RESUMO
BACKGROUND: The brain and the immune systems represent the two primary adaptive systems within the body. Both are involved in a dynamic process of communication, vital for the preservation of mammalian homeostasis. This interplay involves two major pathways: the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. SUMMARY: The establishment of infection can affect immunoneuroendocrine interactions, with functional consequences for immune organs, particularly the thymus. Interestingly, the physiology of this primary organ is not only under the control of the central nervous system (CNS) but also exhibits autocrine/paracrine regulatory circuitries mediated by hormones and neuropeptides that can be altered in situations of infectious stress or chronic inflammation. In particular, Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), impacts upon immunoneuroendocrine circuits disrupting thymus physiology. Here, we discuss the most relevant findings reported in relation to brain-thymic connections during T. cruzi infection, as well as their possible implications for the immunopathology of human Chagas disease. KEY MESSAGES: During T. cruzi infection, the CNS influences thymus physiology through an intricate network involving hormones, neuropeptides, and pro-inflammatory cytokines. Despite some uncertainties in the mechanisms and the fact that the link between these abnormalities and chronic Chagasic cardiomyopathy is still unknown, it is evident that the precise control exerted by the brain over the thymus is markedly disrupted throughout the course of T. cruzi infection.
Assuntos
Encéfalo , Doença de Chagas , Timo , Humanos , Doença de Chagas/imunologia , Doença de Chagas/fisiopatologia , Animais , Encéfalo/imunologia , Timo/imunologia , Timo/fisiologia , Trypanosoma cruzi/fisiologia , Trypanosoma cruzi/imunologia , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Neuroimunomodulação/fisiologia , Neuroimunomodulação/imunologia , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
BACKGROUND: Altered hypothalamic-pituitary-adrenal (HPA) function and related changes in circulating glucocorticoids have been implicated in the pathogenesis of numerous diseases that involve dysregulated immune function. Glucocorticoid hormones have both direct and indirect modulatory effects on both pro- and anti-inflammatory aspects of the immune system, including granulocytic and lymphocytic leukocyte subsets. However, past findings are complicated by inconsistencies across studies in how glucocorticoids and immune markers interact and relate to disease risk. Some incongruencies are likely due to an overreliance on single-unit (e.g., HPA or one immune marker) measures, and a failure to consider ecological exposures that may shape the base levels or correspondence between these systems. Here, we test single-unit and diurnal measures of HPA axis and immune system interactions in a less-industrial ecological setting with relatively high parasite loads. METHODS: In a sample of 114 Honduran women (mean age = 36 years), morning and evening blood samples were analyzed to quantify granulocytes, lymphocytes, and immunoglobulin-E (IgE). Saliva was collected over 2 days (8 samples per woman) to measure peak cortisol, cumulative cortisol, and slope of decline. These repeated measures of saliva and venous blood were used to investigate associations between single-point and diurnal salivary cortisol and leukocytes, under variable levels of past parasite exposure (proxied by IgE). RESULTS: Individuals with less of a decline in cortisol (i.e., "flatter" decline) show less of an increase in lymphocytes (2.27% increase in cells/µL/hr; 95% CI: 0.91-7.29; p = .01) across the day compared to those with steeper cortisol decline (7.5% increase in lymphocytes; 95% CI: 5.79-9.34; p < .001). IgE levels did not modify this association. Interestingly, IgE did moderate relationships between measures of cortisol and granulocytes: diurnal cortisol was positively associated with granulocytes, only in individuals with high previous exposure to parasites. There were no consistent relationships between single-unit measures of cortisol, lymphocytes or granulocytes, regardless of past parasite exposure. DISCUSSION: Results demonstrate that the relationship between HPA function and immune modulation cannot be fully understood without an understanding of local disease ecology. These results highlight the importance of research that seeks to identify etiologies of disease across environmental contexts.
