Aberrant B cells in cGVHD. (A) Cell surface phenotype of B-cell subsets altered in patients with cGVHD. Most CD27 negative (CD27Neg) B-cell subsets are proportionally decreased in active cGVHD, whereas CD21Lo CD27Neg subsets increase in association with cGVHD activity.^44,47  The relative naive B lymphopenia in cGVHD has been associated with a proportional increase in 2 CD27Pos antigen-experienced populations. In contrast, B1 and B10 B-cell subsets are significantly decreased in active cGVHD.^42,43  (B) Abnormalities of B-cell homeostasis in different compartments. Aberrant B-cell homeostasis in patients with cGVHD results in abnormal composition of B cells in different sites. B-cell precursors in bone marrow (1). In patients with cGVHD, the production and output of B-cell precursors is decreased. Abnormal composition of B-cell subsets in peripheral blood (2). Both transitional B cells and CD27Neg mature/naive B cells are decreased in frequency in cGVHD. Naive B cells enter secondary lymphoid organs, encounter antigen, and become activated, leading to increased proportions of several B-cell subsets of potential pathological interest. These include the “transitional-like” CD21Lo, the pre-GC IgDHiCD38HiCD27⁺, and the IgDLoCD38HiCD27Hi populations (all in gray shaded boxes).⁴⁶  In cGVHD, extrafollicular pre-GC CD27⁺ B cells and post-GC plasmablast (PB)–like B cells are increased proportionally, whereas immune regulatory B10 cells are decreased. Generation of activated B cells from secondary lymphoid organs (spleen/lymph node) (3). IgDLoCD38HiCD27⁺ PB-like cells activated in secondary lymphoid tissues produce constitutive IgG and persist in patients with cGVHD who do not respond to B-cell depletion therapy.³³