A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis.

To determine the role that the IL-4/IL13 receptor plays in the development of alternatively activated macrophages (AAM or M2) and their role in the regulation of immunity to the extraintestinal phase of the helminth parasite Taenia crassiceps, we followed the infection in a mouse strain lacking the IL-4Rα gene (IL-4Rα-/-) and in the macrophage/neutrophil-specific IL-4Rα-deficient mouse strain (LysMcreIL-4Rα-/lox or cre/LoxP). While 100% of T. crassiceps-infected IL-4Rα+/+ (WT) mice harbored large parasite loads, more than 50% of th eIL-4Rα-/- mice resolved the infection. Approximately 88% of the LysMcreIL-4Rα-/lox mice displayed a sterilizing immunity to the infection. The remaining few infected cre/LoxP mice displayed the lowest number of larvae in their peritoneal cavity. The inability of the WT mice to control the infection was associated with antigen-specific Th2-type responses with higher levels of IgG1, IL-4, IL-13, and total IgE, reduced NO production, and increased arginase activity. In contrast, IL-4Rα-/- semi-resistant mice showed a Th1/Th2 combined response. Furthermore, macrophages from the WT mice displayed higher transcripts for Arginase-1 and RELM-α, as well as increased expression of PD-L2 with robust suppressive activity over anti-CD3/CD28 stimulated T cells; all of these features are associated with the AAM or M2 macrophage phenotype. In contrast, both the IL-4Rα-/- and LysMcreIL-4Rα-/lox mice did not fully develop AAM or display suppressive activity over CD3/CD28 stimulated T cells, reducing PDL2 expression. Additionally, T-CD8+ but no T-CD4+ cells showed a suppressive phenotype with increased Tim-3 and PD1 expression in WT and IL-4Rα-/-, which were absent in T. crassiceps-infected LysMcreIL-4Rα-/lox mice. These findings demonstrate a critical role for the IL-4 signaling pathway in sustaining AAM and its suppressive activity during cysticercosis, suggesting a pivotal role for AAM in favoring susceptibility to T. crassiceps infection. Thus, the absence of these suppressor cells is one of the leading mechanisms to control experimental cysticercosis successfully.

Crowding of anterior teeth and bullying in schoolchildren / Apiñamiento de dientes anteriores y bullying en escolares

Objective: To compare the crowding of anterior teeth in schoolchildren with and without experience of bullying. Materials and Methods: A prospective, cross-sectional, comparative and observational study was conducted in two educational institutions, one public and one private; The sample consisted of 218 schoolchildren between 11 and 16 years of age. Dental crowding was evaluated in the upper and lower anterior sector using Little's irregularity index. To diagnose bullying, a previously validated questionnaire was applied, with dichotomized questions. The comparison between crowding in patients with and without experience of bullying was evaluated with the U-Mann Whitney statistical test. Results:Statistically significant differences in the amount of crowding (p<0.05) were found. The average crowding for the group subjected to bullying was 11.6 +/- 9.4 mm and in the group without bullying was 9.1+/- 7.9 mm. Conclusion: There was a higher amount of dental crowding in schoolchildren subjected to bullying compared to schoolchildren with no bullying.

Objetivo: Comparar el apiñamiento de dientes anteriores en escolares con y sin experiencia de acoso escolar (bullying). Material y Métodos: Se realizó un estudio prospectivo, transversal, comparativo y observacional en dos instituciones educativas, una pública y otra privada; La muestra estuvo conformada por en 218 escolares entre 11 y 16 años de edad. El apiñamiento dental se evaluó en el sector anterior superior e inferior utilizando el índice de irregularidad de Little. Para diagnosticar acoso escolar, se aplicó un cuestionario validado previamente, con preguntas dicotomizadas. La comparación entre el apiñamiento en pacientes con y sin experiencia de acoso escolar se evaluó con la prueba estadística U-Mann Whitney. Resultados: Se encontraron diferencias estadísticamente significativas la cantidad de apiñamiento (p<0.05). El apiñamiento promedio para el grupo sometido a acoso escolar fue de 11.6 +/- 9.4 mm y en el grupo sin acoso escolar fue de 9.1 +/- 7.9 mm. Conclusion: Hubo un mayor grado de apiñamiento dental en los escolares sometidos al acoso escolar en comparación con los escolares sin acoso escolar.

Taenia crassiceps infection attenuates multiple low-dose streptozotocin-induced diabetes.

