#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Passively Administered Pooled Human Immunoglobulins Exert IL-10 Dependent Anti-Inflammatory Effects that Protect against Fatal HSV Encephalitis


HSV-1 is the leading cause of sporadic encephalitis in humans. HSV infection of susceptible 129S6 mice results in fatal encephalitis (HSE) caused by massive inflammatory brainstem lesions comprising monocytes and neutrophils. During infection with pathogenic microorganisms or autoimmune disease, IgGs induce proinflammatory responses and recruit innate effector cells. In contrast, high dose intravenous immunoglobulins (IVIG) are an effective treatment for various autoimmune and inflammatory diseases because of potent anti-inflammatory effects stemming in part from sialylated IgGs (sIgG) present at 1–3% in IVIG. We investigated the ability of IVIG to prevent fatal HSE when given 24 h post infection. We discovered a novel anti-inflammatory pathway mediated by low-dose IVIG that protected 129S6 mice from fatal HSE by modulating CNS inflammation independently of HSV specific antibodies or sIgG. IVIG suppressed CNS infiltration by pathogenic CD11b+ Ly6Chigh monocytes and inhibited their spontaneous degranulation in vitro. FcγRIIb expression was required for IVIG mediated suppression of CNS infiltration by CD45+ Ly6Clow monocytes but not for inhibiting development of Ly6Chigh monocytes. IVIG increased accumulation of T cells in the CNS, and the non-sIgG fraction induced a dramatic expansion of FoxP3+ CD4+ T regulatory cells (Tregs) and FoxP3 ICOS+ CD4+ T cells in peripheral lymphoid organs. Tregs purified from HSV infected IVIG treated, but not control, mice protected adoptively transferred mice from fatal HSE. IL-10, produced by the ICOS+ CD4+ T cells that accumulated in the CNS of IVIG treated, but not control mice, was essential for induction of protective anti-inflammatory responses. Our results significantly enhance understanding of IVIG's anti-inflammatory and immunomodulatory capabilities by revealing a novel sIgG independent anti-inflammatory pathway responsible for induction of regulatory T cells that secrete the immunosuppressive cytokine IL-10 and further reveal the therapeutic potential of IVIG for treating viral induced inflammatory diseases.


Vyšlo v časopise: Passively Administered Pooled Human Immunoglobulins Exert IL-10 Dependent Anti-Inflammatory Effects that Protect against Fatal HSV Encephalitis. PLoS Pathog 7(6): e32767. doi:10.1371/journal.ppat.1002071
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002071

Souhrn

HSV-1 is the leading cause of sporadic encephalitis in humans. HSV infection of susceptible 129S6 mice results in fatal encephalitis (HSE) caused by massive inflammatory brainstem lesions comprising monocytes and neutrophils. During infection with pathogenic microorganisms or autoimmune disease, IgGs induce proinflammatory responses and recruit innate effector cells. In contrast, high dose intravenous immunoglobulins (IVIG) are an effective treatment for various autoimmune and inflammatory diseases because of potent anti-inflammatory effects stemming in part from sialylated IgGs (sIgG) present at 1–3% in IVIG. We investigated the ability of IVIG to prevent fatal HSE when given 24 h post infection. We discovered a novel anti-inflammatory pathway mediated by low-dose IVIG that protected 129S6 mice from fatal HSE by modulating CNS inflammation independently of HSV specific antibodies or sIgG. IVIG suppressed CNS infiltration by pathogenic CD11b+ Ly6Chigh monocytes and inhibited their spontaneous degranulation in vitro. FcγRIIb expression was required for IVIG mediated suppression of CNS infiltration by CD45+ Ly6Clow monocytes but not for inhibiting development of Ly6Chigh monocytes. IVIG increased accumulation of T cells in the CNS, and the non-sIgG fraction induced a dramatic expansion of FoxP3+ CD4+ T regulatory cells (Tregs) and FoxP3 ICOS+ CD4+ T cells in peripheral lymphoid organs. Tregs purified from HSV infected IVIG treated, but not control, mice protected adoptively transferred mice from fatal HSE. IL-10, produced by the ICOS+ CD4+ T cells that accumulated in the CNS of IVIG treated, but not control mice, was essential for induction of protective anti-inflammatory responses. Our results significantly enhance understanding of IVIG's anti-inflammatory and immunomodulatory capabilities by revealing a novel sIgG independent anti-inflammatory pathway responsible for induction of regulatory T cells that secrete the immunosuppressive cytokine IL-10 and further reveal the therapeutic potential of IVIG for treating viral induced inflammatory diseases.


