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Infection and Immunity, July 2002, p. 3701-3706, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3701-3706.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Deletion of T Cells Bearing the Vß8.1 T-Cell Receptor following Mouse Mammary Tumor Virus 7 Integration Confers Resistance to Murine Cerebral Malaria

Unité d'Immunophysiopathologie Infectieuse (CNRS URA 1961),¹ Unité de Génétique des Mammifères (CNRS URA 1960), Département d'Immunologie, Institut Pasteur, 75724 Paris Cedex 15,³ INSERM U511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, CHU Pitié-Salpêtrière, 75643 Paris Cedex 13, France²

Received 30 October 2001/ Returned for modification 24 January 2002/ Accepted 25 March 2002

	ABSTRACT

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Plasmodium berghei ANKA induces a fatal neurological syndrome known as cerebral malaria (CM) in susceptible mice. Host genetic elements are among the key factors determining susceptibility or resistance to CM. Analysis of mice of the same H-2 haplotype revealed that mouse mammary tumor virus 7 (MTV-7) integration into chromosome 1 is one of the key factors associated with resistance to neurological disease during P. berghei ANKA infection. We investigated this phenomenon by infecting a series of recombinant inbred mice (CXD2), derived from BALB/c (susceptible to CM) and DBA/2 (resistant to CM) mice, with P. berghei ANKA. We observed differences in susceptibility to CM induced by this Plasmodium strain. Mice with the MTV-7 sequence in their genome were resistant to CM, whereas those without integration of this gene were susceptible. Thus, an integrated proviral open reading frame or similar genomic sequences may confer protection against neuropathogenesis during malaria, at least in mice.

	INTRODUCTION

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Cerebral malaria (CM) is a neurological syndrome caused by the asexual blood stage of Plasmodium falciparum in humans and Plasmodium berghei ANKA in experimental rodent models. Numerous parameters, such as the diversity of parasite populations and genetic polymorphisms in the vertebrate host, influence host-parasite interactions and pathogenesis during malaria infection (6, 22, 27, 29). It is important to increase our understanding of the mechanisms by which these factors contribute to the development of neuropathogenesis because CM continues to kill 2 to 2.5 million people annually, mostly children in areas where the parasite is endemic (2).

Several studies with humans have shown that host immunogenetic factors have a significant effect on susceptibility to severe forms of malaria (13, 20, 23). Genes encoding certain alleles of HLA molecules are known to be associated with protection against pathogenesis during malaria (14, 15). Alleles of the tumor necrosis factor alpha (TNF-) gene have also been shown to be associated with protection against severe malaria (21). TNF- plays a role in CM development by inducing the expression of adhesion molecules on the surface of endothelial cells of brain microvessels, leading to the sequestration of parasitized erythrocytes due to their cytoadhesion within the vascular system of the brain (7).

In experimental models, mice lacking interferon (IFN) regulatory factor-1 (IRF-1) have been found to be protected against death due to CM (24). IRF-1 has been associated with malarial neuropathogenesis via the high level of production of type-1 cell-derived cytokines such as TNF- and IFN- (8-12). Moreover, inbred mice with the same H-2 haplotype show various degrees of susceptibility to CM and can be divided into three categories: highly susceptible, such as B10.D2 mice; weakly susceptible, such as BALB/c mice; and resistant, such as DBA/2 mice. This suggests that H-2 locus does not play a predominant role in determining susceptibility or resistance to neuropathogenesis during malaria in the mouse model (4).

Attempts to estimate the relationship between the immune response and disease severity have shown that ßT cells play a direct role in the complex pathogenesis of malaria (4). In a previous study, we demonstrated that the development of neurological syndromes in B10.D2 mice infected with P. berghei ANKA was associated with an increase in the number of CD8Vß8.1⁺ and CD8Vß8.2⁺ T cells in peripheral blood. Strong evidence for a causal link between the expansion of populations of T cells bearing Vß8.1 and/or Vß8.2 and the pathological consequences of P. berghei ANKA infection has been provided by the significantly lower levels of CM observed in mice treated with a monoclonal antibody eliminating all populations of cells bearing T-cell-receptor (TCR) Vß8.1 and Vß8.2 chains. In addition, BALB.D2 mice, which are congenic for a mouse mammary tumor virus (MTV-7) that constitutively depletes Vß6, Vß7, Vß8.1, and Vß9 populations, is susceptible to P. berghei ANKA infection but does not develop CM (4).