Assuntos
Ritmo Circadiano/imunologia , Hidrocortisona , Leucócitos/imunologia , Doenças Parasitárias/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Honduras , Humanos , Hidrocortisona/sangue , Hidrocortisona/imunologia , Sistema Hipotálamo-Hipofisário/imunologia , Imunoglobulina E/sangue , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/imunologia , Saliva/química , Adulto JovemRESUMO
The serotonergic and immunological hypothesis of depression proposes that certain types of excessive stress distort the relationship between the activities of the innate immune and central nervous systems, so that the stress caused by an infection, or excessive psychological stress, activate toll-like receptors such as the TLR-4, the transcription factor NF-kB, the inflammasome NLRP3, as well as the secretion of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and other factors of the innate immune response, causing first, the general symptoms of the disease which appear with any infection, but also those characteristic of depressive illness such as dysphoria and anhedonia. The evidence indicates that, if the stimulus persists or recurs within 24 hours, the indole-2, 3-dioxygenase enzyme (IDO) of the kynurenine metabolic pathway, which increases the synthesis of quinolinic acid, is activated with an associated reduction of serotonin synthesis. Quinolinic acid activates NMDA receptors in the central nervous system and stimulates the secretion of interleukins IL-6 and 1L-1ß, among others, promoting hyper-activity of the HPA axis and reinforcing a bias of the tryptophan metabolism to produce quinolinic acid, and interleukins by the innate immune system, further reducing the synthesis of serotonin and consolidating the depressive process. We discuss the evidence showing that this process can be initiated by either interleukin stimulated by an infection or some vaccines or excessive psychological stress that activates the HPA axis together with said innate immune response, causing a process of aseptic inflammation in the central nervous system.
Assuntos
Depressão/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Cinurenina/metabolismo , Modelos Neurológicos , Modelos Psicológicos , Sistema Hipófise-Suprarrenal/fisiopatologia , Serotonina/metabolismo , Animais , Infecções Bacterianas/imunologia , Infecções Bacterianas/fisiopatologia , Encéfalo/fisiopatologia , Citocinas/fisiologia , Depressão/imunologia , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Comportamento de Doença/fisiologia , Imunidade Inata , Indolamina-Pirrol 2,3,-Dioxigenase/fisiologia , Inflamação/imunologia , Inflamação/fisiopatologia , Interleucinas/fisiologia , Neuroglia/fisiologia , Sistema Nervoso Periférico/imunologia , Sistema Nervoso Periférico/fisiopatologia , Sistema Hipófise-Suprarrenal/imunologia , Ácido Quinolínico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Serotonina/deficiência , Isolamento Social , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologia , Receptor 4 Toll-Like/fisiologia , Triptofano/metabolismo , Vacinas/efeitos adversosRESUMO
Although stress is an adaptive physiological response to deal with adverse conditions, its occurrence during the early stages of life, such as infancy or adolescence, can induce adaptations in multiple physiological systems, including the reproductive axis, the hypothalamic-pituitary-adrenal (HPA) axis, the limbic cortex and the immune system. These early changes have consequences in adult life, as seen in the physiological and behavioural responses to stress. This review highlights the impact of several stress challenges incurred at various stages of development (perinatal, juvenile, adolescent periods) and how the developmental timing of early-life stress confers unique physiological adaptations that may persist across the lifespan. In doing so, we emphasise how intrinsic sex differences in the stress response might contribute to sex-specific vulnerabilities, the molecular processes underlying stress in the adult, and potential therapeutic interventions to mitigate the effects of early stage stress, including the novel molecular mechanism of SUMOylation as a possible key target of HPA regulation during early-life stress.
Assuntos
Sistema Hipotálamo-Hipofisário/crescimento & desenvolvimento , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipófise-Suprarrenal/crescimento & desenvolvimento , Sistema Hipófise-Suprarrenal/imunologia , Estresse Fisiológico , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologia , Adaptação Fisiológica , Consumo de Bebidas Alcoólicas , Animais , Etanol/administração & dosagem , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Lipopolissacarídeos/administração & dosagem , Privação Materna , Sistema Hipófise-Suprarrenal/efeitos dos fármacosRESUMO
The concept of immunoendocrine interactions, existing in normal and pathological conditions, is relatively recent. Accordingly, cells from the immune system and from endocrine glands share common receptors for cytokines and hormones, allowing systemic and local regulatory mechanisms. In this context, lymphoid organs are under physiological hormonal control. Disturbances in these systems, as those caused by pathogens changes the physiological profile of these interactions, with the release of proinflammatory cytokines and hormones, and one example is the hypothalamus-pituitary-adrenal (HPA) axis. Within endocrine tissues, inflammation occurs with local increase of cytokines, extracellular matrix proteins, and influx of inflammatory cells. One example of lymphoid organ that can be influenced by pathogens and hormonal response is the thymus, with changes in the normal T-cell differentiation process. Several viruses, bacteria, and protozoa induce severe thymic atrophy with massive death of developing thymocytes. In several conditions, this is at least partially due to the activation of the HPA axis and ultimate rise in systemic glucocorticoid release. In the case of Trypanosoma cruzi infection (a protozoan that is the causative agent of Chagas disease), another stress-related hormone, prolactin can partially revert this pathogen-induced thymic atrophy and the abnormal release of immature thymocytes from the organ. Overall, our data clearly reveal that pathogens and more particularly T. cruzi, can promote an immunoendocrine imbalance, with emphasis on stress-related hormones, which can influence lymphocyte dynamics, with consequences in the system and local immune response.
