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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