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The Journal of Immunology, 2005, 174: 435-440.
Copyright © 2005 by The American Association of Immunologists

Enhanced Egg-Induced Immunopathology Correlates With High IFN-{gamma} in Murine Schistosomiasis: Identification of Two Epistatic Genetic Intervals1

Laura I. Rutitzky2,*, Hector J. Hernandez2,*, Young-Sun Yim2,{dagger}, David E. Ricklan*, Eduardo Finger*, Chandra Mohan{dagger}, Inga Peter{ddagger}, Edward K. Wakeland{dagger} and Miguel J. Stadecker3,*

* Department of Pathology, Tufts University School of Medicine, Boston, MA 02111; {dagger} Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and {ddagger} Institute of Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, MA 02111


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The genetic basis of dissimilar immunopathology development among mouse strains infected with Schistosoma mansoni is not known. We performed a multipoint parametric linkage analysis on a cohort of F2 mice, offspring of brother-sister mating between (high pathology CBA x low pathology BL/6)F1 mice, to examine whether the observed differences in the type of immune response or the extent of hepatic immunopathology are linked to any particular genomic intervals. The F2 mice exhibited cytokine responses and immunopathologies that revealed a statistically significant correlation between prominent egg Ag-stimulated IFN-{gamma} production by mesenteric lymph node cells and hepatic egg granuloma size. Increased IFN-{gamma} production showed suggestive linkage to a dominant CBA locus on chromosome 1 and a recessive CBA locus on chromosome 5; significantly, there was an epistatic interaction between the two IFN-{gamma} loci. An additional locus with suggestive linkage to granuloma formation and a CBA-recessive mode of inheritance was mapped to centromeric chromosome 13. Our analysis identified the first three genetic regions that appear to influence the immunopathology in murine schistosomiasis; however, further congenic dissection studies will furnish a more precise understanding of the genetic control of this disease.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Schistosomiasis is a serious parasitic disease responsible for >200 million human infections and 200,000 deaths each year. The causal agents are trematode helminths of the genus Schistosoma (1, 2, 3). Several species of schistosomes cause pathology in specific permissive vertebrate hosts and in designated anatomic locations. The main pathology in schistosomiasis is a granulomatous and fibrosing reaction against the parasite eggs, which, in the case of Schistosoma mansoni, takes place in the liver and intestines; this host reaction is an immunopathological process mediated by MHC class II-restricted CD4+ Th lymphocytes specific for schistosome egg Ags (SEA)4 (4, 5). An early Th1-type (IFN-{gamma}, IL-2) cytokine reaction to SEA normally transitions to a Th2-dominant (IL-4, IL-5, IL-10) response as the disease evolves (6, 7, 8).

S. mansoni infection results in considerable variation of disease severity, both in humans and in a relevant experimental murine model. In humans, the severe "hepatosplenic" schistosomiasis, characterized by the development of pronounced liver fibrosis, portal hypertension, portal-systemic shunting, ascites, gastrointestinal hemorrhage and death, contrasts with the milder, often symptomless "intestinal" form of the disease (1). In mice, different inbred strains develop different degrees of pathology; among these, the CBA and C3H strains develop significantly larger egg granulomas than the C57BL/6 (BL/6) strain (9, 10). CD4+ T cell stimulation with SEA in the high pathology mice results in strong mixed cytokine production with a lingering Th1 component (11); in contrast, low pathology mice attain a net Th2-type environment (6, 8). A particularly severe form of murine schistosomiasis in some chronically infected male CBA mice is associated with high levels of TNF-{alpha} (12) and low levels of IL-10 (13).

Remarkably, this striking heterogeneity in egg-induced immunopathology develops under ostensibly similar environmental conditions in humans or experimental conditions in mice. This has prompted the search for host-related genetic factors that may account for the heterogeneity. Studies on human patient populations from different endemic areas have suggested that differences in clinical disease are under the control of several genes, both within and outside of the MHC (14, 15, 16, 17, 18, 19, 20, 21). However, in contrast to humans, there have been thus far no genetic studies on schistosomiasis in the mouse, despite the availability of inbred strains with clear-cut variations in immune response and immunopathology (9, 10, 22, 23), and the long held presumption that disease severity is controlled by genetic factors.