Assuntos
Doença de Chagas/imunologia , Doença de Chagas/metabolismo , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Timo , Trypanosoma cruzi/patogenicidade , Animais , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Timo/imunologia , Timo/metabolismo , Timo/patologiaRESUMO
In recent decades, several neurodegenerative diseases have been shown to be exacerbated by systemic inflammatory processes. There is a wide range of literature that demonstrates a clear but complex relationship between the central nervous system (CNS) and the immunological system, both under naïve or pathological conditions. In diseased brains, peripheral inflammation can transform "primed" microglia into an "active" state, which can trigger stronger pathological responses. Demyelinating diseases are a group of neurodegenerative diseases characterized by inflammatory lesions associated with demyelination, which in turn induces axonal damage, neurodegeneration, and progressive loss of function. Among them, the most important are multiple sclerosis (MS) and neuromyelitis optica (NMO). In this review, we will analyze the effect of specific peripheral inflammatory stimuli in the progression of demyelinating diseases and discuss their animal models. In most cases, peripheral immune stimuli are exacerbating.
Assuntos
Envelhecimento/imunologia , Encéfalo/imunologia , Encefalomielite Autoimune Experimental/imunologia , Microglia/imunologia , Esclerose Múltipla/imunologia , Neuromielite Óptica/imunologia , Envelhecimento/patologia , Animais , Axônios/imunologia , Axônios/patologia , Encéfalo/patologia , Comunicação Celular , Encefalomielite Autoimune Experimental/patologia , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/patologia , Sistema Imunitário/patologia , Inflamação , Microglia/patologia , Esclerose Múltipla/patologia , Neuromielite Óptica/patologia , Obesidade/imunologia , Obesidade/patologia , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/patologiaRESUMO
The course of Strongyloides stercoralis infection is usually asymptomatic with a low discharge of rhabditoid larva in feces. However, the deleterious effects of alcohol consumption seem to enhance the susceptibility to infection, as shown by a fivefold higher strongyloidiasis frequency in alcoholics than in nonalcoholics. Moreover, the association between S. stercoralis infection and alcoholism presents a risk for hyperinfection and severe strongyloidiasis. There are several possible mechanisms for the disruption of the host-parasite equilibrium in ethanol-addicted patients with chronic strongyloidiasis. One explanation is that chronic ethanol intake stimulates the hypothalamic-pituitary-adrenal (HPA) axis to produce excessive levels of endogenous cortisol, which in turn can lead to a deficiency in type 2 T helper cells (Th2) protective response, and also to mimic the parasite hormone ecdysone, which promotes the transformation of rhabditiform larvae to filariform larvae, leading to autoinfection. Therefore, when untreated, alcoholic patients are continuously infected by this autoinfection mechanism. Thus, the early diagnosis of strongyloidiasis and treatment can prevent serious forms of hyperinfection in ethanol abusers.
