Stress in the regulation of the immune response in Leishmaniasis
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Presentacion en la Rede Leish vacina de CYTED, Salvador, Bahia, Brasil 21-09-09
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Stress in the regulation of the immune response in Leishmaniasis
- 1. Stress in the regulation of the immune response in Leishmaniasis Felix J. Tapia Instituto de Biomedicina Facultad de Medicina Universidad Central de Venezuela Reuniäo Cyted 2009 Projecto Mecanismo de controle e imunoprofilaxia na Leishmaniose Faculdade de Medicina da Bahia (FAMEB)
- 2. Neuroendocrine-immune axis Diffuse neuroendocrine system Peripheral Immune system Bioactive Polypeptides hormones neuropeptides cytokines Molecules of communication
- 3. Murine models of American cutaneous Leishmaniasis C57BL/6 BALB/c Th1 IFN- Th2 IL-4 L. mexicana MHOM/BZ/82/BEL21 Sánchez et al. Acta Micros 1993, 2: 180-187 Aguilar-Torrentera et al. Am J Trop Med Hyg 2002, 66: 273–279 Díaz et al. Clin Exp Dermatol 2003, 28: 288-293
- 4. Sensory peptides: Calcitonin gene-related peptide (CGRP) Substance (Sub P) mediators of neurogenic inflammation Epidermal dendritic (Langerhans) cells: Skin take up and antigen processing Peripheral lymphoid organs initiate primary T cell responses Leishmania infection of BALB/c and C57BL/6 mice : 10 3 amastigotes L. mexicana strain MHOM/BZ/82/BEL21 Course of infection 12 weeks Sites of evaluation
- 6. Phases of Cutaneous Regulation Activation Inmunostimulation Effector Phase Challenging Antigen Capture Migration Antigen Presentation Clonal Expansion Recruitment Retention Proliferation Suppression
- 7. epidermis dermis Mo ganglio linfático endotelio vascular C T T Mo ag .. . granuloma IL-4 mastocyte IFN- NK M Φ IL-12 T memory QC CL GM-CSF IL-1 TNF- chemokines
- 9. Acute stressor (2, 8 hrs): Immobilization by placement in 50 ml polypropylene centrifuge tubes, before inoculation of Leishmania parasites. Materials and methods Stress procedure
- 10. BALB/c C57/BL6 Measurement footpad thickness every week for 12 weeks Mice stressed for 2 hr and infected with L. mexicana Mice stressed for 8 hr and infected with L. mexicana Mice infected with L. mexicana Infection Control Mice stressed for 2 hr and non-infected with L. mexicana Stress Control (n=20) (n=20) (n=20) (n=20) (n=20) (n=20) (n=20) (n=20) Experimental design Footpad biopsies taken at weeks 0, 4 and 8 after infection Cryopreservation Immunodetection of CD205+ Langerhans cells, CGRP and Sub P
- 11. Progression of L. mexicana infection in experimental groups of BALB/c and C57BL/6 mice 0 1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 Weeks of i infec tio n Size of lesi o n i n mm 0 1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 2hr stress healthy 2hr stress infect ed 8hr stress infect ed Non-stressed infect ed
- 12. Langerhans cell density in experimental groups of BALB/c and C57BL/6 at weeks O, 4 and 8 0.0 4.0 8.0 12.0 0 250 500 750 1000 2hr stress healthy 2hr stress infect ed 8hr stress infec ed Non-stressed infect ed 0 1000 2000 0 sem 4 sem 8 sem Weeks of infec tion c ells /mm 2
- 13. Progression of infection with L. mexicana in BALB/c mice subjected to acute stress
- 14. Langerhans cells Ia d + in separated epidermis of BALB/c mice infected with L. mexicana Non stressed Stressed for 2 hr
- 15. Substance P in skin lesions of BALB/c mice stressed and infected with L. mexicana week 4 - stressed for 8 hr Vascular edothelium infiltrate
- 18. Odorant inhalation stress in resistant and susceptible mouse models of cutaneous leishmaniasis
- 19. Acute stressor (48 hrs): Inhalation of citral for 48 hours. At 24 hrs of stress, mice were infected Leishmania mexicana Materials and methods Stress procedure
- 20. Odorant inhalation stress alters the immune response in resistant and susceptible mice infected with L. mexicana
- 21. Odorant inhalation stress alters the immune response in resistant and susceptible mice infected with L. mexicana
- 22. Odorant inhalation stress alters the immune response in resistant and susceptible mice infected with L. mexicana
- 23. Conclusions Citral inhalation stress induces clinical and immunological alterations in the natural course of infection in mice inoculated with L. mexicana. These alterations include decreased numbers of dendritic Langerhans cells and their morphological, and downregulation of Th1 and Th2 cytokines in both resistant and susceptible mice. Only IL-12 and iNOS remained in normal values. The results indicate that citral inhalation suppress the immune response against the Leishmania parasite regardless the genetic background of the host.
