IL-17A/F in Leishmania major-resistant C57BL/6 mice.

Proinflammatory IL-17 plays an important role in various diseases and defence against extracellular microorganisms. Healing of leishmaniasis is promoted by Th1/Tc1 cells, whereas Th2/Treg are associated with worsened disease outcome. In addition, high expression of IL-17A in Leishmania-susceptible BALB/c and artificial overexpression of IL-17A in T cells in resistant C57BL/6 mice worsened disease outcome. Since C57BL/6 mice lacking only IL-17A exhibited no phenotype, and IL-17A and IL-17F share similar receptors, but differentially regulate chemokine secretion, we studied mice lacking both IL-17A and IL-17F (IL-17A/F-/- ) in infections with Leishmania major. Interestingly, lesion volumes and parasite burdens were comparable to controls, IL-17A/F-/- mice developed a Th1/Tc1 phenotype, and exhibited normal lesion resolution. Thus, in C57BL/6 mice, secretion of IL-17A and IL-17F does not influence disease progression. It appears that-depending on the genetic background-cytokines of the IL-17 family might be responsible for disease progression primarily in susceptible mice.

Mast cells as protectors of health.

Mast cells (MCs), which are well known for their effector functions in TH2-skewed allergic and also autoimmune inflammation, have become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs, such as the skin or gut. MCs can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T-cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focuses on the beneficial effects of MCs on tissue homeostasis and elimination of toxins or venoms. MCs can enhance pathogen clearance in many bacterial, viral, and parasitic infections, such as through Toll-like receptor 2-triggered degranulation, secretion of antimicrobial cathelicidins, neutrophil recruitment, or provision of extracellular DNA traps. The role of MCs in tumors is more ambiguous; however, encouraging new findings show they can change the tumor microenvironment toward antitumor immunity when adequately triggered. Uterine tissue remodeling by α-chymase (mast cell protease [MCP] 5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in central nervous system trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, proteases, such as carboxypeptidase A, released by FcεRI-activated MCs detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MCs will help improve these advantageous effects and hint at ways to cut down detrimental MC actions.

Insufficient generation of Th17 cells in IL-23p19-deficient BALB/c mice protects against progressive cutaneous leishmaniasis.

Healing of leishmaniasis-a parasitic skin disease-is associated with high levels of secreted interferon (IFN)γ and IL-12 in resistant C57BL/6 mice and humans. Susceptible BALB/c mice predominantly react with a Th17/Th2/Treg-related immune response and finally succumb to infection. Previously, we showed that BALB/c IL-17A-/- mice are protected against Leishmania (L.) major infections, indicating that IL-17A-predominantly produced by Th17 cells-plays an important role for disease outcome. We now investigated DC-derived cytokines and finally identified IL-23p19 as key cytokine responsible for induction of Leishmania-specific Th17 cells that play an important role for progressive disease in susceptible BALB/c mice.

In silico prediction of Leishmania major-specific CD8+ epitopes.

Infections with Leishmania (L.) major induce protective IFN-γ-dependent Th1/Tc1 immunity in C57BL/6 mice as well as in immunocompetent humans. Even though antigen-specific immunity provides lifelong immunity against reinfection, a vaccine against this pathogen does not yet exist. Here, we compared the results obtained from in silico predictions of murine CD8-specific L. major peptides using the algorithm SYFPEITHI with the number and predicted affinity of known proteins/peptides. Our results indicate that the majority of "immunodominant" epitopes of L. major have not been identified so far; thus, computer-based prediction algorithms may aid the development of an effective vaccine.

Myeloid cells do not contribute to gender-dependent differences in disease outcome in murine cutaneous leishmaniasis.

Gender-associated differences in the outcome of infections are well known. Apart from behavior-released differences in their incidence, immunological factors also contribute to disease outcome. The underlying mechanisms are often unknown. Here, we show that in murine experimental leishmaniasis, female mice develop larger skin lesions that harbor significantly more parasites, exhibit increased parasite dissemination to visceral organs associated with a shift towards T helper (Th) 2 immunity with increased levels of IL-4. Antigen presenting cells (APC) responsible for T cell priming, such as macrophages or dendritic cells, were not involved in the process. Additionally, in adoptive transfer experiments, we show that differences in the lymphoid lineage are also not critical for mediating these gender-dependent effects. In summary, neither myeloid nor lymphoid cells contribute to disease outcome against this important human pathogen, but stromal cells influenced by e.g. hormonal effects in addition to other parts of the immune system might play a role.

Animal model for cutaneous leishmaniasis.

Using cutaneous leishmaniasis of mice, the existence of so-called T helper (Th) cells type 1 and type 2 had been identified more than 20 years ago. Nowadays, it is well accepted that additional T cell populations as well as B cell-mediated immunity is required for immunity against Leishmania major. Finally, using inbred mouse strains, the relevance of genetical factors that influence anti-pathogen immunity as well as elements of the skin-immune system have been identified. This protocol describes a model for murine experimental leishmaniasis that tries to mimic natural parasite transmission by several means: (1) utilization of only infectious-stage parasites that are found in sand fly saliva, (2) intradermal inoculation, and (3) infection with only 1,000 parasites similar to the numbers inoculated by an infected sand fly.

Dendritic cells in Leishmania major infections: mechanisms of parasite uptake, cell activation and evidence for physiological relevance.

Leishmaniasis is one of the most important infectious diseases worldwide; a vaccine is still not available. Infected dendritic cells (DC) are critical for the initiation of protective Th1 immunity against Leishmania major. Phagocytosis of L. major by DC leads to cell activation, IL-12 release and (cross-) presentation of Leishmania antigens by DC. Here, we review the role of Fcγ receptor- and B cell-mediated processes for parasite internalization by DC. In addition, the early events after parasite inoculation that consist of mast cell activation, parasite uptake by skin-resident macrophages (MΦ), followed by neutrophil and monocyte immigration and DC activation are described. All these events contribute significantly to antigen processing in infected DC and influence resulting T cell priming in vivo. A detailed understanding of the role of DC for the development of efficient anti-Leishmania immunity will aid the development of potent anti-parasite drugs and/or vaccines.