Assuntos
Alcoolismo , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Strongyloides stercoralis , Estrongiloidíase , Células Th2 , Alcoolismo/imunologia , Alcoolismo/metabolismo , Alcoolismo/parasitologia , Alcoolismo/patologia , Animais , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Fatores de Risco , Strongyloides stercoralis/imunologia , Strongyloides stercoralis/metabolismo , Estrongiloidíase/imunologia , Estrongiloidíase/metabolismo , Estrongiloidíase/patologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologiaRESUMO
The neuropeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the G-protein-coupled receptor NOP. Cells from the immune system express the precursor preproN/OFQ and the NOP receptor, as well as secrete N/OFQ. The activation of the N/OFQ-NOP pathway can regulate inflammatory and immune responses. Several immune activities, including leukocyte migration, cytokine and chemokine production, and lymphocytes proliferation are influenced by NOP activation. It was demonstrated that cytokines and other stimuli such as Toll-like receptor agonist (e.g., lipopolysaccharide) induce N/OFQ production by cells from innate and adaptive immune response. In this context, N/OFQ could modulate the outcome of inflammatory diseases, such as sepsis and immune-mediated pathologies by mechanisms not clearly elucidated. In fact, clinical studies revealed increased levels of N/OFQ under sepsis, arthritis, and Parkinson's disease. Preclinical and clinical studies pointed to the blockade of NOP receptor signaling as successful strategy for the treatment of inflammatory diseases. This review is focused on experimental and clinical data that suggest the participation of N/OFQ-NOP receptor activation in the modulation of the immune response, highlighting the immunomodulatory potential of NOP antagonists in the inflammatory and immunological disturbances.
Assuntos
Doenças Autoimunes/metabolismo , Autoimunidade , Imunidade Inata , Leucócitos/metabolismo , Modelos Imunológicos , Peptídeos Opioides/metabolismo , Receptores Opioides/agonistas , Animais , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Leucócitos/imunologia , Estresse Oxidativo , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Receptores Opioides/metabolismo , Transdução de Sinais , Estresse Fisiológico , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Receptor de Nociceptina , NociceptinaRESUMO
The aim of this study was to evaluate the effect of ovariectomy on the acute-phase response of inflammatory stress. Ex vivo adrenocortical, peripheral mononuclear cell (PMNC) and adipocyte activities were studied in intact and ovariectomized mice. Endotoxemia was mimicked by intraperitoneal administration of bacterial lipopolysaccharide (LPS; 25 mg per mouse) to sham-operated and 21-day ovariectomized mice. Circulating corticosterone, tumor necrosis factor-α (TNFα) and leptin concentrations were monitored before and 30-120 min after the administration of LPS. Additionally, in vitro experiments were performed with isolated corticoadrenal cells, PMNCs and omental adipocytes from sham-operated and ovariectomized mice incubated with specific secretagogues. The results indicate that while ovariectomy enhanced TNFα secretion after in vivo administration of LPS, it reduced corticoadrenal response and abrogated LPS-elicited leptin secretion into the circulation. While the corticoadrenal sensitivity to ACTH stimulation was reduced by ovariectomy, the LPS-induced PMNC response was not affected. Exogenous leptin enhanced baseline PMNC function regardless of surgery. Finally, ovariectomy drastically reduced in vitro adipocyte functionality. Our data support the notion that ovariectomy modified neuroendocrine-immune-adipocyte axis function and strongly suggest that ovarian activity could play a pivotal role in the development of an adequate immune defense mechanism after injury.
Assuntos
Sistema Hipotálamo-Hipofisário/imunologia , Neuroimunomodulação/imunologia , Ovário/imunologia , Sistema Hipófise-Suprarrenal/imunologia , Doença Aguda , Adipócitos/imunologia , Adipócitos/patologia , Animais , Células Cultivadas , Endotoxemia/imunologia , Endotoxemia/patologia , Feminino , Sistema Hipotálamo-Hipofisário/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovariectomia/efeitos adversos , Ovário/patologia , Sistema Hipófise-Suprarrenal/patologia , Distribuição AleatóriaRESUMO
UNLABELLED: The hypothalamic-pituitary-adrenal and sympathetic-adrenomedullary axes are the main systems activated in response to stress. Alterations in salivary components and flow rate have been associated with oral health problems and psychological stress. OBJECTIVES: The aim of the present study was to investigate the influence of psychological stress on salivary flow, total protein concentration and IgG, IgM and IgA concentrations. METHODS: Thirty-eight medical students, average age of 21.4 +/- 2.1 years and enrolled in the 2nd to 5th years of their course, took part voluntarily in the study which involved two different periods: the first after vacations and the second during the final exams (a gap of 4 months). An Oral Health Questionnaire and the Lipp Inventory of Stress Symptoms for Adults (ISSL) were applied during both these periods. The flow rate, total protein concentration and immunoglobulin titers of saliva samples, collected after stimulation and stored in a container with protease inhibitor, were measured. RESULTS: Analysis of the ISSL showed that 42.1% (n = 16) of the students had stress during the post-vacation period, and 44.7% (n = 17) during the final exams. The students' salivary flow rate was significantly lower during the latter period than during the post-vacation period (p < 0.0001), regardless of the presence or absence of psychological stress as measured by the ISSL. There was a reduction in salivary flow rate and a consequent reduction in total protein concentration during the exam period (p = 0.0058). However, during both periods of the study there was no significant difference in total salivary protein concentration between the groups of students with or without psychological stress according to the ISSL (p > 0.05). IgG predominated over IgA and IgM (p < 0.001) during both study periods, regardless of the presence or absence of psychological stress. The study period and the presence of stress influenced the secretion of salivary immunoglobulins. IgM titers during the post-vacation period (p = 0.0044), and IgA (p = 0.028), IgG (p = 0.022) and IgM (p = 0.0075) titers during the final exams were higher in students with symptoms of psychological stress. CONCLUSIONS: Although the immunoglobulin titers were high, there was a reduction in the students' salivary flow rates and a consequent reduction in total protein concentrations.