Zdroje

1. WhitleyR 2003 Herpsvirus Infections of the Central Nervous Ssytem. Herpes 11 1 84

2. LundbergPWelanderPOpenshawHNalbandianCEdwardsC 2003 A locus on mouse chromosome 6 that determines resistance to herpes simplex virus also influences reactivation, while an unlinked locus augments resistance of female mice. J Virol 77 11661 11673

3. LundbergPRamakrishnaCBrownJTyszkaJMHamamuraM 2008 The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice is a Major Cause of CNS Pathology Resulting in Fatal Encephalitis. J Virol 82 7078 7088

4. MarquesCPCheeranMCJPalmquistJMHuSUrbanSL 2008 Prolonged Microglial Cell Activation and Lymphocyte Infiltration following Experimental Herpes Encephalitis. J Immunol 181 6417 6426

5. CohenJ 1988 Intravenous immunoglobulin (IVIG) for gram-negative infection–a critical review. J Hosp Infect 12 47 54

6. LooneyJRHugginsJ 2006 Use of intravenous immunoglobulin G (IVIG). Best Prac Res Cl Ha 19 3 25

7. NegiV-SElluruSSibÉRilSGraff-DuboisSMouthonLUC 2007 Intravenous Immunoglobulin: An Update on the Clinical Use and Mechanisms of Action. J Clin Immunol 27 233 245

8. ErlichKSDixRDMillsJ 1987 Prevention and treatment of experimental herpes simplex virus encephalitis with human immune serum globulin. Antimicrob Agents Chemother 31 1006 1009

9. DalaiSKPesnicakLMillerGFStrausSE 2002 Prophylactic and therapeutic effects of human immunoglobulin on the pathobiology of HSV-1 infection, latency, and reactivation in mice. J Neurovirol 8 35 44

10. NimmerjahnFRavetchJV 2008 Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8 34 47

11. Tha-InTBayryJMetselaarHJKaveriSVKwekkeboomJ 2008 Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol 29 608 615

12. EphremAChamatSMiquelCFissonSMouthonL 2008 Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood 111 715 722

13. KesselAAmmuriHPeriRPavlotzkyERBlankM 2007 Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol 179 5571 5575

14. NimmerjahnFRavetchJV 2007 The antiinflammatory activity of IgG: the intravenous IgG paradox. J Exp Med 204 11 15

15. SeiteJ-FShoenfeldYYouinouPHillionS 2008 What is the contents of the magic draft IVIg? Autoimmun Rev 7 435 439

16. ClynesR 2007 Protective mechanisms of IVIG. Curr Opin Immunol 19 646 651

17. DurandyAKaveriSVKuijpersTWBastaMMiescherS 2009 Intravenous immunoglobulins - understanding properties and mechanisms. Clin Exp Immunol 158 2 13

18. NimmerjahnFRavetchJV 2010 Antibody-mediated modulation of immune responses. Immunol Rev 236 265 275

19. BruhnsPSamuelssonAPollardJWRavetchJV 2003 Colony-Stimulating Factor-1-Dependent Macrophages Are Responsible for IVIG Protection in Antibody-Induced Autoimmune Disease. Immunity 18 573 581

20. AnthonyRRavetchJ 2010 A Novel Role for the IgG Fc Glycan: The Anti-inflammatory Activity of Sialylated IgG Fcs. J Clin Immunol 30 9 14

21. KanekoYNimmerjahnFRavetchJV 2006 Anti-Inflammatory Activity of Immunoglobulin G Resulting from Fc Sialylation. Science 313 670 673

22. BleekerWKTeelingJLVerhoevenAJRigterGMAgterbergJ 2000 Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase. Blood 95 1856 1861

23. TankersleyDL 1994 Dimer formation in immunoglobulin preparations and speculations on the mechanism of action of intravenous immune globulin in autoimmune diseases. Immunol Rev 139 159 172

24. KoelleDMCoreyL 2008 Herpes Simplex: Insights on Pathogenesis and Possible Vaccines. Annu Rev Med 59 381 395

25. NimmerjahnFRavetchJV 2006 Fc[gamma] Receptors: Old Friends and New Family Members. Immunity 24 19 28

26. LundbergPOpenshawHWangMYangHJCantinE 2007 Effects of CXCR3 Signaling on Development of Fatal Encephalitis and Corneal and Periocular Skin Disease in HSV-Infected Mice Are Mouse-Strain Dependent. Invest Ophthalmol Vis Sci 48 4162 4170

27. NimmerjahnFRavetchJV 2007 Fc-receptors as regulators of immunity. San Diego Elsevier Academic Press Inc 179 204 Advances in Immunology, Vol 96.