- 24. Macrophages treated by sera from mice sressed and infected with L. mexicana 24 hours , Giemsa
- 25. 1 3 5 9 11 0 100 200 BALB/c stressed & infect BALB/c infect Weeks of infection Density of DC-SIGN positive cells in lesions of stressed and L.mexicana -infected BALB/c mice c ells /mm 2
- 26. 1 3 5 9 11 0 1000 2000 3000 BALB/c infectado y estresado BALB/c infectado * * * * Density of macrophages MOMA-2 positive cells in lesions of stressed and L.mexicana -infected BALB/c mice * p 0.05 Weeks of infection c ells /mm 2
- 27. TLR-2 positive cells in BALB/c mice stressed and infected with L. mexicana 5 weeks 1 3 5 9 11 0 100 200 300 BALB/c stressed & infect BALB/c infect Weeks of infection c ells /mm 2
- 28. 1 3 5 9 11 0 100 200 BALB/c stressed & infect BALB/c infect * Weeks of infection TLR- 4 positive cells in BALB/c mice stressed and infected with L. mexicana 5 weeks * p 0.05 c ells /mm 2
- 29. CD14 positive cells in BALB/c mice stressed and infected with L. mexicana 5 weeks 1 3 5 9 11 0 100 200 300 BALB/c stressed & infect BALB/c infect Weeks of infec tion c ells /mm 2
- 30. 1 3 5 9 11 0 100 200 TLR- 9 positive cells in BALB/c mice stressed and infected with L. mexicana 5 weeks Weeks of infection BALB/c stressed & infect BALB/c infect c ells /mm 2
- 31. Laboratorio de Biología Molecular Instituto de Biomedicina Estudiantes: Ysamar Chirinos Alba Quiñones María del Rosario Ruiz Fabiola Cabrera María Alejandra Sarabia Eliana Figueira Mónica Fernández Adriana Arbeláez Celsy Hernández Alejandra Da Almeida Pedro Salazar María García Izaskun Urdanibia Laboratorio: Nilka L. Díaz Iraima B. Monsalve Mónica Suárez Miguel Marzal Luis González Colaboradores: Martín A. Sánchez Zelandia Fermín Ladys Sarmiento
- 33. American cutaneous leishmaniasis C57BL/6 IFN- BALB/c IL-4 LCL Intermediate forms MCL CCL DCL C BA IFN / IL-4
Notes de l'éditeur
- The neuroendocrine immune axis comprise s the diffuse neuroendocrine system and the peripheral immune system. The skin is an important component of the peripheral immune system characterized by a common communication language governed by bioactive polypeptides termed neurotransmitters, hormones or cytokines by the different specialists.
- In order to understand some of the mechanisms that modulate the immune response in cutaneous leishmaniasis. W e have evaluate d the effect of acute stress on the natural course of experimental murine leishmaniasis, by analyzing: Langerhans cells , which are mobile antigen-presenting cells that take up and process antigen in the skin, and migrate to peripheral lymph organs where they stimulate naïve T cells, thus initiating primary T cell responses. Sensory peptide s , the principal mediators of neurogenic inflammation, a term first used to describe the contribution of sensory peptides to local cutaneous inflammatory processes, are calcitonin gene-related peptide (CGRP) and Substance P (Sub P). In two models of cutaneous leishmaniasis using susceptible BALB/c mice and resistant C57BL7/6 mice inoculated with Leishmania mexicana .
