Keratinocytes Determine Th1 Immunity during Early Experimental Leishmaniasis

Abstract

Experimental leishmaniasis is an excellent model system for analyzing Th1/Th2 differentiation. Resistance to Leishmania (L.) major depends on the development of a L. major specific Th1 response, while Th2 differentiation results in susceptibility. There is growing evidence that the microenvironment of the early affected tissue delivers the initial triggers for Th-cell differentiation. To analyze this we studied differential gene expression in infected skin of resistant and susceptible mice 16h after parasite inoculation. Employing microarray technology, bioinformatics, laser-microdissection and in-situ-hybridization we found that the epidermis was the major source of immunomodulatory mediators. This epidermal gene induction was significantly stronger in resistant mice especially for several genes known to promote Th1 differentiation (IL-12, IL-1β, osteopontin, IL-4) and for IL-6. Expression of these cytokines was temporally restricted to the crucial time of Th1/2 differentiation. Moreover, we revealed a stronger epidermal up-regulation of IL-6 in the epidermis of resistant mice. Accordingly, early local neutralization of IL-4 in resistant mice resulted in a Th2 switch and mice with a selective IL-6 deficiency in non-hematopoietic cells showed a Th2 switch and dramatic deterioration of disease. Thus, our data indicate for the first time that epidermal cytokine expression is a decisive factor in the generation of protective Th1 immunity and contributes to the outcome of infection with this important human pathogen.

Osteopontin and allergic disease: pathophysiology and implications for diagnostics and therapy

“…One has to consider that these experiments were conducted with both BALB/c and C57BL/6 mice, which strongly differ with regard to their Th1/Th2 response. In accordance with this, these strains produce very different levels of OPN, with BALB/c mice producing only 30% of the OPN in C57BL/6 during infection [130]. However, much work remains to be done to further delineate the effects of OPN in allergic airway disease, taking into account that OPN may strongly affect not only DCs, but also T cells, which highly express OPN receptors and have been shown to respond to OPN by downmodulating IL-4 [102], but at the same time increasing IL-17 secretion [107].…”

Assessment of β-lapachone loaded in lecithin-chitosan nanoparticles for the topical treatment of cutaneous leishmaniasis in L. major infected BALB/c mice

“…braziliensis and L. infantum-chagasi [45], IL-1 production was irrelevant [46] or detrimental in early L. major infections and the effect should be mediated by Th2-bias adaptive immune response [47]. IL-1b was one of the genes significantly stronger up-regulated in resistant C57BL/6 mice vs susceptible BALB/c mice although the analysis was made from 16 h L. major infected mice [48]. Our study would indicate poor contribution of IL-1b in the chronic state of the infection.…”

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“…The way agents pathogens regulate the expression of CD200 is not clear [45]. (figure: 9) indicates, initiation of protective immunity Th1 against Leishmania [50], [51]. L'IL-4, IL-10 mediated activation of macrophage (M2) [52].…”