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Objective To investigate the capacity of blood draining from the central nervous system of patients with acute brain injury to induce cell death, and to determine whether this phenomenon could be a way to induce the production of autoantibodies. Methods The induction of cell death of several human leukemia cell lines cultured in vitro in the presence of serum collected from the brain or the systemic circulation of patients with acute brain injury was analyzed by flow cytometry after staining with annexin V and propidium iodide. The percentages of apoptotic lymphocytes derived directly from the patients were also quantified. To investigate the mechanisms responsible for the induction of cell death, the expression of apoptosis-related molecules, as well as the effect of addition of several molecules known to interfere with apoptosis, was evaluated in the cell cultures. The presence of serum autoantibodies at the time of injury and 6 months later was studied. Results Systemic serum and, especially, serum draining from the brain lesions induced the in vitro death of the leukemia cell lines used. Moreover, there were higher percentages of ex vivo dead lymphocytes in regional blood than in systemic blood 48 hours after injury. These effects seemed to be induced by an exogenous and/or endogenous opioid, since they were blocked by the opioid antagonist, naloxone. Furthermore, such effects were mediated by an increased expression of Bax. Importantly, apoptotic Jurkat cells were bound to autoantibodies, and patients with acute brain injury produced serum autoantibodies some months after the injury. However, they did not develop a full autoimmune disease at that time. Conclusion Serum factors from acute brain injuries induce cell death, both in vivo and in vitro. Apoptotic cells and, even more so, necrotic cells in acute brain injury are potential sources for autoantigen presentation that may stimulate autoimmune responses.