A Novel Hypothesis: Regulatory B Lymphocytes Shape Outcome from Experimental Stroke
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ORIGINAL ARTICLE
A Novel Hypothesis: Regulatory B Lymphocytes Shape Outcome from Experimental Stroke Halina Offner & Patricia D. Hurn
Received: 12 March 2012 / Revised: 23 April 2012 / Accepted: 25 April 2012 / Published online: 9 May 2012 # Springer Science+Business Media, LLC 2012
Abstract Although inflammatory immune cells clearly contribute to the development of middle cerebral artery occlusion (MCAO) in mice, the failure to block neutrophil-associated injury in clinical stroke trials has discouraged further development of immunotherapeutic approaches. However, there is renewed interest in a possible protective role for regulatory T and B cells that can suppress inflammation and limit central nervous system damage induced by infiltrating proinflammatory cells. Our failure to implicate CD4+FoxP3+ T cells in limiting brain lesion volume after MCAO turned our focus towards regulatory B cells known to mediate protection against other inflammatory CNS conditions. Our results clearly demonstrated that B cell-deficient mice developed larger infarct volumes, higher mortality, and more severe functional deficits compared to wild-type mice and had increased numbers of activated T cells, macrophages, microglial cells, and neutrophils in the affected brain hemisphere. These MCAO-induced H. Offner (*) Neuroimmunology Research R&D-31, Portland Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, USA e-mail: [email protected] H. Offner Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201, USA H. Offner Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA P. D. Hurn The University of Texas System, Office of Health Affairs, Austin, TX, USA
changes were completely prevented in B cell-restored mice after transfer of highly purified WT B cells but not IL-10deficient B cells. Our novel observations are the first to implicate IL-10-secreting B cells as a major regulatory cell type in stroke and suggest that enhancement of regulatory B cells might have application as a novel therapy for this devastating neurologic condition. Keywords Experimental stroke . Bregs . IL-10 . PD-1 . Immunotherapy
Human stroke results not only in brain infarction, but also in multi-organ systemic disease. Many patients who survive the initial cerebral ischemic insult will go on to die from strokeinduced immune system suppression and resulting fatal infection [1–3]. We and others have modeled the double-edged sword of immune cell action during experimental stroke in animals [4–16]. The systemic consequences of CNS injury are best described as a serial and long-lasting process: first, there is an induction of lymphoid tissue (e.g., spleen and thymus) into a pro-inflammatory activation state; second, one observes apoptotic self-destruction of these same organs and selective loss of many immunocytes nurtured within [8, 10]. Splenic activation also leads to expulsion of immun
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