Glucocorticoids and sympathetic neurotransmitters modulate the acute immune response to Trypanosoma cruzi.

Evidence suggests that natural and adaptive immune responses can trigger neuroendocrine responses. Here, we discuss changes in the activity of the hypothalamus-pituitary-adrenal axis and in autonomic nerves, predominantly of the sympathetic nervous system, in a mouse model of acute infection with Trypanosoma cruzi. The endocrine response includes a marked increased release of glucocorticoid and a decrease of immune-stimulatory hormones, such as dehydroepiandrosterone sulfate, prolactin, and growth hormone during infection. These endocrine changes result in reduced proinflammatory cytokine production, increased regulatory/effector T cell ratio, and thymus atrophy. The sympathetic activity in the spleen of infected mice is also markedly reduced. However, the residual sympathetic activity can modulate the immune response to the parasite, as shown by increased mortality and production of proinflammatory cytokines in sympathetically denervated, infected mice. The outcome of the neuroendocrine response is the moderation of the intensity of the immune response to the parasite, an effect that results in delayed mortality in susceptible mice, and favors the course toward chronicity in more resistant animals.

Amebic liver abscess in rat: morphological evidence of innate immune modulation by the sympathetic nervous system / Absceso hepático amebiano en rata: evidencia morfológica de la modulación de la respuesta inmune innata por el sistema nervioso simpático

All organs of the immune system are innervated and almost all neurotransmitter receptors are present on immune cells. We studied the effects of sympathetic innervation in the development of amebic liver abscess (ALA) in rats. Our results showed that lack of sympathetic innervation promote a decrease in size of ALA. We found scarce amoebas, increased the number of neutrophils and a few collagen fibers surrounding the abscess, meanwhile in control group, we observed abscesses areas with typical necrosis including trophozoites and neutrophils. Macrophages were differentially distributed surrounding abscess area in control and vehicle groups, but equally located in and outside of the abscesses in sympathectomized rat. No significant differences were observed on NK cells in analysed groups. In cytokines quantification studies, we observed down-expression of IFN-g and TNF-a, moreover, we found overexpression of IL-10 in sympathectomized and ALA group. In conclusion, our results suggest that elimination of sympathetic nerve fibers in a model rat of amebic liver abscess induces reduction of the innate immune response and presence of amebas through the liver at seven days post-inoculation.

Todos los órganos del sistema inmune están inervados y casi todos los receptores para neurotransmisores están presentes en las células de la respuesta inmune. Nosotros estudiamos el efecto de la inervación simpática en el desarrollo del Absceso Hepático Amebiano (AHA) en ratas. Nuestros resultados muestran que la inervación simpática promueve una disminución en el tamaño del AHA. Nosotros encontramos áreas fibróticas bien definidas con algunas amibas, mayor número de neutrófilos y pocas fibras de colágena rodeando el área de daño, mientras que en el grupo control, nosotros observamos áreas con necrosis, trofozoítos y pocos neutrófilos en el área fibrótica. Los macrófagos se observaron distribuidos en el área fibrótica en los animales simpatectomizados, mientras que en los controles encontramos a los macrófagos distribuidos en la periferia del absceso. No se encontró diferencia significativa en la distribución y cantidad de células NK. En el estudio de citocinas nosotros observamos una disminución de IFN-g y TNF-a y un incremento de IL-10 en animales simpatectomizados. En conclusión, nuestros resultados sugieren que la eliminación de las fibras del sistema nervioso simpático en el modelo de AHA en rata, reduce la respuesta inmune innata y persisten amebas en el tejido dañados a los 7 días post-inoculación.

Emerging evidence for the role of neurotransmitters in the modulation of T cell responses to cognate ligands.

Dendritic cells (DCs) are responsible of priming T cells and promoting their differentiation from naïve T cells into appropriate effector cells. Each different phenotype of effector T cells promotes the elimination of a determined kind of pathogen or tumour. Thus, DCs and T cells play critical roles on orchestrating adaptive immune responses against specific threats. Because of their fundamental functions at controlling immunity, DCs and T cells require tight regulatory mechanisms to ensure efficient, but safe, immune responses. Several studies have shown that neurotransmitters, in addition to mediate interactions into the nervous system, can contribute to the modulation of immunity by promoting the communication between nervous and immune systems and in the interaction between different immune cells. Due to the pivotal role that the DC-T cell interaction plays in the development and regulation of adaptive immune responses, it is important to understand how the function of these cells may be regulated by neurotransmitters. Here, we review the emerging role of neurotransmitters as regulators of DC and T cell physiology and also how these molecules, by acting on the DC-T cell interaction, may modulate the fate of T cells and, therefore, the nature of the adaptive immune response. Moreover, we discuss how alterations on the neurotransmitter-mediated immune regulatory mechanisms can contribute to the onset of immune-related disorders. In addition, we discuss potential new targets for the design of strategies for therapies against tumours, autoimmunity and neuro-immune related diseases.

Role of neurotransmitter autoantibodies in the pathogenesis of chagasic peripheral dysautonomia.

Chagas' disease is caused by a parasite, Trypanosoma cruzi, which is widely distributed in South and Central America. Dysautonomias, derangements of sympathetic and parasympathetic nervous system function, are seen fairly often during the chronic course of Chagas' disease. Many infected subjects developed, in the course of the disease, neurogenic cardiomyopathy or digestive damage. Our investigations show the existence of circulating antibodies in Chagas' disease that bind to beta-adrenergic and muscarinic cholinergic receptor (mAChR). The neurotransmitter receptor-autoantibody interaction triggers in the cells intracellular signal transductions that alter the physiological behavior of the target organs, leading to tissue damage. Moreover, the deposit of autoantibodies behaving as agonists induces desensitization and/or down regulation of the receptors. This in turn can lead to a progressive blockade of them with sympathetic and parasympathetic denervation. Using synthetic peptides for immunoblotting and enzyme immunoassay, we demonstrated that these autoantibodies reacted against the second extracellular loop of the human heart beta 1 adrenoceptor and M2 cholinoceptor. Also, the corresponding affinity-purified antipeptide antibodies displayed an agonist-like activity associated with specific receptor activation. A strong association between circulating antipeptide M2 mAChR autoantibodies and the presence of patients' low heart rate variability index, bradycardia and cardiac or esophageal autonomic dysfunction in chronic chagasic patients was verified. This fact make these antipeptide antibodies a proper marker of cardiac neuromyopathy and achalasia.