Severe CD4 T Cell-Mediated Immunopathology in Murine Schistosomiasis Is Dependent on IL-12p40 and Correlates with High Levels of IL-17

C57BL/6 mice infected with the helminth Schistosoma mansoni develop small hepatic granulomas around parasite eggs, but concomitant immunization with soluble schistosome egg Ags (SEA) in CFA (SEA/CFA) causes marked exacerbation of the lesions in a Th1-dominated environment characterized by high level...

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Bibliographic Details
Published in:	The Journal of immunology (1950) Vol. 175; no. 6; pp. 3920 - 3926
Main Authors:	Rutitzky, Laura I, Lopes da Rosa, Jessica R, Stadecker, Miguel J
Format:	Journal Article
Language:	English
Published:	United States Am Assoc Immnol 15-09-2005
Subjects:	Animals Antigens, Helminth - administration & dosage Antigens, Helminth - pharmacology CD4-Positive T-Lymphocytes - immunology Female Immunization Inflammation - etiology Inflammation - prevention & control Interferon-gamma - analysis Interleukin-12 - deficiency Interleukin-12 - immunology Interleukin-12 Subunit p35 Interleukin-12 Subunit p40 Interleukin-17 - analysis Interleukin-17 - immunology Interleukin-23 Interleukin-23 Subunit p19 Interleukins - analysis Mice Mice, Inbred C57BL Mice, Knockout Protein Subunits - deficiency Protein Subunits - immunology Schistosoma mansoni Schistosomiasis - immunology Schistosomiasis - pathology
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Summary:	C57BL/6 mice infected with the helminth Schistosoma mansoni develop small hepatic granulomas around parasite eggs, but concomitant immunization with soluble schistosome egg Ags (SEA) in CFA (SEA/CFA) causes marked exacerbation of the lesions in a Th1-dominated environment characterized by high levels of IFN-gamma. We explored the cause of the severe immunopathology by using IL-12p40(-/-) and IL-12p35(-/-) mice. SEA/CFA-immunized IL-12p40(-/-) mice, incapable of making IL-12 or IL-23, were completely resistant to high pathology, and their SEA-stimulated lymphoid cells failed to secrete significant IFN-gamma or IL-17. In contrast, SEA/CFA-immunized IL-12p35(-/-) mice, able to make IL-23 but not IL-12, developed severe lesions that correlated with high levels of IL-17, low IFN-gamma, and an expansion of activated CD4 T cells with a CD44(high)/CD62L(low) memory phenotype. In vivo administration of neutralizing anti-IL-17 mAb markedly inhibited hepatic granulomatous inflammation. Importantly, CBA mice, a naturally high pathology strain, also displayed elevated IL-17 levels comparable to those seen in the SEA/CFA-immunized BL/6 mice, and their lesions were similarly reduced by in vivo treatment with anti-IL-17. Our findings indicate that an IL-17-producing T cell population, likely driven by IL-23, significantly contributes to severe immunopathology in schistosomiasis.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-1767 1550-6606
DOI:	10.4049/jimmunol.175.6.3920