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Abstract—Stroke affects the normally well-balanced interplay of the 2 supersystems: the nervous and the immune system.
Recent research elucidated some of the involved signals and mechanisms and, importantly, was able to demonstrate that
brain-immune interactions are highly relevant for functional outcome after stroke. Immunodepression after stroke
increases the susceptibility to infection, the most relevant complication in stroke patients. However, immunodepression
after stroke may also have beneficial effects, for example, by suppressing autoaggressive responses during lesion-
induced exposure of central nervous system-specific antigens to the immune system. Thus, before immunomodulatory
therapy can be applied to stroke patients, we need to understand better the interaction of brain and immune system after
focal cerebral ischemia. Until then, anticipating an important consequence of stroke-induced immunodepression,
bacterial infection, preventive antibiotic strategies have been proposed. In mouse experiments, preventive antibiotic
treatment dramatically improves mortality and outcome. Results of clinical studies on this issue are contradictory at
present, and larger trials are needed to settle the question whether (and which) stroke patients should be preventively
treated. Nevertheless, clinical evidence is emerging demonstrating that stroke-induced immunodepression in humans not
only exists, but has very similar features to those characterized in rodent experiments. (Stroke. 2007;38[part 2]:770-
773.)
Key Words: brain infarction brain ischemia experime tal focal ischemia immu ology infectious disease
inflammation treatment
Received May 17, 2006; final revision received September 4, 2006; accepted September 13, 2006.
From Department of Neurology (U.D., J.K., J.S.B., H.H., K.P., A.M.), Department of Experimental Neurology, Center for Stroke Research and
Department of Medical Immunology (C.M.), Charité Universitätsmedizin, Berlin, Germany; Department of Neurology (T.Z.), University of Dresden,
Germany.
Correspondence to Prof Dr Ulrich Dirnagl, Department of Experimental Neurology, Charite Universitätsmedizin Berlin, Charitéplatz 1, 10098 Berlin,
Germany. E-mail ulrich.dirnagl@charite.de
© 2007 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000251441.89665.bc
What Causes
Stroke-Induced Immunodepression?
Although the phenomenon of stroke-induced immunodepres-
sion is well-established, it remains unclear which signals and
mechanisms trigger the sympathetic nervous system and the
hypothalamic–pituitary axis to downregulate immune re-
sponses after brain ischemia. Several lines of clinical and
experimental evidence indicate that pro-inflammatory cyto-
kines produced by damaged brain tissue can directly lead to
hypothalamic–pituitary axis and CNS activation. Increased
levels of cytokines, such as interleukin-1 , tumor necrosis
factor- , and interleukin-6, have been measured after stroke
in brain parenchyma and cerebrospinal fluid. Because the
autonomic system of the CNS is “hard-wired” with secondary
lymphoid organs, interruption of these circuits can result in
immune dysfunction. Stroke can lead to direct damage of
sympathetic CNS structures involved in vegetative neuroim-
munomodulation. Further support for the concept of an at
least partially neurogenic nature of CIDS comes from studies
on the lateralization of the autonomic nervous system in the
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stroke-induced immunodepression in humans and to answer phages. J Immunol. 2006;176:6523– 6531.
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Victorov IV, Priller J, Dirnagl U, Volk HD, Meisel A. Stroke-induced
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patient. 15. Lindvall O, Kokaia Z. Recovery and rehabilitation in stroke: stem cells.
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Sources of Funding 16. Thum T, Bauersachs J, Poole-Wilson PA, Volk HD, Anker SD. The dying
This study was supported by the Hermann and Lilly Schilling stem cell hypothesis: immune modulation as a novel mechanism for
Foundation and the Helmholtz-Gemeinschaft. progenitor cell therapy in cardiac muscle. J Am Coll Cardiol. 2005;46:
1799 –1802.
17. Barry FP, Murphy JM, English K, Mahon BP. Immunogenicity of adult
Disclosures mesenchymal stem cells: lessons from the fetal allograft. Stem Cells Dev.
U.D., C.M., K.P., and A.M. are inventors on a patent application 2005;14:252–265.
(owner: Charité-Humboldt University) in which stroke-induced im- 18. Meisel C, Prass K, Braun J, Victorov I, Wolf T, Megow D, Halle E, Volk
munodepression is claimed. HD, Dirnagl U, Meisel A. Preventive antibacterial treatment improves the
general medical and neurological outcome in a mouse model of stroke.
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Stroke. 2007;38:770-773
doi: 10.1161/01.STR.0000251441.89665.bc
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