28. NimmerjahnFRavetchJV 2008 Anti-Inflammatory Actions of Intravenous Immunoglobulin. Annu Rev Immunol 26 513 533

29. SmithKGCClatworthyMR 2010 Fc[gamma]RIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat Rev Immunol 10 328 343

30. Tha-InTMetselaarHJBushellARKwekkeboomJWoodKJ 2010 Intravenous immunoglobulins promote skin allograft acceptance by triggering functional activation of CD4+Foxp3+ T cells. Transplantation 89 1446 1455

31. OpenshawHCantinEM 2005 Corticosteroids in herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatry 76 1469

32. AnthonyRMNimmerjahnFAshlineDJReinholdVNPaulsonJC 2008 Recapitulation of IVIG Anti-Inflammatory Activity with a Recombinant IgG Fc. Science 320 373 376

33. SultanYRossiFKazatchkineMD 1987 Recovery from anti-VIII:C (antihemophilic factor) autoimmune disease is dependent on generation of antiidiotypes against anti-VIII:C autoantibodies. Proc Natl Acad Sci U S A 84 828 831

34. AschermannSLuxABaerenwaldtABiburgerMNimmerjahnF 2009 The other side of immunoglobulin G: suppressor of inflammation. Clin Exp Immunol 160 161 167

35. AnthonyRMWermelingFKarlssonMCIRavetchJV 2008 Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci U S A 105 19571 19578

36. BazinRLemieuxRTremblayTSt-AmourI 2004 Tetramolecular immune complexes are more efficient than IVIg to prevent antibody-dependent in vitro and in vivo phagocytosis of blood cells. Br J Haematol 127 90 96

37. SiragamVBrincDCrowARSongSFreedmanJ 2005 Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease? J Clin Invest 115 155 160

38. BazinRLemieuxRTremblayT 2006 Reversal of immune thrombocytopenia in mice by cross-linking human immunoglobulin G with a high-affinity monoclonal antibody. Br J Haematol 135 97 100

39. SamuelssonATowersTLRavetchJV 2001 Anti-inflammatory Activity of IVIG Mediated Through the Inhibitory Fc Receptor. Science 291 484 486

40. KanekoYNimmerjahnFMadaioMPRavetchJV 2006 Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J Exp Med 203 789 797

41. CrowARSongSFreedmanJHelgasonCDHumphriesRK 2003 IVIg-mediated amelioration of murine ITP via Fc{gamma}RIIB is independent of SHIP1, SHP-1, and Btk activity. Blood 102 558 560

42. De GrootASMoiseLMcMurryJAWambreEVan OvertveltL 2008 Activation of natural regulatory T cells by IgG Fc-derived peptide “Tregitopes”. Blood 112 3303 3311

43. LindkvistAEdenANorstromMGonzalezVNilssonS 2009 Reduction of the HIV-1 reservoir in resting CD4+ T-lymphocytes by high dosage intravenous immunoglobulin treatment: a proof-of-concept study. AIDS Res Ther 6 15

44. NandakumarSMillerCKumaraguruU 2009 T regulatory cells: an overview and intervention techniques to modulate allergy outcome. Clin Mol Allergy 7 5

45. PotCJinHAwasthiALiuSMLaiC-Y 2009 Cutting Edge: IL-27 Induces the Transcription Factor c-Maf, Cytokine IL-21, and the Costimulatory Receptor ICOS that Coordinately Act Together to Promote Differentiation of IL-10-Producing Tr1 Cells. J Immunol 183 797 801

46. GabrilovichDINagarajS 2009 Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9 162 174

47. SimpsonTRQuezadaSAAllisonJP 2010 Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS). Curr Opin Immunol 22 326 332

48. LokensgardJRCheeranMCHuSGekkerGPetersonPK 2002 Glial cell responses to herpesvirus infections: role in defense and immunopathogenesis. J Infect Dis 186 Suppl 2 S171 179

49. LokensgardJRHuSShengWvanOijenMCoxD 2001 Robust expression of TNF-alpha, IL-1beta, RANTES, and IP-10 by human microglial cells during nonproductive infection with herpes simplex virus. J Neurovirol 7 208 219

50. MarquesCPHuSShengWCheeranMC-JCoxD 2004 Interleukin-10 attenuates production of HSV-induced inflammatory mediators by human microglia. Glia 47 358 366

51. MooreKWde Waal MalefytRCoffmanRLO'GarraA 2001 Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19 683 765

52. SaraivaMO'GarraA 2010 The regulation of IL-10 production by immune cells. Nat Rev Immunol 10 170 181

53. HaribhaiDLinWRellandLMTruongNWilliamsCB 2007 Regulatory T Cells Dynamically Control the Primary Immune Response to Foreign Antigen. J Immunol 178 2961 2972

54. PharesTWFabisMJBrimerCMKeanRBHooperDC 2007 A Peroxynitrite-Dependent Pathway Is Responsible for Blood-Brain Barrier Permeability Changes during a Central Nervous System Inflammatory Response: TNF-{alpha} Is Neither Necessary nor Sufficient. J Immunol 178 7334 7343

55. LiLBadingJYazakiPJAhujaAHCrowD 2007 A Versatile Bifunctional Chelate for Radiolabeling Humanized Anti-CEA Antibody with In-111 and Cu-64 at Either Thiol or Amino Groups: PET Imaging Of CEA-Positive Tumors with Whole Antibodies. Bioconj Chem 19 89 96

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2011 Číslo 6
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#