The role of B cells in cGVHD. (A) Different steps of cGVHD development. Step 1: antigen (Ag)-presenting cells (APCs) present auto- and alloantigens and prime B cells. Direct activation of B cells via Ag or Ag/Ab complexes. APCs prime B cells against major histocompatibility complexes/peptides or neoantigens (eg, Y chromosome–encoded genes). This is enhanced in certain B-cell subgroups by hyperreactive BCR signaling. In addition to B-cell activation by APCs, there is likely also direct BCR activation via Ag or Ab/Ag complexes. Step 2: expansion of auto- and alloreactive B cells. Step 3: activated T follicular helper cells (Tfhs) produce IL-21 and cell-surface costimulatory molecules that lead to germinal center (GC) formation, which is not counterbalanced by sufficient T follicular regulatory cells (Tfrs). CD4 T helper cells produce IL-4, which promotes Ab class switch in autoreactive B cells. Stroma cells produce BAFF, which promotes B-cell activation. Step 4: plasma cells and plasma blasts produce high amounts of immunoglobulin. Deposition of immunoglobulin G (IgG) can lead to macrophage activation and organ damage. IgG-induced macrophage activation may contribute to cGVHD via secretion of proinflammatory cytokines by macrophages such as IL-6, which promotes B-cell survival and maintains inflammation. (B) Strategies to target B cells in cGVHD. The sketch shows a B cell and the mode of action of multiple immunosuppressive strategies that directly act on B cells or plasma cells in the context of cGVHD. The summary of translation of each approach is provided in Table 1. BTK, Bruton tyrosine kinase; ITK, IL-2–inducible kinase; MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin; MTX, methotrexate; ROCK2, ρ-GTPase kinase-2; SYK, splenic tyrosine kinase.