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A Novel Hypothesis: Regulatory B Lymphocytes Shape Outcome from Experimental Stroke

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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 pro-inflammatory 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 changes were completely prevented in B cell-restored mice after transfer of highly purified WT B cells but not IL-10-deficient 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.

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References

  1. Chamorro A, Urra X, Planas AM. Infection after acute ischemic stroke: a minifestation of brain-induced immunodepression. Stroke. 2007;38:1097–103.

    Article  PubMed  Google Scholar 

  2. Dirnagl U, Klehmet J, Braun JS, et al. Stroke-induced immunodepression: experimental evidence and clinical relevance. Stroke. 2007;38:770–3.

    Article  PubMed  Google Scholar 

  3. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nat Neurosci Rev. 2005;6:775–86.

    Article  CAS  Google Scholar 

  4. Akiyoshi K, Dziennis S, Palmateer J, et al. Recombinant T cell receptor ligands improve outcome after experimental cerebral ischemia. Transl Stroke Res. 2011;2:404–10.

    Article  PubMed  CAS  Google Scholar 

  5. Akiyoshi K, Ren X, Dziennis S, et al. Regulatory B-cells limit CNS inflammation and neurologic deficits in murine experimental stroke. J Neurosci. 2011;31:8556–63.

    Article  PubMed  Google Scholar 

  6. Dziennis S, Kozaburo A, Subramanian S, Offner H, Hurn PD. Role of dihydrotestosterone in post-stroke peripheral immunosuppression after cerebral ischemia. Brain Behav Immun. 2011;25:685–95.

    Article  PubMed  CAS  Google Scholar 

  7. Dziennis S, Mader S, Akiyoshi K, et al. Therapy with recombinant T cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice. Metab Brain Dis. 2011;26:123–33.

    Article  PubMed  CAS  Google Scholar 

  8. Hurn PD, Subramanian S, Parker SM, et al. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab. 2007;27:1798–805.

    Article  PubMed  CAS  Google Scholar 

  9. Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab. 2006;26:654–65.

    Article  PubMed  CAS  Google Scholar 

  10. Offner H, Subramanian S, Parker SM, et al. Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. J Immunol. 2006;176:6523–31.

    PubMed  CAS  Google Scholar 

  11. Offner H, Vandenbark AA, Hurn PD. Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression. Neuroscience. 2009;158:1098–111.

    Article  PubMed  CAS  Google Scholar 

  12. Ren X, Akiyoshi K, Grafe MR, et al. Myelin specific cells infiltrate MCAO lesions and exacerbate stroke severity. Metab Brain Dis. 2012;27:7–15.

    Article  PubMed  CAS  Google Scholar 

  13. Ren X, Akiyoshi K, Vandenbark AA, Hurn PD, Offner H. CD4+FoxP3+ regulatory T-cells in cerebral ischemic stroke. Metab Brain Dis. 2011;26:87–90.

    Article  PubMed  Google Scholar 

  14. Ren X, Akiyoshi K, Vandenbark AA, Hurn PD, Offner H. Programmed death-1 pathway limits CNS inflammation and neurologic deficits in murine experimental stroke. Stroke. 2011;42:2578–83.

    Article  PubMed  Google Scholar 

  15. Subramanian S, Zhang B, Kosaka Y, et al. Recombinant T cell receptor ligand treats experimental stroke. Stroke. 2009. doi:10.1161/STROKEAHA.108.543991.

  16. Zhang B, Subramanian S, Dziennis S, et al. Estradiol and G1 reduce infarct size and improve immunosuppression after experimental stroke. J Immunol. 2010;184:4087–94.

    Article  PubMed  CAS  Google Scholar 

  17. Marsh BJ, Williams-Karnesky RL, Stenzel-Pore MP. Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience. 2008;158:1007–20.

    Article  PubMed  Google Scholar 

  18. Gelderblom M, Leypoldt F, Steinbach K. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke. 2009;40:1849–57.

    Article  PubMed  Google Scholar 

  19. Becker KJ. Anti-leukocyte antibodies: LeukArrest (Hu23F26) and Enlimomab (R6.5) in acute stroke. Curr Med Res Opin. 2002;19:18–22.

    Article  Google Scholar 

  20. Krams M, Lees KR, Hacke W. Acute stroke therapy by inhibition of neutrophils (ASTIN): an adaptive dose–response study of UK-279.276 in acute ischemic stroke. Stroke. 2003;34:2543–8.

    Article  PubMed  CAS  Google Scholar 

  21. Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol. 2001;2:816–22.

    Article  PubMed  CAS  Google Scholar 

  22. Dinesh RK, Hahn BH, Singh RP. PD-1, gender, and autoimmunity. Autoimmun Rev. 2010;9:583–7.

    Article  PubMed  Google Scholar 

  23. Magnus T, Schreiner B, Korn T, et al. Microglial expression of the B7 family member B7 homolog 1 confers strong immune inhibition: implications for immune responses and autoimmunity in the CNS. J Neurosci. 2005;25:2537–46.

    Article  PubMed  CAS  Google Scholar 

  24. Mason D, Powrie F. Control of immune pathology by regulatory T cells. Curr Opin Immunol. 1998;10:649–55.

    Article  PubMed  CAS  Google Scholar 

  25. Roncarolo MG, Levings MK. The role of different subsets of T regulatory cells in controlling autoimmunity. Curr Opin Immunol. 2000;12:676–83.