Taenia crassiceps, like other helminths, can exert regulatory effects on the immune system of its host. This study investigates the effect of chronic T. crassiceps infection on the outcome of Multiple Low Dose Streptozotocin-Induced Diabetes (MLDS). Healthy or previously T. crassiceps-infected mice received MLDS and type 1 diabetes (T1D) symptoms were evaluated for 6 weeks following the induction of MLDS. T. crassiceps-infected mice displayed lower blood glucose levels throughout the study. A significantly lower percentage of T. crassiceps-infected mice (40%) developed T1D compared to the uninfected group (100%). Insulitis was remarkably absent in T. crassiceps-infected mice, which had normal pancreatic insulin content, whereas uninfected mice showed a dramatic reduction in pancreatic insulin. Infected mice that received MLDS did not show an increase in their regulatory T cell population, however, they had a greater number of alternatively activated macrophages, higher levels of the cytokine IL-4, and lower levels of TNF-alpha. Therefore, infection with T. crassiceps causes an immunomodulation that modifies the incidence and development of MLDS-induced autoimmune diabetes.

Nitric oxide contributes to host resistance against experimental Taenia crassiceps cysticercosis.

The immune mechanisms that underlie resistance and susceptibility to cysticercosis are not completely understood. In this paper, using susceptible BALB/c mice and resistant STAT6-/-BALB/c mice, we have analyzed the role of nitric oxide (NO) in determining the outcome of murine cysticercosis caused by the cestode Taenia crassiceps. After T. crassiceps infection, wild-type BALB/c mice developed a strong Th2-like response, produced high levels of IgG1, IgE, IL-5, IL-4, and discrete levels of NO, and remained susceptible to T. crassiceps infection. In contrast, similarly infected BALB/c mice treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NO synthase) mounted a similar immune response but with lower levels of NO and harbored nearly 100% more parasites than N(omega)-nitro-D-arginine methyl ester (D-NAME, inactive enantiomer)-treated mice. To further analyze the role of NO in murine cysticercosis, we treated STAT6-/-male mice (known to be highly resistant to T. crassiceps) with L-NAME during 8 weeks of infection. As expected, STAT6-/-mice mounted a strong Th1-like response, produced high levels of IgG2a, IFN-gamma, and IL-17, whereas their macrophages displayed increased transcripts of tumor necrosis factor (TNF)-alpha as well as inducible nitric oxide synthase (iNOS) and efficiently controlled T. crassiceps infection. However, STAT6-/-male mice receiving L-NAME mounted a similar immune response but with lower iNOS transcripts concomitantly with decreased levels of NO in sera and displayed significantly higher parasite burdens. These findings suggest that macrophage activation and NO production are effector mechanisms that importantly contribute in host resistance to T. crassiceps infection. The immune mechanisms that underlie resistance and susceptibility to cysticercosis are not completely understood. In this paper, using susceptible BALB/c mice and resistant STAT6-/-BALB/c mice, we have analyzed the role of nitric oxide (NO) in determining the outcome of murine cysticercosis caused by the cestode Taenia crassiceps. After T. crassiceps infection, wild-type BALB/c mice developed a strong Th2-like response, produced high levels of IgG1, IgE, IL-5, IL-4, and discrete levels of NO, and remained susceptible to T. crassiceps infection. In contrast, similarly infected BALB/c mice treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NO synthase) mounted a similar immune response but with lower levels of NO and harbored nearly 100% more parasites than N(omega)-nitro-d-arginine methyl ester (D-NAME, inactive enantiomer)-treated mice. To further analyze the role of NO in murine cysticercosis, we treated STAT6-/-male mice (known to be highly resistant to T. crassiceps) with L-NAME during 8 weeks of infection. As expected, STAT6-/-mice mounted a strong Th1-like response, produced high levels of IgG2a, IFN-gamma, and IL-17, whereas their macrophages displayed increased transcripts of tumor necrosis factor (TNF)-alpha as well as inducible nitric oxide synthase (iNOS) and efficiently controlled T. crassiceps infection. However, STAT6-/-male mice receiving L-NAME mounted a similar immune response but with lower iNOS transcripts concomitantly with decreased levels of NO in sera and displayed significantly higher parasite burdens. These findings suggest that macrophage activation and NO production are effector mechanisms that importantly contribute in host resistance to T. crassiceps infection.

Acute cysticercosis favours rapid and more severe lesions caused by Leishmania major and Leishmania mexicana infection, a role for alternatively activated macrophages.