The advent of microsatellite markers and the advances in analytical approaches have greatly simplified the genetic analysis of complex traits (24, 25). In addition, genetic mapping as well as congenic strain construction has greatly augmented our ability to ascertain the function of individual loci as well as to define the epistatic interactions between them (25, 26). Taking advantage of these advances in mouse genetics, we performed a quantitative trait loci analysis on a cohort of F2 mice, offspring of brother-sister mating between (high pathology CBA x low pathology BL/6)F1 hybrids, to ascertain whether the difference in pathology or the nature of the ensuing immune response are linked to any particular genomic intervals.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice and infection

C57BL/6J (BL/6, BL6), CBA/J (CBA), and B6CBAF1/J (F1) mice, 6 wk old, were purchased from The Jackson Laboratory and maintained in the Animal Facility at Tufts University School of Medicine. A total of 62 F2 mice were bred in-house by F1 brother-sister mating. F2 mice of both sexes were weaned and infected at six weeks of age by i.p. injection with 80 cercariae of S. mansoni (Puerto Rico strain), together with age-matched female F1 and parental CBA and BL/6 mice. Cercariae were obtained from infected Biomphalaria glabrata snails, provided to us by the Biomedical Research Institute, through National Institutes of Health/National Institute of Allergy and Infectious Diseases Contract N01-AI-55270. All mice were studied after 8 wk of infection; there was no mortality or evidence of clinical illness in parental or offspring mice at this time.

Histopathology assessment by morphometric analysis

Liver samples from all mouse groups were fixed in 10% buffered formalin and processed for routine histopathological analysis; 5-µm sections stained with H&E were examined for qualitative and quantitative changes. The extent of hepatic granulomatous inflammation around schistosome eggs was measured by computer-assisted morphometric analysis using Image-Pro Plus (Media Cybernetics) software. The lesions were assessed on coded slides by an observer unaware of the experimental setting. To reflect more accurately the true shape and dimension of the granulomas, only those with a visible central egg were counted. A minimum of 20 granulomas per liver section was studied. Granuloma size means measured in square micrometers ± SEM were reported and further used for the linkage analysis.

Cytokine determination

Mesenteric lymph nodes (MLN) were removed aseptically from 8-wk infected mice. Single-cell suspensions were prepared from each individual mouse by teasing the tissues in RPMI 1640 supplemented with 10% FCS (Atlanta Biologicals), 4 mM L-glutamine, 80 U/ml penicillin, 80 µg/ml streptomycin, 1 mM sodium pyruvate, 10 mM HEPES, 1x non essential amino acids (all from BioWhittaker) and 6 x 10–5 M 2-ME (cRPMI). Erythrocytes were lysed with Tris-ammonium chloride buffer, pH 7.2 (Sigma-Aldrich), for 15 min on ice. Cells were washed, and live cells that excluded trypan blue were counted and resuspended at the desired concentrations in cRPMI. IFN-{gamma}, IL-2, IL-5, and IL-10 were measured in 48-h supernatants from MLN cells cultured at a concentration of 5 x 106/ml in the presence of 20 µg/ml SEA. Cytokine levels were determined by ELISA, using Abs, standards. and protocol obtained from BD Pharmingen.

Genetic mapping and statistical analysis

Genetic mapping was conducted as described before (27). DNA was extracted from the kidneys and tails for genotyping. Single-strand conformation polymorphism loci were selected from the variety of polymorphic microsatellite markers (<www-genome.wi.mit.edu>); primers were obtained from Research Genetics. Marker positions were obtained from The Jackson Laboratory Mouse Genome Database (<www.informatics.jax.org>). A panel of 82 primers that readily distinguished CBA from BL/6 alleles was used for genotyping the F2 offspring. Together, they spanned 1500 cM of the autosomal genome (covering all 19 chromosomes), with an average intermarker distance of 15.5 cM. Standard PCR was performed at experimentally determined optimal annealing temperature for each primer pair. Amplified products were electrophoresed onto 5% agarose gels and visualized by ethidium bromide staining and UV transillumination. Data were analyzed using Mapmaker. Mapmaker is a quantitative trait loci mapping program that tests whether markers show evidence of linkage to the tested phenotypes. The linkage was considered "significant/probable" if the logarithm of the odds favoring linkage (LOD) score exceeded 3.3, and "suggestive" if the LOD score was >1.9 according to the system of Lander and Kruglyak (28) in the context of genome search using an intercross study.

