title: The IL-10 polarized cytokine pattern in innate and adaptive immunity cells contribute to the development of FVIII inhibitors.
abstract: BACKGROUND
  Hemophilia A (HA) is an X-linked inherited bleeding disorder, resulting from a qualitative or quantitative deficiency of clotting factor VIII (FVIII). Antibodies against FVIII, also called inhibitors, block the procoagulant activity of FVIII; thus, impairing hemostatic activity in patients with HA. The exact mechanism underlying the immunological events behind the development of inhibitors remains unknown. This study aimed to understand immune response to FVIII in patients with HA who were either positive [HAα-FVIII(+)] or negative [HAα-FVIII(-)] for inhibitors.
  
  
  METHODS
  Cytokine profiles [interferon-γ (IFN - γ), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-5, and IL-10] of innate and adaptive immune cells present in the peripheral blood of participants were characterized.
  
  
  RESULTS
  Presence of inhibitors was significantly associated with decreased frequencies of TNF-α-positive monocytes and neutrophils, IL-5-positive monocytes, IL-4-positive neutrophils, and increased frequencies of IL-10-positive neutrophils and T cells. T cells from HAα-FVIII(-) patients expressed increased levels of almost all cytokines. In contrast, HAα-FVIII(+) patients showed lower levels of all cytokines in CD4(+) and CD8(+) T cells, except IL-10. B cells from HAα-FVIII(-) patients expressed increased levels of IL-4 while those from HAα-FVIII(+) patients expressed increased levels of IL-10.
  
  
  CONCLUSIONS
  The global cytokine profiles of innate and adaptive immune cells showed an anti-inflammatory/regulatory pattern in HAα-FVIII(+) patients and a mixed pattern, with a bias toward inflammatory cytokine profile, in HAα-FVIII(-) patients. The occurrence of these profiles seems to be associated with presence FVIII inhibitors.
authors: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, FIOCRUZ/MG, Belo Horizonte, Minas Gerais Brazil.
authors: Amanda Co
authors: AC
authors: Silveira
authors: Serviço de Pesquisa, Fundação Hemominas, Belo Horizonte, Minas Gerais Brazil.
authors: Marcio Ap
authors: MA
authors: Santana
authors: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, FIOCRUZ/MG, Belo Horizonte, Minas Gerais Brazil.|Serviço de Pesquisa, Fundação Hemominas, Belo Horizonte, Minas Gerais Brazil.
authors: Isabella G
authors: IG
authors: Ribeiro
authors: Serviço de Pesquisa, Fundação Hemominas, Belo Horizonte, Minas Gerais Brazil.
authors: Daniel G
authors: DG
authors: Chaves
authors: Laboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, FIOCRUZ/MG, Belo Horizonte, Minas Gerais Brazil.
authors: Olindo A
authors: OA
authors: Martins-Filho
keywords: Cytokine profile; FVIII inhibitors; Hemophilia A; Immune regulation; Intracellular cytokine staining
references: Blood. 2006 Apr 15;107(8):3167-72
references: 16380445
references: Haemophilia. 2013 May;19(3):e139-42
references: 23387800
references: Haemophilia. 2006 Dec;12 Suppl 6:15-22
references: 17123389
references: J Thromb Haemost. 2008 Dec;6(12 ):2095-104
references: 18826393
references: Eur J Haematol. 1988 Oct;41(4):334-40
references: 3264249
references: Haemophilia. 2012 Sep;18(5):794-7
references: 22630053
references: Curr Opin Immunol. 2008 Jun;20(3):332-8
references: 18417336
references: Vojnosanit Pregl. 2011 Dec;68(12):1047-50
references: 22352266
references: Int Immunol. 1999 Aug;11(8):1351-6
references: 10421792
references: Int J Immunogenet. 2010 Apr;37(2):79-82
references: 20082647
references: J Thromb Haemost. 2011 Jun;9(6):1163-70
references: 21645224
references: Thromb Haemost. 2007 May;97(5):788-94
references: 17479189
references: Clin Exp Immunol. 2010 Dec;162(3):425-37
references: 20846164
references: Clin Exp Immunol. 2006 Dec;146(3):443-7
references: 17100763
references: Pharm World Sci. 2008 Jun;30(3):287-92
references: 18085428
references: Clin Rev Allergy Immunol. 2009 Oct;37(2):58-66
references: 19148784
references: J Immunol. 2004 Mar 15;172(6):3422-7
references: 15004141
references: Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1890-3
references: 1371884
references: Eur J Immunol. 2009 Aug;39(8):2106-19
references: 19609979
references: J Immunol. 2005 Dec 1;175(11):7093-7
references: 16301610
references: Br J Haematol. 2008 Aug;142(4):644-52
references: 18510679
references: Haemophilia. 2010 May;16(102):35-43
references: 20536984
references: Curr Drug Targets Inflamm Allergy. 2005 Jun;4(3):273-9
references: 16101533
references: Thromb Haemost. 2002 Oct;88(4):568-75
references: 12362225
references: Blood. 2008 Jul 15;112(2):240-9
references: 18469198
references: Haemophilia. 2012 Nov;18(6):e416-8
references: 22970761
references: Br J Haematol. 2002 Nov;119(2):310-22
references: 12406063
references: J Thromb Haemost. 2007 Jul;5(7):1383-90
references: 17456190
references: Blood. 2006 Dec 1;108(12):3739-45
references: 16926287
references: Thromb Haemost. 2003 Aug;90(2):279-92
references: 12888876
references: Nat Immunol. 2000 Dec;1(6):475-82
references: 11101868
references: Blood. 2007 Jun 1;109(11):4648-54
references: 17289808
references: J Immunol. 2005 Apr 1;174(7):4098-104
references: 15778368
references: Biochemistry. 1991 Oct 29;30(43):10363-70
references: 1931959
references: J Thromb Haemost. 2004 Jul;2(7):1082-95
references: 15219191
references: J Med Virol. 2013 Jun;85(6):1009-18
references: 23591975
references: Clin Rev Allergy Immunol. 2009 Oct;37(2):105-13
references: 19165635
references: Immunity. 2009 Mar 20;30(3):421-33
references: 19249230
references: J Thromb Haemost. 2013 Jan;11(1):47-55
references: 23140211
references: Rheumatology (Oxford). 2010 Sep;49(9):1618-31
references: 20338884
references: Haemophilia. 2003 Jul;9(4):418-35
references: 12828678
references: Haemophilia. 2012 Mar;18(2):187-92
references: 21883704
references: Haemophilia. 2003 Jul;9(4):376-81
references: 12828671