Susceptibility to Leishmania major infection in mice: multiple loci and heterogeneity of immunopathological phenotypes

Lipoldová, Marie; Svobodová, Milena; Krulová, Magdaléna; Havelková, Helena; Badalová, Jana; Nohýnková, Eva; Holáň, Vladimı́r; Hart, Andrew; Volf, Petr; Démant, Peter

doi:10.1038/sj.gene.6363660

Cited by 75 publications

(79 citation statements)

References 34 publications

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“…These regions were assumed to have no effect in our system, as they have not been implicated in any genetic study of response to L. major infection. [8][9][10][11][12] Many comparisons were made between the different groups of mice in these experiments. We have employed a rigorous and honest statistical approach, carefully choosing levels of significance taking into account project-wide multiple testing.…”

Section: Discussionmentioning

confidence: 99%

“…7 This has hampered the identification of individual genes affecting the phenotype. Whereas linkage has been found in different studies to loci on chromosomes 5, 6, 9, 10, 11, 15, 17 and X, [8][9][10][11][12] so far only a single locus on chromosome 11 has been confirmed as playing a role in response to disease in L. major-infected mice. 9 In addition to work carried out on the genetics of host response to L. major, this system has long fascinated immunologists because a marked polarisation in the immune response is observed upon challenge with L. major parasites.…”

Section: Introductionmentioning

confidence: 99%

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Leishmaniasis host response loci (lmr1–3) modify disease severity through a Th1/Th2-independent pathway

et al. 2003

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Leishmaniasis host response loci (lmr1–3) modify disease severity through a Th1/Th2-independent pathway

et al. 2003

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“…6 Studies are underway in many laboratories to map the genes that determine susceptibility to leishmaniasis in the expectation that they may help identify mechanisms of polarisation of the T helper cell responses. Although linkage to L. major response phenotypes has been mapped to loci on chromosomes 5, 6, 9, 10, 11, 15, 17 and X, [7][8][9][10][11] the relationship between these loci and the control of the polarisation of T cell responses in response to L. major has not been determined.…”

Section: Introductionmentioning

confidence: 99%

Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

et al. 2004

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Severity of disease caused by Leishmania major depends on the genetics of the host. Early induction of T helper cell type 1 (Th1)-type responses in resistant C57BL/6 mice and T helper cell type 2 (Th2) in susceptible BALB/c mice is thought to determine cure or disease respectively. We have mapped three loci that confer susceptibility or resistance upon congenic mice on the C57BL/6 or BALB/c backgrounds. Here we examine the histopathology and production of interleukin 4 (IL-4) and interferon gamma (IFN-g) in the skin and draining lymph nodes in the congenic and parental mice. We show an evolving granuloma with a staged infiltration of inflammatory cells, but no difference between the groups. As an indication of an earlypolarised Th1/Th2 response we measured IFN-g and IL-4 in the lymph nodes and found no difference between any of the mice during the first 48 h. During infection, the level of IL-4 correlated with the lesion size, indicating that IL-4 reflects the disease severity rather than controls it. Considering this effect, B6.C(lmr1,lmr2) mice had similar cytokine levels to the parental C57BL/ 6 mice despite increased susceptibility and C.B6(lmr1,lmr2) were similar to BALB/c despite increased resistance. We conclude that the lmr loci affect disease severity by a mechanism independent of conventional helper T-cell responses. Genes and Immunity (2004) IntroductionThe first demonstration that the balance of T helper cell responses determines the severity of the pathology in an infectious disease model came from studies on murine cutaneous leishmaniasis caused by infection with Leishmania major. A large number of studies have shown that susceptibility to disease in BALB/c mice correlated with the dominance of interleukin 4 (IL-4)-driven T helper cell type 2 (Th2)-type responses, while resistance in C57BL/6 mice correlated with the dominance of interferon gamma (IFN-g)-driven T helper cell type 1 (Th1) responses. 1,2 However, as pointed out by Sacks and Noben-Trauth, 3 the simplicity of this model has begun to be challenged. For example, there are data indicating that IL-4 is not sufficient to mediate progressive disease, 4 nor is it essential for the induction of Th2 responses 5 and ablation of IL-4 or IL-4 signaling in BALB/c mice does not necessarily lead to resistance. 6 Studies are underway in many laboratories to map the genes that determine susceptibility to leishmaniasis in the expectation that they may help identify mechanisms of polarisation of the T helper cell responses. Although linkage to L. major response phenotypes has been mapped to loci on chromosomes 5, 6, 9, 10, 11, 15, 17 and X, 7-11 the relationship between these loci and the control of the polarisation of T cell responses in response to L. major has not been determined.We used a genome-wide scan on two large populations of F2 mice created from a cross between the susceptible BALB/c and the resistant C57BL/6 strains, and showed that susceptibility to disease caused by intradermal infection at the base of the tail with L. major is controlle...

