The pathophysiology of chronic GVHD. (A) General mechanisms. The acute graft-versus-host reaction is characterized by tissue damage mediated by inflammatory mediators, T cells, and cells from the innate immune system. Among target organs, two are particularly important for the development of subsequent chronic GVHD: (1) thymic epithelial cells (TECs) are damaged by alloreactive T cells leading to decreased generation of natural Tregs and release of self-reactive T cells. (2) Bone marrow microenvironment damage may explain disturbed B-cell homeostasis. The potent role of antigen-presenting cells (APCs) and the cross talk between B and T cells in chronic GVHD is poorly understood. (B) B cells and chronic GVHD. Patients with chronic GVHD have increased B-cell activation factor (BAFF):B-cell ratios, delayed reconstitution of naive B cells, and increased numbers of pregerminal center B cells. Patients with active chronic GVHD have elevated numbers of CD21^– transitional B cells and a deficiency of memory CD27⁺ B cells. Patients who develop chronic GVHD have elevated levels of BAFF, a relative reduction in naive B cells, and relatively higher numbers of activated memory type B cells. Patients with hypogammaglobulinemia have elevated CD19⁺CD21^low (immature) and CD19⁺CD21^highCD38^highIgM^high (transitional) B cells. CD19⁺CD10^–CD27^–CD21^high naive B cells are elevated in all patients with chronic GVHD. (C) Conventional T cells, Tregs, and chronic GVHD. An appropriate balance between Tregs and Tconv is critical for the maintenance of peripheral tolerance. In the setting of allogeneic HSCT, Tregs have been shown to play an important role in the establishment of tolerance between recipient tissues and donor-derived immunity. Monitoring of CD4⁺ T-cell subsets shows that Tregs rapidly expand after HSCT, but Treg levels subsequently decline in patients with prolonged CD4⁺ lymphopenia. This results in a relative deficiency of Tregs, which is associated with a high incidence of extensive chronic GVHD. In chronic lichenoid GVHD, a mixed Th1/Th17 signature with upregulated Th1/Th17 cytokine/chemokine transcripts and elevated numbers of interferon gamma (IFN-γ)– and IL-17–producing CD8⁺ T cells has been described. (D) Current issues in chronic GVHD pathophysiology. The hallmark of chronic GVHD is inflammatory fibrosis; putative mechanisms are described in the left part of the figure. Although a role of B- and T-cell subsets has been described, the cross talk between B and T cells is not well understood. Recent evidence from an experimental model suggests that a key player might be the T-follicular helper (TfH) cells. ICOS, inducible costimulatory [molecule]; NK, natural killer [cell]; TGFβ, transforming growth factor beta; TNFα, tumor necrosis factor alpha.