Pathophysiology of mature BM lymphocytes in autoimmune cytopenias. (A) In healthy BM, mature lymphocyte populations regulate HSC self-renewal, maintenance and hematopoietic output by producing soluble factors and likely by (as yet undefined) direct cell-cell interactions. (B-C) In AA and ITP, this delicate regulatory balance is distorted. For example, chronic exposure to high levels of inflammatory cytokines results in HSC loss, as seen in AA, and megakaryocyte (Mk) malfunction, as seen in ITP. (B) In AA, the patients’ BM is infiltrated by activated autoreactive (auto-)CD8⁺ T cells that express high levels of CX₃CR1 and are recruited by CX₃CL1 present in AA BM. BM auto-CD8⁺ T cells secrete high amounts of TNF-α and IFN-γ, and also use perforin- and granzyme-mediated mechanisms to directly target HSCs. Polyclonal BM auto-CD4⁺ T-cell numbers are increased in AA, and Th17-cell expansion is characteristic. Elevated levels of IL-17 impair hematopoiesis by depleting Tregs, directly inhibiting HSCs, and recruiting additional Th1 cells. IL-17 also promotes the secretion of TNF-α by macrophages (Mϕs), which in turn stimulates IFN-γ secretion by T cells. Patients with AA have reduced NK- and NKT-cell numbers in their BM. Whereas the significance of this finding for NKT cells is unclear, the reduction of BM NK cells in patients with AA may contribute to the excess of auto-CD8⁺ T cells as result of decreased T-cell killing by NK cells. (C) In patients with ITP, low platelet (plt) numbers are the predominant clinical feature. Presumably, BM auto-CD8⁺ T cells recognize megakaryocyte-derived antigens presented on platelets via MHC-I and can lyse platelets directly or induce platelet apoptosis. Moreover, suppression of megakaryocyte apoptosis by BM auto-CD8⁺ T cells directly inhibits platelet formation. BM auto-CD4⁺ T cells induce the production of anti-platelet autoantibodies (anti-plt abs) involved in disease pathogenesis. Patients with ITP have lower total numbers of CD4⁺ T cells in the BM than healthy controls. The disproportional loss of BM Th2 cells, as well as Tregs, results in a Th1 shift that contributes to autoantibody-mediated platelet destruction and T-cell cytotoxicity. The localizations and functions of BM NK and NKT cells in ITP are largely unknown.