The parental phenotypes (granuloma size and cytokines) were analyzed by a two-tailed Student t test. Linear regression analysis with logarithmic transformation of granuloma size data was used to determine the association between IFN-{gamma} levels and granuloma size. Nonparametric ANOVAs were used to estimate the phenotypes of homozygous and heterozygous (CBA/CBA, CBA/BL6, BL6/BL6) F2 mice. GraphPad Prism software version 4.0 was used to perform the statistical analysis.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Our findings demonstrated that CBA and BL/6 mice differ considerably in the magnitude of egg-induced immunopathology. Hence, whereas CBA mice develop large granulomas (mean size, 15.87 µm2 x 10–4), the BL/6 strain exhibits significantly smaller granulomas (mean size, 8.08 µm2 x 10–4), as illustrated in Fig. 1A. Although closer to the BL/6 parent, (CBA x BL/6)F1 mice exhibited intermediate phenotypes, alluding to the potential contribution of the CBA genotype. To elucidate the genetic basis of this phenotype, a (CBA x BL/6)F2 mouse progeny was studied in a similar manner. The F2 progeny exhibited a wide spread of phenotypes, with some F2 mice resembling the CBA or BL/6 parents; most progeny exhibited intermediate phenotypes (Fig. 1A).



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  		FIGURE 1. Granuloma size and IFN-{gamma} production by SEA-stimulated MLN cells from CBA, BL/6, F1, and F2 mice. A, Granulomas were measured in liver sections obtained from 8-wk-infected CBA (n = 6), BL/6 (n = 6), (CBA x BL/6)F1 (n = 6), and (CBA x BL/6)F2 mice (n = 62), as detailed in Materials and Methods. A minimum of 20 granulomas was measured per mouse. Bars represent mean ± SEM granuloma sizes, pertaining to each mouse group. B, IFN-{gamma} production by SEA-stimulated MLN cells from the same 8-wk-infected CBA, BL/6, (CBA x BL/6)F1 and (CBA x BL/6)F2 mice was measured by ELISA as detailed in Materials and Methods. Bars represent mean cytokine levels of triplicate determinations ± SEM pertaining to each mouse group.

 
Given the reported observation that a Th1-skewed immune response may be of pathogenic significance in schistosomiasis (29, 30, 31, 32), we next examined the cytokine production of CBA, BL/6, F1, and F2 MLN cells challenged in vitro with SEA. CBA lymphocytes produced significantly more IFN-{gamma} than BL/6 lymphocytes, with the F1 mice exhibiting a phenotype close to the latter. The F2 offspring displayed varying levels of SEA-stimulated IFN-{gamma} (Fig. 1B), which significantly correlated with egg granuloma size (Fig. 2). IL-2, IL-5, and IL-10 production by the SEA-stimulated MLN cells was also significantly higher in CBA than in BL/6 mice, although the differences were not as striking as in the case of IFN-{gamma} (Fig. 3). The F1 and F2 progenies variously produced intermediate cytokine levels ranging and rarely exceeding those observed in the parental strains (Fig. 3). There was no statistically significant correlation between granuloma size and the secretion of these cytokines.



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  		FIGURE 2. Mean granuloma size vs IFN-{gamma} production by SEA-stimulated MLN cells for each of the (CBA x BL/6) F2 mice. Shown p value is from a linear regression analysis with logarithmic transformation of granuloma size data.

 


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  		FIGURE 3. IL-2, IL-5 and IL-10 production by SEA-stimulated MLN cells from CBA, BL/6, F1, and F2 mice. IL-2 (A), IL-5 (B), and IL-10 (C) production by SEA-stimulated MLN cells from the same 8-wk-infected CBA, BL/6, (CBA x BL/6)F1 and (CBA x BL/6)F2 mice was measured by ELISA as detailed in Materials and Methods. Bars represent mean cytokine levels of triplicate determinations ± SEM pertaining to each mouse group.

