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An understanding of the immunogenetic basis of naturally acquired immunity to Plasmodium falciparum infection would aid in the designing of a rationally based malaria vaccine. Variants within the Fc gamma receptors (FcγRs) mediate immunity through engagement of immunoglobulin G and other immune mediators, such as gamma interferon (IFN-γ), resulting in erythrophagocytosis and production of inflammatory cytokines in severe malarial anemia (SMA). The Toll-like receptors (TLRs) trigger transcription of proinflammatory cytokines and induce adaptive immune responses. Therefore, these receptors may condition malaria disease pathogenesis through alteration in adaptive and innate immune responses. To further delineate the impacts of FcγRIIIA and TLR9 in SMA pathogenesis, the associations between FcγRIIIA -176F/V and TLR9 -1237T/C variants, SMA (hemoglobin [Hb] < 6.0 g/dl), and circulating IFN-γ levels were investigated in children (n = 301) from western Kenya with acute malaria. Multivariate logistic regression analysis (controlling for potential confounders) revealed that children with the FcγRIIIA -176V/TLR9 -1237C (VC) variant combination had 64% reduced odds of developing SMA (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.20 to 0.64; P = 0.001), while carriers of the FcγRIIIA -176V/TLR9 -1237T (VT) variant combination were twice as susceptible to SMA (OR, 2.04; 95% CI, 1.19 to 3.50; P = 0.009). Children with SMA had higher circulating IFN-γ levels than non-SMA children (P = 0.008). Hemoglobin levels were negatively correlated with IFN-γ levels (r = -0.207, P = 0.022). Consistently, the FcγRIIIA -176V/TLR9 -1237T (VT) carriers had higher levels of circulating IFN-γ (P = 0.011) relative to noncarriers, supporting the observation that higher IFN-γ levels are associated with SMA. These results demonstrate that FcγRIIIA-176F/V and TLR9 -1237T/C variants condition susceptibility to SMA and functional changes in circulating IFN-γ levels.

Titel:	Polymorphisms in the Fc gamma receptor IIIA and Toll-like receptor 9 are associated with protection against severe malarial anemia and changes in circulating gamma interferon levels.
Autor/in / Beteiligte Person:	Munde, EO ; Okeyo, WA ; Anyona, SB ; Raballah, E ; Konah, S ; Okumu, W ; Ogonda, L ; Vulule, J ; Ouma, C
Link:	Zum Volltext
Zeitschrift:	Infection and immunity, Jg. 80 (2012-12-01), Heft 12, S. 4435
Veröffentlichung:	Washington, DC : American Society For Microbiology ; <i>Original Publication</i>: [Bethesda, Md.] American Society for Microbiology., 2012
Medientyp:	academicJournal
ISSN:	1098-5522 (electronic)
DOI:	10.1128/IAI.00945-12
Schlagwort:	Anemia epidemiology Anemia physiopathology Child, Preschool Cross-Sectional Studies Female Genotype Humans Infant Kenya epidemiology Malaria, Falciparum epidemiology Male Promoter Regions, Genetic genetics Severity of Illness Index Anemia prevention & control Genetic Predisposition to Disease Interferon-gamma blood Malaria, Falciparum complications Polymorphism, Single Nucleotide genetics Receptors, IgG genetics Toll-Like Receptor 9 genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural Language: English [Infect Immun] 2012 Dec; Vol. 80 (12), pp. 4435-43. <i>Date of Electronic Publication: </i>2012 Oct 08. MeSH Terms: Genetic Predisposition to Disease* ; Anemia / prevention & control ; Interferon-gamma / blood ; Malaria, Falciparum / complications ; Polymorphism, Single Nucleotide / genetics ; Receptors, IgG / genetics ; Toll-Like Receptor 9 / genetics ; Anemia / epidemiology ; Anemia / physiopathology ; Child, Preschool ; Cross-Sectional Studies ; Female ; Genotype ; Humans ; Infant ; Kenya / epidemiology ; Malaria, Falciparum / epidemiology ; Male ; Promoter Regions, Genetic / genetics ; Severity of Illness Index References: Blood. 1997 Aug 1;90(3):1109-14. (PMID: 9242542) ; Malar J. 2012 May 17;11:168. (PMID: 22594374) ; Hum Genet. 2012 Feb;131(2):289-99. (PMID: 21818580) ; Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8676-80. (PMID: 1528880) ; Am J Trop Med Hyg. 2007 Dec;77(6 Suppl):23-8. (PMID: 18165471) ; Am J Trop Med Hyg. 2006 Apr;74(4):573-7. (PMID: 16606986) ; Infect Immun. 