IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice

Biedermann, Tilo; Zimmermann, Stephan; Himmelrich, Hayo; Gumy, Alain; Egeter, Oliver; Sakrauski, Arne K.; Seegmüller, I.; Voigt, Heike; Launois, Pascal; Levine, Alan D.; Wagner, Hermann; Heeg, Klaus; Louis, Jacques; Röcken, Martin

doi:10.1038/ni725

Cited by 253 publications

(261 citation statements)

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“…This is in contrast to previously published observations made in the murine model using subcutaneous infection in the footpad, where a rapid and intense production of IL-4 was detected in the draining lymph nodes of BALB/c mice but not mice of resistant strains. 17,22,23 In addition, although cytokine producing cells were detected in the skin at 24 h by immunohistochemistry, a similar number of IL-4 producing cells was observed in both C57BL/6 and BALB/c mice. The discrepancy in the early IL-4 production may be related to the different model of infection used, since there is evidence that the route of infection may lead to different disease phenotypes and different cytokine profiles.…”

Section: Discussionmentioning

confidence: 90%

“…29 Another factor that may contribute significantly to the outcome of infection is the innate immune system and its interaction with the adaptive immune system. 23,31,32 This modified view was supported by examination of the expression of IL-4 and IFN-g in the lymph nodes at several time points between the two extremes of the early hours of initiation of infection and the late stages of established disease. In the case of IFN-g, there was a difference in expression based only on the background strain of the mouse tested.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is evidence that, paradoxically, the presence of IL-4 during the initial activation of dendritic cells may be required for the induction of Th1 immune responses. 23 The pivotal importance of IL-4 production for the establishment of a host protective or deleterious immune response to L. major has recently been re-examined, 3,25 and concludes that factors other than the conventional CD4 þ cells and their cytokines may contribute significantly to the disease phenotype. [26][27][28] One such factor may be the CD4 þ CD25 þ regulatory T cells that have recently been shown to be critically important to the establishment of infection in the BALB/c mice as well as to parasite persistence in the C57BL/6 mice.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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“…This seems to be relevant for Th1 cell-mediated skin inflammation in mice and in humans (2,8,36). Deviating Th1 responses into Th2 responses improved Th1 cellmediated inflammation and protected against inflammation-induced angiogenesis in mice and humans (36)(37)(38). Most importantly, Th1 cells seem to coevolve simultaneously with IL-17-producing Th17 cells (39); IL-17 is a cytokine with strong proangiogenic effects (40,41).…”

Section: Discussionmentioning

confidence: 98%

Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice

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Hültner

Pichler

et al. 2007

Arthritis & Rheumatism

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Objective. Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but isResults. Comparing wild-type mice, mast celldeficient Kit W /Kit W-v mice, and mast cell-reconstituted Kit W /Kit W-v mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and ␣v␤3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented ␣v␤3 integrin activation, angiogenesis, and joint destruction.Conclusion. Mast cell engraftment fully restores susceptibility to ␣v␤3 integrin activation, angiogenesis, and joint destruction in GPI antibody-induced arthritis. Importantly, selective mast cell stabilization prevents ␣v␤3 integrin activation, angiogenesis, and joint destruction.

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“…BALB/c produces T helper (Th)2-type cytokines, in particular IL-4, which has been shown to be associated with disease progression and susceptibility, 13 whereas recovery from infection in resistant C57BL/6 depends critically upon the induction of a Th1-type response resulting in the activation of macrophages to kill the intracellular organisms. 14,15 This has led to the intensive study of the regulators of the polarised Th1/Th2 helper T-cell responses by immunologists.…”

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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IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice

Cited by 253 publications

References 53 publications

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

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

Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice

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

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