 
We next performed a linkage analysis to elucidate the genetic loci associated with the observed phenotypes. A linkage to granuloma size was noted close to the marker D13Mit3 on chromosome 13 (position, 10 cM; LOD 2.2; Fig. 4A), which appeared to be CBA recessive (Fig. 4B). CBA/CBA F2 mice exhibited the largest granuloma size, with a mean of 12.36 µm2 x 10–4, compared with the CBA/BL6 mice with a mean size of 10.79 µm2 x 10–4, and the BL6/BL6 mice with a mean size of 10.04 µm2 x 10–4 (Fig. 4B).



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  		FIGURE 4. Mapping of susceptibility loci for granulomatous inflammation. A, Mapmaker was used to interval-map susceptibility loci for granuloma size. Indicated on the x-axis are the chromosomal positions (cM). One marker was mapped with an LOD score of 2.2, with a peak linkage around 10 cM. B, Granuloma size segregated according to the genotype at the peak locus D13Mit3: CBA/CBA (n = 14); CBA/BL6 (n = 34); or BL6/BL6 (n = 14). Average granuloma size was calculated for each individual mouse before pooling. Each bar represents mean granuloma size ± SEM. Shown p value is from posttest analyses.

 
Increased in vitro IFN-{gamma} production showed linkage to D1Mit151 on chromosome 1 (position, 101 cM; LOD 2.6) and to D5Mit81 on chromosome 5 (position, 28 cM; LOD 3.2), as illustrated in Figs. 5, A and B. Whereas the locus on telomeric chromosome 1 was inherited in a dominant manner (Fig. 5C), the locus on chromosome 5 was CBA recessive (Fig. 5D). There appeared to be an epistatic interaction between these two loci because mice that were CBA/CBA or CBA/BL6 at D1Mit151 (i.e., CBA dominant) and CBA/CBA at D5Mit81 (i.e., CBA recessive) exhibited the highest levels of IFN-{gamma} production. Hence, increased genetic load was clearly associated with a more pronounced IFN-{gamma} production in response to SEA. Interestingly, mice that possessed both loci for high IFN-{gamma} (Fig. 6) also had a significantly larger granuloma size than the mice that lacked both loci (means, 11.59 µm2 x 10–4 vs 9.26 µm2 x 10–4; p < 0.01); however, their granuloma sizes were not significantly larger than those in mice that possessed only one high IFN-{gamma} locus (mean, 11.11 µm2 x 10–4) (data not shown), suggesting a recessive mode of inheritance.



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  		FIGURE 5. Mapping of susceptibility loci for IFN-{gamma} production by SEA-stimulated MLN cells. A and B, Mapmaker was used to interval-map susceptibility loci for IFN-{gamma} production by SEA-stimulated MLN cells. Indicated on the x-axis are the chromosomal positions (cM). Two markers were mapped with LOD scores 2.6 and 3.2, with peak linkages around 101 and 28 cM, respectively. C and D, Levels of IFN-{gamma} production (expressed in nanograms per milliliter) segregated according to the genotype at D1Mit151 (CBA/CBA (n = 13), CBA/BL6 (n = 31), BL6/BL6 (n = 18)) or the genotype at D5Mit81 (CBA/CBA (n = 12), CBA/BL6 (n = 34), or BL6/BL6 (n = 15)). Each bar represents mean IFN-{gamma} levels ± SEM. Shown p values are from posttest analyses.

 


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  		FIGURE 6. Epistatic interaction between loci on chromosomes 1 and 5 dictates IFN-{gamma} production by SEA-stimulated MLN cells. IFN-{gamma} production by SEA-stimulated MLN cells observed in the different genotype groups segregated according to genotypes at D1Mit151 and D5Mit81. Each bar represents mean IFN-{gamma} levels ± SEM. Shown p values are from posttest analyses.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Despite the presence of a well-established murine model of schistosomiasis mansoni, the genetic basis of previously observed strain differences in immune response pattern (22, 23) or immunopathology (9, 10) has not been formally investigated. This is the first report elucidating the genetic basis of murine schistosomiasis based on the analysis of an F2 progeny resulting from the cross between a high (CBA) with a low (BL/6) pathology mouse strain. Our results showed that the F2 progeny displayed intermediate levels of pathology and SEA-induced IFN-{gamma} production. Although both of these parameters were closer to the lower end of the spectrum determined by the parental strains (Fig. 1), there was a significant correlation between granuloma size and SEA-induced IFN-{gamma} levels (Fig. 2). This observation suggests that a more prominent immunopathology takes place in a cytokine environment with a relatively enhanced Th1 component; however, it does not mean that IFN-{gamma} plays a direct pathogenic role. Rather, the egg-induced inflammation is the product of a complex series of biological events launched by the initial SEA-specific CD4+ T cell response and subsequently conducted and regulated by pro- vs anti-inflammatory signals involving numerous cytokines and chemokines.