The open reading frame in the 3' long terminal repeat of the MTV-7 provirus, which is integrated into chromosome 1 in several mouse strains, encodes a superantigen, Mls1^a. Like all superantigens, Mls1^a elicits a very powerful response from mature T cells bearing the appropriate TCR Vß chains, and during T-cell maturation in the thymus, this response results in clonal elimination or clonal inactivation of the responding cells (3, 28). Superantigens may therefore have significant deleterious effects on the T-cell repertoire in the periphery (19).

These observations indicate that there is an association between the presence of certain TCR-restricted lymphocyte subpopulations and the development of neuropathogenesis in experimental models of malaria. In the present study, we identified a specific example of such an association based on the observation that BALB/c mice (MTV-7^-) are susceptible to CM induced by P. berghei ANKA clone 1.49L, whereas BALB.D2 and DBA/2 mice (MTV-7⁺) are resistant. We analyzed the susceptibility and/or resistance to CM of various recombinant inbred (RI) lines of the CXD2 series derived from BALB/c x DBA/2 crosses to investigate the possible role of MTV-7 integration in determining susceptibility or resistance to CM.

	MATERIALS AND METHODS

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Mice. We used 6- to 8-week-old male and female mice of various CXD2 RI (n > 20) lines: (CXD2) D (n = 32), (CXD2) E (n = 30), (CXD2) F (n = 23), (CXD2) J (n = 10), (CXD2) K (n = 25), (CXD2) L (n = 26), and (CXD2) N (n = 22). These lines were developed and maintained at the Pasteur Institute (5). Eight-week-old BALB/c J Rj and DBA/2 mice were obtained from Janvier (Le Genest St. Isle, France) and Charles River (Les Elboeuf, France), respectively.

Parasites and induction of cerebral malaria. Erythrocytic stages of clone 1.49L of P. berghei ANKA strain, kindly provided by D. Walliker (Institute of Genetics, Edinburgh, United Kingdom), were maintained in C57BL/6 mice. This clone was selected for its great capacity to induce CM, with neurological signs (ataxia, paralysis, deviation of the head, and convulsion) appearing 6 to 8 days after infection (1). Blood stages of the clone were used as stabilates (10⁷ parasitized red blood cells [pRBC]/ml in Alsever's solution supplemented with 10% glycerol) stored in liquid nitrogen. CM was induced by the intraperitoneal injection of 10⁶ PbA-infected RBCs (pRBCs). Parasitemia was monitored by evaluating daily blood smears for parasites after Giemsa staining.

Southern blotting. Genomic DNA samples were isolated from the tail (25), and Southern blot analysis was carried out as previously described (16). Probes were derived from MMTV-C3H (18) and consisted of a 1.8-kb BglII/HindIII fragment encompassing the 3' long terminal repeat and a 2.3-kb HindIII/BglII fragment encompassing the env region.

Antibodies and flow cytometry. Fluorescein isothiocyanate-conjugated monoclonal antibodies specific for the mouse CD3 chain (145-2C11) and biotin-conjugated monoclonal antibodies against various Vß TCR families (Vß4 [KT4]; Vß6 [44-22-1]; Vß7 [RM4415]; Vß8.1,2 [KJ16]; Vß8.1, Vß8.2, and Vß8.3 [F23.1]; and Vß9 [MR10]) were produced in the laboratory.

Lymphocyte preparation and staining. Peripheral blood lymphocytes (PBL) were isolated from uninfected control mice by centrifugation in Ficoll-Hypaque (Pharmacia) and washed twice with 3% fetal calf serum (Gibco-BRL) in phosphate-buffered saline. For cytofluorometry, lymphocytes were incubated first with biotinylated monoclonal antibody directed against the various Vßs and subsequently with anti-CD3 fluorescein-labeled monoclonal antibody in the presence of phycoerythrin-conjugated streptavidin. Analysis was carried out with a FACScan cytofluorometer (Becton Dickinson, Grenoble, France) and CellQuest software. Viable lymphocytes were gated on the basis of light scattering (FSC/SSC) and for all Vß analyses (5,000 to 10,000 events were acquired and recorded per sample). The percentage of fluorescent cells was determined by integrating profiles according to the number of viable lymphocytes.

