Genetic control of severe egg-induced immunopathology and IL-17 production in murine schistosomiasis.
Infection with the trematode parasite Schistosoma mansoni results in a distinct heterogeneity of disease severity, both in humans and in an experimental mouse model. Severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation in a proinflammatory cytokine environment, whereas mild disease corresponds with reduced hepatic inflammation in a Th2 skewed cytokine environment. This marked heterogeneity indicates that genetic differences play a significant role in disease development, yet little is known about the genetic basis of dissimilar immunopathology. To investigate the role of genetic susceptibility in murine schistosomiasis, quantitative trait loci analysis was performed on F(2) progeny derived from SJL/J and C57BL/6 mice, which develop severe and mild pathology, respectively. In this study, we show that severe liver pathology in F(2) mice 7 wk after infection significantly correlated with an increase in the production of the proinflammatory cytokines IL-17, IFN-gamma, and TNF-alpha by schistosome egg Ag-stimulated mesenteric lymph node cells. Quantitative trait loci analysis identified several genetic intervals controlling immunopathology as well as IL-17 and IFN-gamma production. Egg granuloma size exhibited significant linkage to two loci, D4Mit203 and D17Mit82, both of which were inherited in a BL/6 dominant manner. Furthermore, a significant reduction of hepatic granulomatous inflammation and IL-17 production in interval-specific congenic mice demonstrated that the two identified genetic loci have a decisive effect on the development of immunopathology in murine schistosomiasis.
Smith
Patrick M
PM
Department of Pathology, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
Shainheit
Mara G
MG
Bazzone
Lindsey E
LE
Rutitzky
Laura I
LI
Poltorak
Alexander
A
Stadecker
Miguel J
MJ
D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D008040:Genetic Linkage / Q000276:immunology; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008109:Liver Diseases, Parasitic / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D010063:Ovum / Q000276:immunology*; D020161:Physical Chromosome Mapping; D040641:Quantitative Trait Loci / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D013045:Species Specificity
D020381:Interleukin-17
J Immunol. 2005 Sep 15;175(6):3920-6
16148138
Immunity. 1999 Aug;11(2):131-9
10485648
Genes Immun. 2002 Jun;3(4):177-86
12058252
Nature. 2003 May 29;423(6939):506-11
12724780
Am J Hum Genet. 1999 Sep;65(3):709-21
10441577
Immunity. 2004 May;20(5):623-35
15142530
J Clin Invest. 1997 Feb 1;99(3):469-74
9022080
Genomics. 2001 Jan 1;71(1):70-7
11161799
Nat Genet. 1995 Jul;10(3):313-7
7545492
J Immunol. 2004 Jan 15;172(2):1295-303
14707108
Arthritis Rheum. 2000 Feb;43(2):349-55
10693874
Genomics. 1995 Oct 10;29(3):755-9
8575770
Ann Biol Clin (Paris). 1993;51(6):619-26
8172401
Genes Immun. 2006 Apr;7(3):220-33
16511555
Mamm Genome. 2003 Jul;14(7):429-36
12925891
Genes Immun. 2001 Nov;2(7):388-97
11704805
Am J Trop Med Hyg. 1998 Aug;59(2):302-6
9715951
Nat Immunol. 2008 Nov;9(11):1297-306
18849990
Genes Immun. 2005 Sep;6(6):528-38
16015371
Genetics. 2006 Feb;172(2):1147-53
16299394
J Immunol. 2008 Feb 15;180(4):2634-40
18250475
Ir J Med Sci. 2007 Dec;176(4):253-60
18004613
J Immunol. 1998 Aug 15;161(4):1860-7
9712054
Nat Genet. 2005 Aug;37(8):835-43
15995705
Eur J Immunol. 1998 Oct;28(10):3321-8
9808201
Trends Immunol. 2003 May;24(5):269-77
12738422
J Exp Med. 1970 Sep 1;132(3):488-507
5535626
Nat Genet. 1996 Oct;14(2):181-4
8841190
Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13243-8
11606762
Nat Rev Genet. 2007 Jan;8(1):58-69
17173058
J Infect Dis. 2002 Jan 1;185(1):98-105
11756987
Eur J Immunol. 2005 Sep;35(9):2659-69
16106372
Int J Parasitol. 2001 May 15;31(7):674-80
11336748
Immunity. 2008 Jan;28(1):29-39
18164222
Mamm Genome. 2004 Aug;15(8):630-6
15457342
Eur J Immunol. 1997 May;27(5):1170-6
9174607
Genes Immun. 2006 Mar;7(2):122-9
16395389
J Immunol. 2006 Oct 1;177(7):4612-9
16982899
Scand J Immunol. 1997 Oct;46(4):393-8
9350291
J Immunol. 2005 Jan 1;174(1):435-40
15611268
J Immunol. 1996 Jun 15;156(12):4715-21
8648117
Nat Genet. 1995 Nov;11(3):241-7
7581446
Nat Genet. 1997 Jun;16(2):194-6
9171834
Scand J Immunol. 1990 Feb;31(2):205-11
2106723
J Immunol. 2006 May 1;176(9):5374-87
16622005
Infect Immun. 1999 Sep;67(9):4689-92
10456917
J Immunol. 2008 Feb 15;180(4):2486-95
18250458
J Infect Dis. 1996 Nov;174(5):1131-5
8896524
Genes Immun. 2005 Sep;6(6):500-8
15973461
Am J Trop Med Hyg. 2001 Dec;65(6):754-8
11791970
Nat Rev Immunol. 2002 Jul;2(7):499-511
12094224
J Immunol. 1998 Feb 15;160(4):1992-9
9469463
J Exp Med. 1997 May 5;185(9):1705-10
9151907
J Immunol. 2008 Dec 15;181(12):8559-67
19050275
Nat Genet. 2001 Mar;27(3):259-60
11242105
Am J Physiol Renal Physiol. 2004 Sep;287(3):F347-52
15297276
Infect Dis Clin North Am. 2000 Sep;14(3):583-604, viii
10987111
Am J Trop Med Hyg. 1987 Jul;37(1):85-97
3111283
Genes Dev. 2000 Jul 15;14(14):1693-711
10898785
Cell. 2006 Sep 22;126(6):1121-33
16990136