According to Lander and Kruglyak (28), our genetic analysis demonstrated that of the two regions controlling IFN-{gamma} levels, there was only a "suggestive" linkage with the locus in chromosome 1, but a strong, nearly "significant/promising" linkage with the locus in chromosome 5 (Fig. 5). The implicated interval on chromosome 1 contains several candidate genes such as Adprt1, which plays a key role in immune reactions, and Tlr5, which is a member of a group of Toll-like receptors involved in the activation of the immune system in response to various pathogens that has been frequently implicated in murine autoimmunity (27, 33, 34, 35, 36, 37, 38). This locus corresponds to a region on human chromosome 1, ~30 Mb apart from the D1S498 marker and ~60 Mb from the D1S252 marker, that demonstrated linkage (p ~ 0.01 and p ~ 0.0001, respectively) with infection levels by S. mansoni in humans (39). In the case of chromosome 5, the identified interval has been linked with Lyme arthritis, collagen vascular diseases, and colitis (40, 41, 42, 43, 44, 45), as well as susceptibility to Listeria infection (46). The genetic analysis also localized suggestive linkage with granuloma formation to centromeric chromosome 13 (Fig. 4). This region is in close proximity (~2–3 cM) to genes of the serpin family of protease inhibitors (e.g., serpinb1c, serpinb6b, serpinb9), which serve to control deleterious proteolytic cascades in various physiologically important systems (47). Additionally, this region has been implicated in wound healing, as well as in neutrophil infiltration (48, 49).

The genetic basis of disease variation in human schistosomiasis has been the subject of several studies. On the one hand, disease severity in infection with the three pathogenic schistosome species (S. mansoni, Schistosoma japonicum, and Schistosoma hematobium) has been linked with a variety of HLA haplotypes (14, 15, 17, 21). On the other, a region outside the MHC on chromosome 5q31-q33, containing the SM1 gene, has been found to control disease susceptibility vs resistance in terms of intensity of infection (16, 39, 50); this region includes a cluster of cytokine/cytokine receptor genes that influence the outcome of immune responses against pathogens. Schistosome Ag-reactive T cell clones, derived from individuals homozygous for the allele that determines susceptibility, tended to be of the Th0/Th1 type, whereas those derived from individuals homozygous for the resistance allele, tended to be of the Th0/Th2 type (19). This observation is in agreement with field reports suggesting that the more severe clinical presentations of human schistosomiasis, including the acute form of schistosomiasis, tend to correlate with a cytokine balance tilted in the Th1 direction (51, 52, 53, 54, 55, 56).

In sum, our study in murine schistosomiasis revealed at least three genetic regions influencing the levels of granulomatous inflammation (hepatic fibrosis was not specifically analyzed) and SEA-elicited IFN-{gamma} response. These findings clearly indicate, as is the case in humans, that the control of murine immunopathology is polygenic. Although because of the limited cohort size our analysis has only led to suggestive linkages, it nevertheless has introduced an entirely novel genetic perspective into murine schistosomiasis, which paves the way for further congenic dissection studies to better understand the pathogenesis and high variability in magnitude of disease.


   Footnotes
 
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 National Institutes of Health Grants AI-18919 and AI-48736 (to M.J.S.) and by Agency for Healthcare Research and Quality Grant T32 HS00060 (to I.P.). Back

2 L.I.R., H.J.H., and Y.-S.Y. contributed equally to this work. Back

3 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 Back

4 Abbreviations used in this paper: SEA, schistosomal egg antigens; MLN, mesenteric lymph nodes; LOD, logarithm of the odds favoring linkage. Back

Received for publication August 6, 2004. Accepted for publication October 21, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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