Assuntos
Imunoglobulinas/biossíntese , Saliva/imunologia , Saliva/metabolismo , Proteínas e Peptídeos Salivares/metabolismo , Salivação/imunologia , Estresse Psicológico/imunologia , Adulto , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Imunoglobulina A Secretora/biossíntese , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Masculino , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismo , Glândulas Salivares/imunologia , Glândulas Salivares/inervação , Glândulas Salivares/metabolismo , Inquéritos e Questionários , Adulto JovemRESUMO
Acute leukemia is the most frequent cancer in children. Recently, a new hypothesis was proposed for the pathogenesis of childhood acute lymphoblastic leukemia (ALL). The so-called 'adrenal hypothesis' emphasized the role of endogenous cortisol in the etiology of B-cell precursor ALL. The incidence peak of ALL in children between 3 to 5 years of age has been well documented and is consistent with this view. The adrenal hypothesis proposes that the risk of childhood B-cell precursor ALL is reduced when early childhood infections induce qualitative and quantitative changes in the hypothalamus-pituitary-adrenal axis. It suggests that the increased plasma cortisol levels would be sufficient to eliminate all clonal leukemic cells originating during fetal life. Because Brazil is a continental and tropical country, the exposure to infections is diversified with endemic viral and regionally non-viral infections, with some characteristics that support the recent adrenal hypothesis. Here we discuss this new hypothesis in terms of data from epidemiological studies and the possible implications of the diversity of infections occurring in Brazilian children.
Assuntos
Doenças Transmissíveis/complicações , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipófise-Suprarrenal/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Adolescente , Brasil/epidemiologia , Criança , Pré-Escolar , Doenças Transmissíveis/imunologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Fatores de RiscoRESUMO
Acute leukemia is the most frequent cancer in children. Recently, a new hypothesis was proposed for the pathogenesis of childhood acute lymphoblastic leukemia (ALL). The so-called "adrenal hypothesis" emphasized the role of endogenous cortisol in the etiology of B-cell precursor ALL. The incidence peak of ALL in children between 3 to 5 years of age has been well documented and is consistent with this view. The adrenal hypothesis proposes that the risk of childhood B-cell precursor ALL is reduced when early childhood infections induce qualitative and quantitative changes in the hypothalamus-pituitary-adrenal axis. It suggests that the increased plasma cortisol levels would be sufficient to eliminate all clonal leukemic cells originating during fetal life. Because Brazil is a continental and tropical country, the exposure to infections is diversified with endemic viral and regionally non-viral infections, with some characteristics that support the recent adrenal hypothesis. Here we discuss this new hypothesis in terms of data from epidemiological studies and the possible implications of the diversity of infections occurring in Brazilian children.
Assuntos
Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Transmissíveis/complicações , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipófise-Suprarrenal/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Brasil/epidemiologia , Doenças Transmissíveis/imunologia , Incidência , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Fatores de RiscoRESUMO
Early life stress has been suggested to mediate vulnerability to affective disorders. Traumatic events experienced in childhood such as sexual abuse and/or physical neglect may lead to psychiatric diseases in adult life, including post-traumatic stress disorder (PTSD). Previous studies have focused on adult traumatic events and very little is known regarding the long-term physiological effects of early life stress. Here, we review the complex interplay between most important cognitive, neuroendocrine and immunological changes reported in PTSD, focusing on long-term implications of childhood maltreatment. PTSD has been associated with significant biological changes related to impaired cognitive functions, attenuated hypothalamic-pituitary-adrenal (HPA) axis function (hypocortisolism) and activation of innate immune responses (low-grade inflammation).