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“…14 RC strains may be especially useful in analysis of relationships of different components of complex traits, such as susceptibility to infections. 15,16 In our previous work we have analyzed the genetic basis of the response to different alloantigens by the strains BALB/cHeA (BALB/c) and STS/A (STS), STS being a high and BALB/c a low responder to all alloantigens tested. Subsequently, the response of 20 BALB/c-c-STS/Dem (CcS/Dem) RC strains was tested.…”

Section: Introductionmentioning

confidence: 99%

A new type of genetic regulation of allogeneic response. A novel locus on mouse chromosome 4, Alan2 controls MLC reactivity to three different alloantigens: C57BL/10, BALB/c and CBA

et al. 2000

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The intensity of the mixed lymphocyte response (MLR) depends on the genetic disparity between the donors of responding and stimulating cells. Differences in the major histocompatibility complex (MHC) and Mls1 antigens induce the strongest responses. However, even with comparable incompatibilities in MHC and Mls antigens, some strains of genetically defined mice respond remarkably better than other strains. Apparently other, so far undefined, genetic factors contribute to the magnitude of the MLR. The strain OcB-9 (H2 pz ) has 87.5% genes from the strain O20/A (O20) and 12.5% genes from strain B10.O20 (both H2 pz ). In spite of the overal similarity of their genomes, OcB-9 mice differed from O20 mice in response to three different alloantigens C57BL/10 (H2 b ), BALB/c (H2 d ) and CBA (H2 k ). As both O20 and OcB-9 strains carry identical haplotype H2 pz , their differences in alloantigen response depend only on non-MHC genes. We analyzed the genetic basis of these strain differences using (OcB-9 × O20)F 2 hybrids, and we mapped a novel locus Alan2 (Alloantigen response 2) on chromosome 4 near D4Mit72 that influences the response to all alloantigens tested. This linkage was significant for C57BL/10 and for BALB/c alloantigens (corrected P values 0.0475 and 0.0158, respectively) and highly suggestive for CBA (corrected P = 0.0661). The response to DBA/1 (H2 q ) alloantigens exhibited a similar pattern but the linkage was not significant. As MLR reflects the recognition phase of transplantation reaction, identification of human counterparts of the Alan genes and a better understanding of the regulation of alloresponsiveness might lead to a better prediction of patients' reactions to allografts and to a more individualized measures to prevent rejection. Genes and Immunity (2000) 1, 483-487.

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Susceptibility to Leishmania major infection in mice: multiple loci and heterogeneity of immunopathological phenotypes

Cited by 75 publications

References 34 publications

Leishmaniasis host response loci (lmr1–3) modify disease severity through a Th1/Th2-independent pathway

Leishmaniasis host response loci (lmr1–3) modify disease severity through a Th1/Th2-independent pathway

Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

A new type of genetic regulation of allogeneic response. A novel locus on mouse chromosome 4, Alan2 controls MLC reactivity to three different alloantigens: C57BL/10, BALB/c and CBA

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