Statistical analysis. Statistical analysis was carried out with StatView version 4.5 software. Kaplan-Meier tests were used to assess survival. Differences between the survival curves of MTV-7⁺ and MTV-7^- mice were analyzed by the Logrank (Mantel-Cox) test. P values of <0.05 were considered to be significant. Parasitemia is expressed as the mean percentage of all erythrocytes that were infected.

	RESULTS AND DISCUSSION

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Malaria induced by P. berghei ANKA in susceptible mice typically presents neurological signs (ataxia, paralysis, deviation of the head, and convulsions), which appear 6 to 13 days after infection. In a previous study, we showed that mice of the same major histocompatibility complex haplotype (H-2^d)—B10.D2, BALB/c, and DBA/2—displayed different phenotypes in terms of susceptibility to neuropathogenesis induced by intraperitoneal infection with 10⁶ P. berghei ANKA-parasitized erythrocytes. All of the B10.D2 mice and 40% of the BALB/c mice were susceptible to CM, whereas DBA/2 mice presented a resistant phenotype (4). We also demonstrated that the immunopathogenesis of CM in susceptible H-2^d mice was associated with the expansion before death of a restricted T-cell subpopulation bearing Vß8.1 or Vß8.2 receptor chains. Strong evidence supporting the existence of a link between the increase in number of T cells bearing the Vß8.1 or Vß8.2 segment and the pathological consequences of P. berghei ANKA infection was provided by the observation that the incidence of CM was significantly lower in BALB.D2 mice congenic for MTV-7, resulting in the depletion of Vß8.1⁺ T cells through the open reading frame superantigen and in the (BALB.D2 x B10.D2)F₁ mice (4). We investigated whether MTV-7 was sufficient to induce resistance to CM by using (CXD2) RI strains derived from BALB/c mice bearing MTV-6, -8, and -9 (susceptible to CM) and DBA/2 mice bearing MTV-1, -6, -7, -8, -11, -13, -14, and -17 (resistant to CM). We determined the MTV integration profile in the various (CXD2) RI strains by Southern blotting (Fig. 1). Of the seven strains analyzed, only the (CXD2) E and F strains had not inherited the MTV-7 locus (Table 1). The Mtv-7 gene encodes a superantigen known to deplete all T-cell subpopulations bearing TCR Vß6, Vß7, Vß8.1, and Vß9 (26). We therefore assessed the ability of MTV-7 to act as a superantigen by analyzing the TCR Vß repertoire of PBL by flow cytometry to detect the clonal depletion of cells bearing the reactive TCR Vßs. We observed a loss of TCR Vß6-, Vß7-, Vß8.1-, and Vß9-bearing T cells among the PBL of the (CXD2) D, J, K, L, and N mouse strains, all of which are MTV-7⁺. In contrast, we observed no depletion in (CXD2) E and F mice, which are MTV-7^- (Fig. 2). We also analyzed neuropathogenesis in the various (CXD2) RI strains after intraperitoneal inoculation with 10⁶ P. berghei ANKA-infected erythrocytes. Only (CXD2) E and F mice remained as susceptible to CM as their relative BALB/c parents, whereas (CXD2) D, N, J, K, and L mice displayed a resistant phenotype similar to that of DBA/2 mice (Fig. 3). All of the mice that developed CM died 7 to 13 days after parasite inoculation; these mice displayed 10 to 15% parasitemia and severe neurological symptoms associated with CM, including hemiplegia and coma. The resistance to neuropathogenesis of MTV-7⁺ CXD2 mice does not seem to be directly due to resistance to infection by the parasite, since we observed no significant difference in susceptibility, as shown by the parasitemia curves of the CXD2 strains during the first 2 weeks of infection (Fig. 4). We also observed no correlation between the level of parasitemia and neuropathogenesis. The mice that escaped CM died 20 days later from anemia due to hyperparasitemia.

View larger version (31K): [in this window] [in a new window]   FIG. 1. Profiles of MTV integration in the various (CXD2) RI strains. Genomic DNA was digested with EcoRI, subjected to electrophoresis in a 0.7% agarose gel, and Southern blotted. The membrane was then probed with envelope (A) or long terminal repeat (B) probes. Lambda HindIII DNA was used as a molecular mass marker.