2011 Nov;79(11):4674-80. (PMID: 21859849) ; Br J Haematol. 1980 Oct;46(2):171-83. (PMID: 7000157) ; Am J Trop Med Hyg. 2010 Apr;82(4):548-55. (PMID: 20348497) ; Clin Diagn Lab Immunol. 2002 Mar;9(2):348-51. (PMID: 11874876) ; Curr Opin Hematol. 2009 May;16(3):157-64. (PMID: 19384231) ; Pharmacol Ther. 2003 Aug;99(2):221-60. (PMID: 12888113) ; J Infect Dis. 2006 Jul 15;194(2):184-8. (PMID: 16779724) ; Microbes Infect. 2008 Jul;10(8):885-91. (PMID: 18657459) ; J Exp Med. 2005 Jan 3;201(1):19-25. (PMID: 15630134) ; Lancet. 2002 Apr 13;359(9314):1311-2. (PMID: 11965279) ; Eur Cytokine Netw. 2000 Sep;11(3):362-71. (PMID: 11022119) ; Infect Immun. 2010 Mar;78(3):1345-52. (PMID: 20038537) ; Genes Immun. 2009 Jul;10(5):380-9. (PMID: 19421223) ; J Infect Dis. 2002 Apr 1;185(7):971-9. (PMID: 11920322) ; J Clin Microbiol. 2011 Feb;49(2):671-6. (PMID: 21106789) ; Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5789-94. (PMID: 19297619) ; Mol Cell Biol. 1993 Oct;13(10):6326-35. (PMID: 8413231) ; Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1919-24. (PMID: 17261807) ; Am J Trop Med Hyg. 1998 Apr;58(4):406-13. (PMID: 9574783) ; J Trop Pediatr. 2011 Oct;57(5):392-5. (PMID: 21118871) ; Am J Trop Med Hyg. 1999 May;60(5):733-7. (PMID: 10344643) ; Malar J. 2005 Dec 01;4:56. (PMID: 16321150) ; Annu Rev Immunol. 2002;20:197-216. (PMID: 11861602) ; J Exp Med. 1986 Aug 1;164(2):474-89. (PMID: 2941515) ; Nat Rev Genet. 2002 Aug;3(8):611-21. (PMID: 12154384) ; Immunol Today. 1989 Mar;10(3):92-9. (PMID: 2525910) ; J Exp Med. 2002 Apr 1;195(7):881-92. (PMID: 11927632) ; Blood. 1995 Dec 15;86(12):4389-99. (PMID: 8541526) ; Am J Trop Med Hyg. 1999 Apr;60(4):641-8. (PMID: 10348241) ; J Immunol. 1995 Sep 1;155(5):2545-56. (PMID: 7650384) ; Annu Rev Immunol. 1997;15:203-34. (PMID: 9143687) ; Am J Trop Med Hyg. 2001 Nov;65(5):614-22. (PMID: 11716124) ; Curr Opin Immunol. 2003 Feb;15(1):5-11. (PMID: 12495726) ; Clin Infect Dis. 2008 Dec 1;47(11):1380-7. (PMID: 18947328) ; Annu Rev Immunol. 1991;9:457-92. (PMID: 1910686) ; Infect Immun. 2000 Aug;68(8):4399-406. (PMID: 10899836) ; Am J Trop Med Hyg. 1996 May;54(5):449-57. (PMID: 8644897) ; Cell. 2006 Feb 24;124(4):783-801. (PMID: 16497588) ; Malar J. 2011 Apr 04;10:77. (PMID: 21457584) ; Q J Med. 1986 Mar;58(227):305-23. (PMID: 3526385) ; Tissue Antigens. 2003 Mar;61(3):189-202. (PMID: 12694568) ; Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R134-9. (PMID: 17911157) ; Am J Trop Med Hyg. 2004 Aug;71(2 Suppl):1-15. (PMID: 15331814) ; Jpn J Infect Dis. 2002 Oct;55(5):167-9. (PMID: 12501257) ; Eur J Immunol. 1993 Apr;23(4):882-7. (PMID: 8458376) ; Am J Trop Med Hyg. 1999 Dec;61(6):932-40. (PMID: 10674673) ; N Engl J Med. 1995 May 25;332(21):1399-404. (PMID: 7723795) ; Acta Trop. 2007 Mar;101(3):258-65. (PMID: 17379175) ; J Infect Dis. 2008 Sep 1;198(5):772-80. (PMID: 18662133) ; Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9237-42. (PMID: 11470918) ; Am J Trop Med Hyg. 2006 Mar;74(3):376-85. (PMID: 16525094) ; AIDS. 2006 Jan 9;20(2):275-80. (PMID: 16511422) ; J Immunol. 1995 May 15;154(10):5338-44. (PMID: 7537305) ; J Immunol. 1989 Jul 1;143(1):15-22. (PMID: 2525146) ; J Immunol. 2004 Apr 15;172(8):4926-33. (PMID: 15067072) ; J Exp Med. 1991 Mar 1;173(3):523-9. (PMID: 1900073) ; Malar J. 2009 Mar 13;8:44. (PMID: 19284650) ; Br J Haematol. 1999 May;105(2):505-8. (PMID: 10233428) Grant Information: D43 TW005884 United States TW FIC NIH HHS; R01 TW008306 United States TW FIC NIH HHS; 7R01-TW008306-05 United States TW FIC NIH HHS Substance Nomenclature: 0 (FCGR3A protein, human) ; 0 (Receptors, IgG) ; 0 (TLR9 protein, human) ; 0 (Toll-Like Receptor 9) ; 82115-62-6 (Interferon-gamma) Entry Date(s): Date Created: 20121010 Date Completed: 20130207 Latest Revision: 20211021 Update Code: 20240513 PubMed Central ID: PMC3497437

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Polymorphisms in the Fc gamma receptor IIIA and Toll-like receptor 9 are associated with protection against severe malarial anemia and changes in circulating gamma interferon levels.