Parasitic helminths have developed complex mechanisms to modulate host immunity. In the present study we found that previous infection of mice with the cestode Taenia crassiceps favours parasitemia and induces larger cutaneous lesions during both Leishmania major and Leishmania mexicana co-infections. Analysis of cytokine responses into draining lymph nodes indicated that co-infection of T. crassiceps-Leishmania did not inhibit IFN-gamma production in response to Leishmania antigens, but significantly increased IL-4 production. Additionally, anti-Leishmania-specific IgG1 antibodies and total IgE increased in co-infected mice, whereas, IgG2a titers remained similar. Macrophages from Taenia-infected mice displayed increased mRNA transcripts of arginase-1, Ym1, and Mannose Receptor, as well as greater production of urea (all markers for an alternate activation state) compared to macrophages from Leishmania-infected mice. In contrast, lower mRNA transcripts for IL-12p35, IL-12p40, IL-23p19, and iNOS were detected in macrophages obtained from cestode-infected mice compared to uninfected and Leishmania-infected mice after LPS stimulation. The presence of cestode also generated impaired macrophage anti-leishmanicidal activity in vitro, as evidenced by the inability of these macrophages to prevent Leishmania growth compared to macrophages from uninfected mice. This was observed despite the fact that both groups of cells were exposed to IFN-gamma. Flow cytometry showed high IFN-gammaR expression on Taenia-induced macrophages. Thus, lack of response to IFN-gamma is not associated with the absence of its receptor. Our data suggest that cestode infection may favour Leishmania installation by inducing alternatively activated macrophages rather than inhibiting Th1-type responses.

Macrophage migration inhibitory factor contributes to host defense against acute Trypanosoma cruzi infection.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is involved in the host defense against several pathogens. Here we used MIF-/- mice to determine the role of endogenous MIF in the regulation of the host immune response against Trypanosoma cruzi infection. MIF-/- mice displayed high levels of blood and tissue parasitemia, developed severe heart and skeletal muscle immunopathology, and succumbed to T. cruzi infection faster than MIF+/+ mice. The enhanced susceptibility of MIF-/- mice to T. cruzi was associated with reduced levels of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin-12 (IL-12), IL-18, gamma interferon (IFN-gamma), and IL-1beta, in their sera and reduced production of IL-12, IFN-gamma, and IL-4 by spleen cells during the early phase of infection. At all time points, antigen-stimulated splenocytes from MIF+/+ and MIF-/- mice produced comparable levels of IL-10. MIF-/- mice also produced significantly less Th1-associated antigen-specific immunoglobulin G2a (IgG2a) throughout the infection, but both groups produced comparable levels of Th2-associated IgG1. Lastly, inflamed hearts from T. cruzi-infected MIF-/- mice expressed increased transcripts for IFN-gamma, but fewer for IL-12 p35, IL-12 p40, IL-23, and inducible nitric oxide synthase, compared to MIF+/+ mice. Taken together, our findings show that MIF plays a role in controlling acute T. cruzi infection.

Carbohydrate components of Taenia crassiceps metacestodes display Th2-adjuvant and anti-inflammatory properties when co-injected with bystander antigen.

Common helminth infections promote Th2-skewed immune responses in their hosts. We have studied the role of intact carbohydrate structures on Taenia crassiceps compounds in the induction of biased type 2 and anti-inflammatory immune responses on peptide-stimulated T cells by using DO11.10 transgenic (OVA Tg) mice. While OVA Tg mice co-injected with OVA peptide (323-339) (OVA(323-339)) plus intact Taenia soluble antigens (iTSA) displayed significantly higher titers of OVA-specific IgG1 and total IgE, low amounts of these antibodies were detectable in sera from OVA Tg mice co-injected with OVA(323-339) plus periodate-carbohydrate altered TSA (paTSA). Spleen cells from OVA Tg mice failed to efficiently produce OVA-specific IFN-gamma but displayed higher IL-4, IL-5 and IL-10 production when they received OVA(323-339) plus iTSA, compared with OVA Tg mice similarly co-injected with OVA(323-339) plus paTSA. Moreover, after in vivo stimulation with OVA(323-339) plus iTSA, spleen cells did show elevated mRNA transcripts for Arginase 1, Ym1, IL-4, IL-10, TGF-beta, and Mannose Receptor (MR) genes, all them associated with Th2-type and anti-inflammatory responses. Similar results were obtained using TLR4 mutant mice. Together these findings suggest that carbohydrate components in TSA are involved in modulating immune responses to bystander antigens and that do not signal via TLR4.