View larger version (16K): [in this window] [in a new window]   FIG. 2. Fluorescence-activated cell sorting analysis of PBL from the various (CXD2) RI strains. Data indicate the mean percentage ± the standard deviation of Vß+ cells among CD3+ cells from two separate experiments. Mice (n = 3) were tested individually for each RI strain.

View larger version (23K): [in this window] [in a new window]   FIG. 3. Kaplan-Meier graph of survival from CM of (CXD2) RI strains of mice. All mice were infected intraperitoneally with 106 P. berghei ANKA clone 1.49L pRBCs. Neurological manifestations appeared 7 to 13 days after parasite inoculation. Mice that escaped CM died 20 to 28 days after inoculation from anemia due to hyperparasitemia. Results for BALB/c (n = 20), DBA/2 (n = 19), (CXD2) D (n = 17), (CXD2) E (n = 20), (CXD2) F (n = 8), (CXD2) J (n = 7), (CXD2) K (n = 23), and (CXD2) N (n = 8) mice are shown. The results were obtained from two separate experiments.

View larger version (29K): [in this window] [in a new window]   FIG. 4. Parasitemia curve for the various (CXD2) RI strains of mice infected with P. berghei ANKA clone 1.49L. Results for BALB/c (n = 20), DBA/2 (n = 19), (CXD2) D (n = 17), (CXD2) E (n = 20), (CXD2) F (n = 8), (CXD2) J (n = 7), (CXD2) K (n = 23), and (CXD2) N (n = 8) mice are shown. The results are expressed as the mean parasitemias per day for two separate experiments.

View larger version (23K): [in this window] [in a new window]   FIG. 5. Frequency of CM in MTV-7+ and MTV-7- (CXD2) RI mice. The results are expressed as the percent occurrence of CM in MTV-7+ (n = 115) and MTV-7- (n = 53) mice.

View larger version (15K): [in this window] [in a new window]   FIG. 6. Parasitemia curve for MTV-7+ (n = 63) and MTV-7- (n = 20) RI mice infected with P. berghei ANKA clone 1.49L. The results are expressed as the mean percentage of erythrocytes infected from two separate experiments. D13, day 13 after parasite inoculation.

In agreement with results presented here and our results demonstrating that the development of CM in H-2^d haplotype (B10.D2) mice is correlated with an increase of PBL bearing Vß8.1 TCR before death and that all mouse strains lacking Vß8.1⁺ T cells due to antibody depletion or deletion and anergy resulting from superantigen activity are resistant to CM (4), we therefore conclude that MTV-7, whether provided endogenously or exogenously, is sufficient to confer resistance to CM in laboratory mice strains with the H-2^d haplotype via the deletion of Vß8.1⁺ cells. It is still unclear how Vß8⁺ cells affect neuropathogenesis. These cells may release IFN- and TNF, two major mediators of malaria pathogenesis, by inducing the expression of adhesion molecules on the endothelial cells of brain capillaries responsible for the sequestration of infected erythrocytes, leukocytes, and monocytes (27).

MTV has also been shown to protect against pathogenesis in Leishmania major infection. The mice of most inbred strains are resistant to infection by L. major, whereas the BALB/c strain is unable to control the infection and develops progressive disease. In this experimental model, Vß4V8 TCR⁺ CD4 T cells have been demonstrated to be responsible for the early burst of interleukin-4 involved in the Th2 response that confers susceptibility to disease (17). Moreover, it has been shown that BALB/c mice infected with MMTV-SIM, resulting in the depletion of cells expressing Vß4 TCR, become specifically resistant to infection by L. major, whereas BALB/c mice infected with MMTV-SW, resulting in the depletion of Vß6⁺ T cells, do not become resistant.

In conclusion, this study, as well as previously published data (4), provides a defined genetic and cellular basis for susceptibility and resistance in experimental murine CM involving modification of the T-cell repertoire by depletion of a precise T-cell subset. Future studies should seek to determine the underlying mechanism and, perhaps most important of all, whether similar mechanisms operate in P. falciparum infection in humans.

	ACKNOWLEDGMENTS

 
We thank Jack Formentin and Maurel Tefit for animal care, Monique Bauzou for parasite detection on blood smears, Danièle Voegtle for excellent technical assistance, and Wendy Houssin for help in preparing the manuscript.

