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Background and Objectives Autoimmune phenomena, mainly directed against red blood cells are described in myelodysplastic syndromes (MDS), particularly early MDS, i.e. refractory anemia (RA) and RA with ringed sideroblasts (RARS). Dysregulation of apoptosis and immunoregulatory cytokines are thought to play a role in the pathogenesis of MDS.Design and Methods This work was aimed to investigate anti-erythroid autoimmunity in unstimulated and mitogen-stimulated peripheral blood and bone marrow cultures of 26 patients with early MDS (RA and RARS), and to relate its presence with apoptotic markers and cytokine production. Bone marrow cytokine production in culture supernatants, and caspase-3 and nuclear factor-κB activity in cell extracts were tested by enzyme-linked immunosorbent assays.Results Fourteen of the 26 (53.8%) patients showed the presence of autoantibodies in bone marrow cultures, whereas none displayed a positive direct antiglobulin test in peripheral blood cultures. Incubation of culture supernatants from positive patients with autologous CD45– enriched-cell suspensions showed that the autoimmune reaction was directed against autologous erythroblasts. These patients had mild signs of hemolysis and increased numbers of erythroblasts, compared with negative patients. Patients with anti-erythroblast autoimmunity displayed higher caspase-3 activity and lower tumor necrosis factor-αand interleukin-4 production than did negative patients.Interpretation and Conclusions Half of the patients with early MDS showed autoimmunity against erythroblasts. This evidence might support a more rationale use of steroid therapy in these patients. The lower levels of cytokines in patients with anti-erythroblast autoimmunity are consistent with the suggested hypothesis that the autoimmune phenomena observed in MDS are probably initiated and perpetuated through alterations of pro-inflammatory and/or immunoregulatory cytokine production.