Assuntos
Sistema Hipotálamo-Hipofisário/imunologia , Neuroimunomodulação/fisiologia , Sistemas Neurossecretores/imunologia , Sistema Hipófise-Suprarrenal/imunologia , Transtornos de Estresse Pós-Traumáticos/imunologia , Sobreviventes Adultos de Maus-Tratos Infantis/psicologia , Criança , Encefalite/imunologia , Encefalite/metabolismo , Encefalite/fisiopatologia , Humanos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Imunidade Celular/fisiologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologiaRESUMO
Stress has long been recognized as a putative modulator of immunity. Several clinical and experimental reports point to a role of physical and psychological stressors on progression or resistance to disease. Nonetheless, literature in this field is sometimes controversial due to the wide variety of stressors employed and parameters of immunity analyzed. This variation should not be considered a consequence of methodological inaccuracy. The stress response, although theoretically stereotyped in nature, may lead to slightly different outcomes according to several modifiers. Our group has compared the effects of several stressors over different parameters of brain activity, behavior, immunity and glucocorticoid levels. These data show altogether that while increased turnover of noradrenaline in the hypothalamus, along with anxiety-like behaviors and increase in serum corticosterone are present very often, the magnitude of changes in immunity may vary considerably. Thus, we review data from our group generated over the past decade to support that effects of stressors on immunity and behavior highly depend on their specifics, animal model, frequency, duration, intensity, perception, and coping by the stressed animal.
Assuntos
Sistema Hipotálamo-Hipofisário/imunologia , Neuroimunomodulação/fisiologia , Sistema Hipófise-Suprarrenal/imunologia , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologia , Animais , Ansiedade/imunologia , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Corticosterona/metabolismo , Modelos Animais de Doenças , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Tolerância Imunológica/fisiologia , Camundongos , Norepinefrina/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Comportamento SocialRESUMO
A classical view of the neuroendocrine-immune network assumes bidirectional interactions where pro-inflammatory cytokines influence hypothalamic-pituitary-adrenal (HPA) axis-derived hormones that subsequently affect cytokines in a permanently servo-controlled circle. Nevertheless, this picture has been continuously evolving over the last years as a result of the discovery of redundant expression and extended functions of many of the molecules implicated. Thus, cytokines are not only expressed in cells of the immune system but also in the central nervous system, and many hormones present at hypothalamic-pituitary level are also functionally expressed in the brain as well as in other peripheral organs, including immune cells. Because of this intermingled network of molecules redundantly expressed, the elucidation of the unique roles of HPA axis-related molecules at every level of complexity is one of the major challenges in the field. Genetic engineering in the mouse offers the most convincing method for dissecting in vivo the specific roles of distinct molecules acting in complex networks. Thus, various immunological, behavioral, and signal transduction studies performed with different HPA axis-related mutant mouse lines to delineate the roles of beta-endorphin, the type 1 receptor of corticotropin-releasing hormone (CRHR1), and its ligand CRH will be discussed here.
Assuntos
Comportamento/fisiologia , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipófise-Suprarrenal/imunologia , Transdução de Sinais , Animais , Sistema Hipotálamo-Hipofisário/enzimologia , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Sistema Hipófise-Suprarrenal/enzimologiaRESUMO
The prevalence of atopic diseases and diabetes is increasing worldwide, though the co-occurrence of both diseases in the same individual is less frequent than predicted. Previously published studies suggest that the Th1/Th2 concept could explain the inverse relationship between allergic diseases and type 1 diabetes. However, down-regulation of the IgE-mast cell system can also markedly contribute to the lack of responsiveness to local and systemic allergen challenges in diabetic conditions. Moreover, dysregulation of the hypothalamic-pituitary-adrenocortical axis and elevated endogenous glucocorticoid levels play a pertinent role in some of the pathological-related processes associated with poorly controlled or uncontrolled diabetes.