This work was supported by the "Programme de Recherche Fondamentale en Microbiologie Maladies Infectieuses et Parasitaires" from the French Ministry of Research and was conducted as part of the CNRS Laboratoire Européen Associé "Génétique et Développement de la Tolérance Naturelle." M.I.B. was supported by the Institut Lilly. S.B. is a recipient of a fellowship from the Fondation pour la Recherche Médicale. S.P. and P.-A.C. were recipients of the Visiting Scientist fellowship from the FCT (Portugal).

O.G. and A.E. contributed equally to this study.

	FOOTNOTES

 
* Corresponding author. Mailing address: Unité d'Immunophysiopathologie Infectieuse, Département d'Immunologie, 25 Rue du Dr Roux, 75724 Paris Cedex 15, France. Phone: 33-1-40-61-35-75. Fax: 33-1-40-61-30-66. E-mail: spied{at}pasteur.fr.

Editor: S. H. E. Kaufmann

	REFERENCES

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1.	Amani, V., M. I. Boubou, S. Pied, M. Marussig, D. Walliker, D. Mazier, and L. Rénia. 1998. Cloned lines of Plasmodium berghei ANKA differ in their abilities to induce experimental cerebral malaria. Infect. Immun. 66:4093-4099.[Abstract/Free Full Text]
2.	Bagot, S., M. I. Boubou, S. Campino, C. Behrschmidt, O. Gorgette, J.-L. Guénet, C. Penha-Gonçalves, D. Mazier, S. Pied, and P.-A. Cazenave. 2002. Susceptibility to experimental cerebral malaria induced by Plasmodium berghei ANKA in inbred mouse strains recently derived from wild stock. Infect. Immun. 70:2049-2056.[Abstract/Free Full Text]
3.	Beutner, U., W. N. Frankel, M. S. Cote, J. M. Coffin, and B. T. Huber. 1992. Mls-1 is encoded by the long terminal repeat open reading frame of the mouse mammary tumor provirus Mtv-7. Proc. Natl. Acad. Sci. USA 89:5432-5436.[Abstract/Free Full Text]
4.	Boubou, M. I., A. Collette, D. Voegtle, D. Mazier, P. A. Cazenave, and S. Pied. 1999. T-cell response in pathogenesis: selective increase in T cells carrying the TCR Vß8 during experimental cerebral malaria. Int. Immunol. 11:1553-1562.[Abstract/Free Full Text]
5.	Cazala, P., and J. L. Guenet. 1980. Recombinant inbred strains: a tool for the genetic analysis of differences observed in the self-stimulation behavior of the mouse. Physiol. Behav. 24:1057-1060.[CrossRef][Medline]
6.	Clark, I. A., W. B. Cowden, and K. A. Rockett. 1994. The pathogenesis of human cerebral malaria. Parasitol. Today 10:417-423.[CrossRef][Medline]
7.	Clark, I. A., and K. A. Rockett. 1994. The cytokine theory of human cerebral malaria. Parasitol. Today 10:410-412.[CrossRef][Medline]
8.	Clark, I. A., K. M. Gray, E. J. Rockett, W. B. Cowden, K. A. Rockett, A. Ferrante, and B. B. Aggarwal. 1992. Increased lymphotoxin in human malarial serum, and the ability of this cytokine to increase plasma interleukin-6 and cause hypoglycemia in mice: implications for malarial pathology. Trans. R. Soc. Trop. Med. Hyg. 86:602-607.[CrossRef][Medline]
9.	Grau, G. E., L. F. Fajardo, P. F. Piguet, B. Allet, P. H. Lambert, and P. Vassalli. 1987. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 237:1210-1212.[Abstract/Free Full Text]
10.	Grau, G. E., T. E. Taylor, M. E. Molyneux, J. J. Wirima, P. Vassalli, M. Hommel, and P. H. Lambert. 1989. Tumor necrosis factor and disease severity in children with falciparum malaria. N. Engl. J. Med. 320:1586-1591.[Abstract]
11.	Grau, G. E., H. Heremans, P. F. Piguet, P. Pointaire, P. H. Lambert, A. Billiau, and P. Vassalli. 1989. Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor. Proc. Natl. Acad. Sci. USA 86:5572-5584.[Abstract/Free Full Text]
