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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901504v1 183/5/3317    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Smith, P. M. Articles by Stadecker, M. J. PubMed PubMed Citation Articles by Smith, P. M. Articles by Stadecker, M. J.

Genetic Control of Severe Egg-Induced Immunopathology and IL-17 Production in Murine Schistosomiasis¹

Patrick M. Smith, Mara G. Shainheit, Lindsey E. Bazzone^*, Laura I. Rutitzky^*, Alexander Poltorak^*, and Miguel J. Stadecker^2,*,

^* Department of Pathology and Immunology Program, Sackler School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111

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 F₂ 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 F₂ mice 7 wk after infection significantly correlated with an increase in the production of the proinflammatory cytokines IL-17, IFN-, and TNF- 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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service Grant R01-18919.

² Address correspondence and reprint requests to Dr. Miguel J. Stadecker, Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, MA 02111. E-mail address: miguel.stadecker{at}tufts.edu

³ Abbreviations used in this paper: QTL, quantitative trait loci; CI, confidence interval; CIA, collagen induced arthritis; EAE, experimental autoimmune encephalomyelitis; LOD, logarithm of the odds; MLN, mesenteric lymph node; SEA, Schistosome egg antigens; SLE, systemic lupus erythematosus.