Exosites mediate the anti-inflammatory effects of a multifunctional serpin from the saliva of the tick Ixodes ricinus.

Serine protease inhibitors (serpins) are a structurally related but functionally diverse family of ubiquitous proteins. We previously described Ixodes ricinus immunosuppressor (Iris) as a serpin from the saliva of the tick I. ricinus displaying high affinity for human leukocyte elastase. Iris also displays pleotropic effects because it interferes with both the immune response and hemostasis of the host. It thus inhibits lymphocyte proliferation and the secretion of interferon-gamma or tumor necrosis factor-alpha by peripheral blood mononuclear cells, and also platelet adhesion, coagulation and fibrinolysis. Its ability to interfere with coagulation and fibrinolysis, but not platelet adhesion, depends on the integrity of its antiproteolytic reactive center loop domain. Here, we dissect the mechanisms underlying the interaction of recombinant Iris with peripheral blood mononuclear cells. We show that Iris binds to monocytes/macrophages and inhibits their ability to secrete tumor necrosis factor-alpha. Recombinant Iris also has a protective role in endotoxemic shock. The anti-inflammatory ability of Iris does not depend on its antiprotease activity. Moreover, we pinpoint the exosites involved in this activity.

Splenic dendritic cells pulsed with Ixodes ricinus tick saliva prime naive CD4+T to induce Th2 cell differentiation in vitro and in vivo.

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) in priming naive T cells. Using an in vitro priming system, we show that DCs incubated with Ixodes ricinus tick saliva initiate the T(h)2 differentiation of CD4(+)T cells. As determined with reverse transcription-PCR, the expression of IL-4 mRNA by these cells is higher than IFN-gamma mRNA. Early endogenous production of IL-4 is thought to be important during the in vitro interaction of saliva-pulsed DCs with CD4(+)T cells. Its neutralization with specific mAbs inhibits the development of IL-4-secreting T(h)2 cells. Moreover, differentiated T(h)2 cells proliferate only when saliva-pulsed DCs and IL-1beta are added together early in the primary culture. As demonstrated by FACS analysis, the treatment in vitro of saliva-pulsed DCs by IL-1beta enhanced the expression of B7 and mainly CD40 co-stimulatory molecules, which provide sufficient signals to stimulate sensitized CD4(+)T cell proliferation. On the other hand, DCs treated with tick saliva only up-regulated mostly B7-2 co-stimulator expression and this was associated with differentiation of naive CD4(+)T cells into T(h)2 type of cells. The in vitro priming system is suitable to investigate the major elements implicated in the anti-tick immune response such as naive CD4(+)T cells, whole DCs population and tick saliva, and it can provide the possibility to delimit further the saliva molecules, the DC subsets and the type of host cells involved in the T(h)2 polarization. Corresponding in vivo experiments involving subcutaneous injection of tick saliva-pulsed DCs into BALB/c mice also elicited a T(h)2 immune response. Ex vivo cultures of draining lymph node T cells stimulated with tick saliva produced higher IL-4 : IFN-gamma ratios compared with controls, confirming the relevance obtained in the in vitro priming model. These experiments demonstrate the importance of tick saliva in priming DCs to initiate a T(h)2-biased immune response in vitro and in vivo.

Historia del uso reciente de tierras de Las Sabanas de América del Sur: estudios de casos en Sabanas del Orinoco / Recent use history of South American Savannah Land: case studies in the Orinoco Savannahs

Las sabanas de Sudamérica con una superficie de 269×106ha extendidas en Brasil, Colombia, Venezuela, Guyana y Bolivia representan una de las mayores extensiones de tierra con potencial para la producción agrícola, constituyéndose en la principal alternativa para evitar la expansión agrícola hacia áreas de mayor fragilidad ecológica. Hasta hace unos 40 años estas sabanas estuvieron muy poco afectadas por la actividad antrópica, dedicándose principalmente a la ganadería extensiva. En los últimos 40 años las pasturas nativas de bajos requerimientos nutricionales están siendo reemplazadas por pastos africanos principalmente de los géneros Brachiaria y Andropogon. Igualmente, ha ocurrido una reforestación extensiva para producción de madera y papel con especies introducidas de Pinos y Eucaliptos que se adaptan muy bien a las condiciones agroclimáticas del trópico bi-estacional. La introducción de pastos y de cultivos anuales y perennes en sabanas ha sido posible solo, bajo un esquema de fertilización (N, P, K y encalado). Aunque las modificaciones al paisaje introducidas por los nuevos usos de la tierra son ahora en sitios alejados de los grandes centros urbanos y relativamente poco perceptibles, si se toma en consideración las grandes extensiones de tierras de sabanas que están siendo afectadas y las que lo serán por formar parte de proyectos agrícolas, será inevitable una modificación profunda de esos biomas. En este trabajo se hace una revisión preliminar comparativa del proceso de colonización agrícola en los llanos y cerrados. En la necesidad de generar indicadores ligados a los procesos biogeoquímicos afectados, se presentan tres estudios de casos para sabanas venezolanas

Characterization of a novel salivary immunosuppressive protein from Ixodes ricinus ticks.

In tick salivary glands, several genes are induced during the feeding process, leading to the expression of new proteins. These proteins are typically secreted in tick saliva and are potentially involved in the modulation of the host immune and hemostatic responses. In a previous study, the construction and the analysis of a subtractive library led to the identification of Ixodes ricinus immunosuppressor (Iris), a novel protein, differentially expressed in I. ricinus salivary glands during the blood meal. In the present study, the data strongly suggest that this protein is secreted by tick salivary glands into the saliva. In addition, Iris is also found to modulate T lymphocyte and macrophage responsiveness by inducing a Th2 type response and by inhibiting the production of pro-inflammatory cytokines. In conclusion, these results suggest that Iris is an immunosuppressor, which might play an important role in the modulation of host immune response.