    Article  PubMed  CAS  Google Scholar 

  26. Shevach EM. Regulatory T cells in autoimmunity. Ann Rev Immunol. 2000;18:423–49.

    Article  CAS  Google Scholar 

  27. Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15:192–9.

    Article  PubMed  CAS  Google Scholar 

  28. Kim JM, Rasmussen FP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191–7.

    Article  PubMed  CAS  Google Scholar 

  29. Grilli M, Barbieri I, Basudev H, et al. Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. Eur J Neurosci. 2000;12:2265–72.

    Article  PubMed  CAS  Google Scholar 

  30. Spera PA, Ellison JA, Feuerstein GZ, Barone FC. IL-10 reduces rat brain injury following focal stroke. Neurosci Lett. 1998;251:189–92.

    Article  PubMed  CAS  Google Scholar 

  31. Dietrich WD, Busto R, Bethea JR. Postischemic hypothermia and IL-10 treatment provide long-lasting neuroprotection of CA1 hippocampus following transient global ischemia in rats. Exp Neurol. 1999;158:444–50.

    Article  PubMed  CAS  Google Scholar 

  32. Ooboshi H, Ibayashi S, Shichita T, et al. Postischemic gene transfer of intrleukin-10 protects against both focal and global brain ischemia. Circulation. 2005;111:913–9.

    Article  PubMed  CAS  Google Scholar 

  33. Frenkel D, Huang Z, Maron R, Koldzic DN, Moskowitz MA, Weiner HL. Neuroprotection by IL-10-producing MOG CD4+ T cells following ischemic stroke. J Neurol Sci. 2005;233:125–32.

    Article  PubMed  CAS  Google Scholar 

  34. de Bilbao F, Arsenijevic D, Moll T, et al. In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice. J Neurochem. 2009;110:12–22.

    Article  PubMed  Google Scholar 

  35. Vila N, Castillo J, Davalos A, Esteve A, Planas AM, Chamorro A. Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke. 2003;34:671–5.

    Article  PubMed  CAS  Google Scholar 

  36. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887–95.

    PubMed  CAS  Google Scholar 

  37. Keir ME, Francisco LM, Sharpe AH. PD-1 and its ligands in T-cell immunity. Curr Opin Immunol. 2007;19:309–14.

    Article  PubMed  CAS  Google Scholar 

  38. Nishimura H, Minato N, Nakano T, Honjo T. Immunological studies on PD-1-deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol. 1998;10:1563–72.

    Article  PubMed  CAS  Google Scholar 

  39. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239–45.

    Article  PubMed  CAS  Google Scholar 

  40. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 2006;27:195–201.

    Article  PubMed  CAS  Google Scholar 

  41. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219–42.

    Article  PubMed  CAS  Google Scholar 

  42. Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol. 2007;19:337–43.

    Article  PubMed  CAS  Google Scholar 

  43. Wang C, Dehghani B, Li Y, et al. Membrane estrogen receptor regulates experimental autoimmune encephalomyelitis through up-regulation of programmed death 1. J Immunol. 2008;182:3294–303.

    Article  Google Scholar 

  44. Wang C, Dehghani B, Li Y, Kaler LJ, Vandenbark AA, Offner H. Oestrogen modulates experimental autoimmune encephalomyelitis and interleukin-17 production via programmed death 1. Immunology. 2009;126:329–35.

    Article  PubMed  CAS  Google Scholar 

  45. Schreiner B, Bailey SL, Shin T, Chen L, Miller SD. PD-1 ligands expressed on myeloid-derived APC in the CNS regulate T cell responses in EAE. Eur J Immunol. 2008;38:2706–17.

    Article  PubMed  CAS  Google Scholar 

  46. Kuipers H, Muskens F, Willart M, et al. Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur J Neuroimmunol. 2006;36:2472–82.

    Article  CAS  Google Scholar 

  47. Phares TW, Ramakrishna C, Parra GI, et al. Target-dependent B7-H1 regulation contributes to clearance of central nervous system infection and dampens morbidity. J Immunol. 2009;182:5430–8.

    Article  PubMed  CAS  Google Scholar 

  48. Kroner A, Schwab N, Ip CW, et al. PD-1 regulates neural damage in oligodendroglia-induced inflammation. PLoS One. 2009;4:e4405.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank Ms. Eva Niehaus for assistance with manuscript preparation. This work was supported by NIH grants NS075887 (HO) and NR003521 (PDH). This material is the result of work supported with resources and the use of facilities at the Portland VA Medical Center, Portland, OR. The contents do not represent the views of the Department of Veterans Affairs or the US government.

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Authors and Affiliations

  1. Neuroimmunology Research R&D-31, Portland Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR, 97239, USA

    Halina Offner

  2. Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR, 97201, USA

    Halina Offner

  3. Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR, 97239, USA

    Halina Offner

  4. The University of Texas System, Office of Health Affairs, Austin, TX, USA

    Patricia D. Hurn

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  1. Halina Offner
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Correspondence to Halina Offner.

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Offner, H., Hurn, P.D. A Novel Hypothesis: Regulatory B Lymphocytes Shape Outcome from Experimental Stroke. Transl. Stroke Res. 3, 324–330 (2012). https://doi.org/10.1007/s12975-012-0187-4

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  • DOI: https://doi.org/10.1007/s12975-012-0187-4

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