Assuntos
Complicações do Diabetes/imunologia , Complicações do Diabetes/fisiopatologia , Glucocorticoides/imunologia , Hipersensibilidade/imunologia , Hipersensibilidade/fisiopatologia , Tolerância Imunológica/imunologia , Animais , Regulação para Baixo/imunologia , Humanos , Imunoglobulina E/imunologia , Mastócitos/imunologia , Neuroimunomodulação/imunologia , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/fisiopatologiaRESUMO
OBJECTIVE: To investigate hypothalamic-pituitary-adrenal axis activity in well-defined multiple sclerosis (MS) patient subgroups. METHODS: A total of 173 patients with clinically definite MS were studied: 40 with primary progressive, 41 with secondary progressive, 58 with relapsing-remitting in remission, and 34 with relapsing-remitting during acute relapse. Sixty healthy subjects served as controls. No patients were receiving steroid or other immunomodulatory therapy. Plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS), as well as urine cortisol levels, were measured using commercial radioimmunoassays. Glucocorticoid receptor (GR)-binding assay in peripheral blood mononuclear cells (PBMCs) was performed using [(3)H]dexamethasone (Dex). PBMC production of the proinflammatory peptide corticotrophin-releasing hormone (CRH), interleukin (IL)-1beta, IL-6, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha was evaluated using enzyme-linked immunosorbent spot assay. RESULTS: All four groups of patients displayed significantly higher cortisol, ACTH, and DHEAS plasma concentrations and urine cortisol values than controls. Although 62% of MS patients did not suppress Dex, suppression test results did not correlate with IL-1beta, IL-6, IFN-gamma, or TNF-alpha production. GR-binding assays showed no differences in binding sites between patients and controls; however, all MS groups showed decreased GR affinity and sensitivity compared with controls. The numbers of IL-1beta-, IL-6-, and TNF-alpha-secreting cells increased significantly in relapsing-remitting MS patients only during exacerbations; in contrast, IFN-gamma-secreting cells increased during both exacerbations and remission. Finally, PBMC CRH-secreting cell numbers were considerably greater in all forms of MS. CONCLUSIONS: Patients with multiple sclerosis show hypothalamic-pituitary-adrenal axis hyperactivity, with lymphocytes expressing similar glucocorticoid receptor numbers to controls; however, binding affinity and glucocorticoid sensitivity of these lymphocytes seem to be reduced.
Assuntos
Doenças do Sistema Endócrino/imunologia , Sistema Hipotálamo-Hipofisário/imunologia , Esclerose Múltipla/complicações , Sistema Hipófise-Suprarrenal/imunologia , Adulto , Biomarcadores/sangue , Citocinas/sangue , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/fisiopatologia , Ensaio de Imunoadsorção Enzimática , Feminino , Glucocorticoides/sangue , Glucocorticoides/urina , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Neuroimunomodulação/imunologia , Hormônios Hipofisários/sangue , Hormônios Hipofisários/urina , Sistema Hipófise-Suprarrenal/fisiopatologia , Radioimunoensaio , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/imunologia , Receptores de Glucocorticoides/metabolismo , Regulação para Cima/imunologiaRESUMO
Type 1 diabetes (T1D) is linked to an 'encephalopathy' explained by some features common to the aging process, degenerative and functional disorders of the central nervous system. In the present study we describe a manifest hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in two different experimental mouse models of T1D including the pharmacological one induced by streptozotocin and the spontaneous NOD (nonobese diabetic mice). The high expression of hypothalamic hormones like oxytocin and vasopressin were part to this alteration, together with elevated adrenal glucocorticoids and prominent susceptibility to stress. In the hippocampus of diabetic animals a marked astrogliosis, often associated with neural damage, was present. Dentate gyrus neurogenesis was also affected by the disease: proliferation and differentiation measured by bromodeoxyuridine immunodetection were significantly reduced in both experimental models used. Several facts, including changes associated with chronic hyperglycemia, hyperstimulation of the HPA axis, increased levels of circulating glucocorticoids in combination with brain inflammation and low production of new neurons, contribute to emphasize the impact of diabetes on the central nervous system.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Encefalite/fisiopatologia , Doenças do Sistema Endócrino/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Animais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Modelos Animais de Doenças , Encefalite/imunologia , Doenças do Sistema Endócrino/imunologia , Gliose/imunologia , Gliose/fisiopatologia , Glucocorticoides/imunologia , Glucocorticoides/metabolismo , Hipocampo/imunologia , Hipocampo/fisiopatologia , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/imunologia , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
