition, Anti CD20+BAFF, BTK inhibitor, Anti CD38, CAR-T and bispecifics. ANCA vasculitis has trials ongoing in Anti CD20 with BAFF-APRIL, and CAR-T. Membranous Nephropathy has trials ongoing in anti-CD-20, BAFF, BTK inhibitors and Anti CD-38. MCD/FSGS has trials ongoing in Anti CD-20 and BTK inhibitors. IgAN has trials in APRIL, APRIL+BAFF, Anti CD38 and CAR-T as well.
Table: Therapies Targeting B-Cell and Plasma Cell Lineages in Glomerular Disease
| Target / Stage | Examples of Therapeutics | Notes |
|---|---|---|
| Naïve / Mature B Cells | Anti-CD20 mAbs (rituximab, obinutuzumab, ofatumumab) | Deplete most circulating B cells, but not plasma cells |
| B Cell Survival Signals | BAFF inhibitors (belimumab), BAFF/APRIL dual inhibitors (telitacicept) | Block trophic support for B cells and plasmablasts |
| BCR Signaling | BTK inhibitors (ibrutinib, acalabrutinib) | Reduce activation and differentiation |
| Plasmablasts / Short-lived PCs | Proteasome inhibitors (bortezomib, carfilzomib) | Induce apoptosis of antibody-secreting plasmablasts |
| Long-lived Plasma Cells | Anti-CD38 mAbs (daratumumab, isatuximab); anti-BCMA agents | Direct depletion, even in bone marrow niches |
| Novel Cellular Immunotherapy | CAR-T cells (anti-CD19, anti-BCMA); bispecific T-cell engagers | Potent but experimental; risk of profound immunosuppression |
| Regulatory B Cells (Bregs) | Indirectly affected by the above agents | Their depletion may worsen immune dysregulation—needs careful monitoring |
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