12.	Grau, G. E., P. F. Piguet, P. Vassalli, and P. H. Lambert. 1989. Tumor-necrosis factor and other cytokines in cerebral malaria: experimental and clinical data. Immunol. Rev. 112:49-70.[CrossRef][Medline]
13.	Hill, A. V. 1992. Malaria resistance genes: a natural selection. Trans. R. Soc. Trop. Med. Hyg. 86:225-226.[CrossRef][Medline]
14.	Hill, A. V., C. E. Allsopp, D. Kwiatkowski, N. M. Anstey, P. Twumasi, P. A. Rowe, S. Bennett, D. Brewster, A. J. McMichael, and B. M. Greenwood. 1991. Common West African HLA antigens are associated with protection from severe malaria. Nature 352:595-600.[CrossRef][Medline]
15.	Hill, A. V., A. Jepson, M. Plebanski, and S. C. Gilbert. 1997. Genetic analysis of host-parasite coevolution in human malaria. Philos. Trans. R. Soc. Lond. B 352:1317-1325.[CrossRef][Medline]
16.	Jouvin-Marche, E., N. S. Trede, A. Bandera, A. Tomas, D. Y. Loh, and P. A. Cazenave. 1989. Different large deletions of T-cell receptor Vß genes in natural populations of mice. Eur. J. Immunol. 19:1921-1928.[Medline]
17.	Launois, P., I. Maillard, S. Pingel, K. G. Swihart, I. Xenarios, H. Acha-Orbea, H. Diggelmann, R. M. Locksley, H. R. MacDonald, and J. A. Louis. 1997. IL-4 rapidly produced by Vß48CD4+ T cells instruct Th2 development and susceptibility to Leishmania major in BALB/c mice. Immunity 6:541-549.[CrossRef][Medline]
18.	Majors, J. E., and H. E. Varmus. 1983. Nucleotide sequencing of an apparent proviral copy of env mRNA defines determinants of expression at the mouse mammary tumor virus env gene. J. Virol. 47:498-504.
19.	Marrack, P., G. M. Winslow, Y. Choi, M. Scherer, A. Pullen, J. White, and J. W. Kappler. 1993. The bacterial and mouse mammary tumor virus superantigens; two different families of proteins with the same functions. Immunol. Rev. 131:79-92.[CrossRef][Medline]
20.	Mazier, D., J. Nitcheu, and M. Idrissa Boubou. 2000. Cerebral malaria and immunogenetics. Parasite Immunol. 22:613-623.[CrossRef][Medline]
21.	McGuire, W., A. V. Hill, C. E. Allsopp, B. M. Greenwood, and D. Kwiatkowski. 1994. Variation in the TNF- promoter region associated with susceptibility to cerebral malaria. Nature 371:508-510.[CrossRef][Medline]
22.	Miller, L. H., M. F. Good, and G. Milon. 1994. Malaria pathogenesis. Science 264:1878-1882.[Abstract/Free Full Text]
23.	Miller, L. H. 1994. Impact of malaria on genetic polymorphism and genetic diseases in Africans and African Americans. Proc. Natl. Acad. Sci. USA 91:2415-2419.[Abstract/Free Full Text]
24.	Senaldy, G., C. L. Shaklee, J. Guo, L. Martin, T. Boone, W. T. Mak, and T. R. Ulich. 1999. Protection against the mortality associated with disease models mediated by TNF and IFN- in mice lacking IFN regulatory factor-1. J. Immunol. 163:6820-6826.[Abstract/Free Full Text]
25.	Towbin, J. A. 1993. Introduction to the techniques of molecular biology. Herz 18:213-221.[Medline]
26.	Waanders, G. A., A. N. Shakhov, W. Held, O. Karapetian, H. Acha-Orbea, and H. R. MacDonald. 1993. Peripheral T-cell activation and deletion induced by transfer of lymphocyte subsets expressing endogenous or exogenous mouse mammary tumor virus. J. Exp. Med. 177:1359-1366.[Abstract/Free Full Text]
27.	White, N. J., and M. Ho. 1992. The pathophysiology of malaria. Adv. Parasitol. 31:83-132.[Medline]
28.	Winslow, G. M., M. T. Scherer, J. W. Kappler, and P. Marrack. 1992. Detection and biochemical characterization of the mouse mammary tumor virus 7 superantigen (Mls-1a). Cell 71:719-730.[CrossRef][Medline]
29.	World Health Organization. 1990. Severe and complicated malaria. Trans. R. Soc. Trop. Med. Hyg. 84:1-6.

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