OBJETIVO: Trabalhos de pesquisa provenientes do campo da neuroimunomodulação vêm tornando explícitas as intrincadas relações existentes entre o sistema nervoso central e o sistema imune. Uma revisão bibliográfica foi realizada com o objetivo de descrever as bases de estudo da neuroimunomodulação. MODELOS EXPERIMENTAIS: Sabe-se, hoje, que estados emocionais como ansiedade e depressão são capazes de modificar a atividade do sistema imune como também o fazem o estresse e fármacos com ação no sistema nervoso central. COMPORTAMENTO DOENTIO: Os comportamentos apresentados por um organismo doente devem ser encarados como decorrência de estratégias homeostáticas de cada indivíduo. POSSÍVEIS MECANISMOS DE SINALIZAÇÃO DO SISTEMA IMUNE PARA O SISTEMA NERVOSO CENTRAL: Grande destaque tem sido atribuído para a participação do eixo hipotálamo-pituitária-adrenal, do sistema nervoso autônomo simpático e das citocinas nas sinalizações entre o sistema nervoso central e o sistema imune. CONCLUSÃO: O presente artigo pretende mostrar a relevância dos fenômenos de neuroimunomodulação; ele faz uma análise crítica das influências do sistema nervoso central sobre o sistema imune e vice-versa.
OBJECTIVE: Several papers arriving from the neuroimmunomodulation field are showing the relevant relationships between the nervous and the immune systems. A review of studies was carried out to describe the bases of the studies on neuroimmunomodulation. EXPERIMENTAL MODELS: It is clear nowadays that emotional states such as anxiety and depression change immune system activity, an affect also observed after both stress and use of nervous system acting drugs. SICK BEHAVIOR: The behavior displayed by sick organisms might be thought as being a consequence of homeostatic strategies. POSSIBLE MECHANISM OF THE ACTION BY MEANS OF IMMUNE SYSTEM TO NERVOUS SYSTEM: A very big emphasis is being given to Hipothalamus-pituitary-adrenal axis, simpathetic nervous system and cytokines participation on nervous system and immune system relationships. CONCLUSION: The present revision intend to show some essential studies in the neuroimmunomodulation field; it makes a critical analysis of the mutual relationships between nervous system and immune system.
Assuntos
Animais , Humanos , Sistema Nervoso Central/fisiologia , Sistema Imunitário/fisiologia , Neuroimunomodulação/fisiologia , Estresse Fisiológico/imunologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/fisiopatologia , Citocinas/imunologia , Depressão/imunologia , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/fisiopatologia , Modelos Animais , Sistema Hipófise-Suprarrenal/imunologia , Estresse Psicológico/imunologia , Sistema Nervoso Simpático/imunologiaRESUMO
Repeated exposure to lipopolysaccharide (LPS) induces desensitization of hypothalamus-pituitary-adrenal axis (HPA) responses and hypophagia. We investigated the interplay between the neural circuitries involved in the control of food intake and HPA axis activity following single or repeated LPS injections. Male Wistar rats received a single or repeated i.p. injection of LPS (100 microg/kg) for 6 days and were subdivided into four groups: 6 saline, 5 saline+1 LPS, 5 LPS+1 saline and 6 LPS. Animals with a single exposure to LPS showed increased plasma levels of ACTH, CORT, PRL, TNF-alpha and also CRF mRNA in the paraventricular nucleus of the hypothalamus. These animals exhibited a reduced food intake and body weight associated with an increase of CART expression in the arcuate nucleus (ARC). Leptin plasma levels were not altered. On the other hand, repeated LPS administration did not alter ACTH, CORT, PRL and TNF-alpha, but it reduced leptin level, compared to single LPS or saline treatment. Furthermore, repeated LPS administration did not increase CRF or CART mRNA expression. Food intake and weight gain after repeated LPS injections were not different from saline-treated animals. There was no change in NPY and POMC mRNA expression in the ARC after single or repeated injections of LPS. In conclusion, desensitization induced by repeated exposure to LPS involves the blockade of HPA axis activation and anorexigenic response, which are both associated with an unresponsiveness of TNF-alpha production and CRF and CART expression in the hypothalamus.