- Leer diapositiva Background Langerhans cells are involved in the pathogenesis of cutaneous leishmaniasis. Epidermal cell signaling is essential to determine the type of cytokine-related immune response to be generated against Leishmania parasites. Langerhans cells, Sub stance P and CGRP are affected by acute stress in contact hypersensitivity models.
- Leer diapositiva The objective of the study was to a nalyze the effect of acute immobilization stress on Langerhans cells, Sub stance P, CGRP, and the natural course of infection in susceptible and resistant mouse models of cutaneous leishmaniasis.
- Mice were exposed for 2 or 4 hours to a single homotypic stressor just before the inoculation of Leishmania parasites. The stressor consisted of immobilization by placement in restraining cages made from 50 ml centrifuge tubes. Control animals were maintained in standard cages. During stress regimen animals had no access to food and water.
- The experimental animals (susceptible or resistant) were divided into the following groups: 1) Mice placed under immobilization stress for 2 hours before infection with Leishmania mexicana . 2) Mice placed under immobilization stress for 8 hours before infection with Leishmania mexicana . 3) Mice only infected with Leishmania mexicana (Infection control) 4) Mice placed under immobilization stress for 2 hours (Stress control). The course of Leishmania infection was determined by measuring the footpad thickness during 12 weeks . Langerhans cells on separated epidermis were characterized using an antibody against the molecule DEC-205 . Sensory innervation was characterized by immunocytochemistry and specific monoclonal antibodies to CGRP and Substance P
- This slide shows the progression of Leishmania infection by measuring footpad thickness during disease evolution. For both graphs, in GREEN the natural course of infection (Infection control), in BLACK mice under stress for 2 hours, in RED mice under stress for 8 hours, and in GREY mice under stress for 2 hours (Stress control). In susceptible BALB/c mice (LEFT GRAPH), stressed animals became more susceptible to infection, manifested by acceleration and exacerbation of lesions. In contrast, resistance C57BL/6 mice (RIGHT GRAPH), mice under stress for 8 hours showed an early appearance of the lesion with a subsequent fall in lesion size as compared with non-stressed infected mice.
- Stressed and infected BALB/c mice showed a decrease in Langerhans cells density, which was more prominent in those mice stressed for 8 hours In contrast, stressed and infected C57BL/6 mice showed an increase in Langerhans cells, which was more prominent in those mice stressed for 8 hours.
- The photo on the left, sho w ed Langerhans cells in normal non-stressed mice, whereas on the right , cells from stressed animal presented rounded cell bodies and shortened dendrites, when compared to non-stressed infected mice.
- When compared to normal non-stressed mice, s usceptible BALB/c under stress for 8 hours before infection showed greater and antidromic immunoreactivity to Sub stance P at the time of infection . In contrast, resistant C57BL/6 mice under stress for 8 hours before infection showed an increase of Sub stance P induced by the infection that started to decrease after the eighth week (not shown) .
- Leer diapositiva Conclusions Acute immobilization stress affects the numbers and function of Langerhans cells and Substance P and CGRP innervations. T he skew of the skin immune response after stress and infection may be diverted by epidermal accessory signals to distinct Th1 or Th2 responses in resistant or susceptible mice, respectively. The genetic background of the mouse strain determined the response to acute stress in murine leishmaniasis.
- Mice were exposed for 2 or 4 hours to a single homotypic stressor just before the inoculation of Leishmania parasites. The stressor consisted of immobilization by placement in restraining cages made from 50 ml centrifuge tubes. Control animals were maintained in standard cages. During stress regimen animals had no access to food and water.
- Merci Thanks Gracias
- In the Americas, cutaneous leishmaniasis includes immune-responder individuals with acute or localized cutaneous leishmaniasis (LCL) and non-responder individuals with disseminated or diffuse cutaneous leishmaniasis (DCL). The intermediate area of the clinical spectrum comprise s chronic cutaneous leishmaniasis ( C CL) characterized by single or multiple lesions with atypical development and by plaques with many ulcers, and mucocutaneous leishmaniasis (MCL). In mice, depending on the animal strain, it has been possible to reproduce the distinct clinical forms observed in humans. Thus, C57BL/6 mice are resistant and BALB/c mice are susceptible to Leishmania infection.