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1.
Egypt J Immunol ; 31(4): 46-57, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39417740

RESUMO

The adrenergic anti-inflammatory pathway represents a critical intersection between the nervous and immune systems, modulating the body's response to inflammation through the action of catecholamines on adrenergic receptors. This review explored the physiology underlying this pathway, focusing on the mechanisms by which the sympathetic nervous system influences immune function. We delved into the roles of specific adrenergic receptors, primarily the beta-adrenergic receptors, in mediating anti-inflammatory effects, highlighting the involved molecular signaling pathways. Additionally, we examined the immunological implications of adrenergic modulation, discussing how these pathways contributed to the resolution of inflammation and the potential for dysregulation in various disease states. Emerging evidence on the therapeutic potential of targeting the adrenergic anti-inflammatory pathway in conditions such as sepsis, autoimmune diseases, and chronic inflammatory disorders was also reviewed. By integrating current knowledge on the physiology and immunology of this pathway, this review aimed to provide a comprehensive understanding of its role in health and disease, offering insights into future research directions and clinical applications.


Assuntos
Inflamação , Humanos , Inflamação/imunologia , Animais , Transdução de Sinais/imunologia , Receptores Adrenérgicos/imunologia , Receptores Adrenérgicos/fisiologia , Receptores Adrenérgicos/metabolismo , Sistema Nervoso Simpático/imunologia , Receptores Adrenérgicos beta/imunologia , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta/fisiologia , Catecolaminas/imunologia , Catecolaminas/metabolismo , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/imunologia
2.
Immunity ; 54(6): 1219-1230.e7, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-33915109

RESUMO

The sympathetic nervous system (SNS) controls various physiological functions via the neurotransmitter noradrenaline. Activation of the SNS in response to psychological or physical stress is frequently associated with weakened immunity. Here, we investigated how adrenoceptor signaling influences leukocyte behavior. Intravital two-photon imaging after injection of noradrenaline revealed transient inhibition of CD8+ and CD4+ T cell locomotion in tissues. Expression of ß-adrenergic receptor in hematopoietic cells was not required for NA-mediated inhibition of motility. Rather, chemogenetic activation of the SNS or treatment with adrenergic receptor agonists induced vasoconstriction and decreased local blood flow, resulting in abrupt hypoxia that triggered rapid calcium signaling in leukocytes and halted cell motility. Oxygen supplementation reversed these effects. Treatment with adrenergic receptor agonists impaired T cell responses induced in response to viral and parasitic infections, as well as anti-tumor responses. Thus, stimulation of the SNS impairs leukocyte mobility, providing a mechanistic understanding of the link between adrenergic receptors and compromised immunity.


Assuntos
Adrenérgicos/imunologia , Movimento Celular/imunologia , Imunidade/imunologia , Leucócitos/imunologia , Sistema Nervoso Simpático/imunologia , Animais , Sinalização do Cálcio/imunologia , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores Adrenérgicos/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
3.
Mol Biol Cell ; 32(7): 622-633, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33534612

RESUMO

Dysregulation of immune responses has been linked to the generation of immunoglobulin G (IgG) autoantibodies that target human ß1ARs and contribute to deleterious cardiac outcomes. Given the benefits of ß-blockers observed in patients harboring the IgG3 subclass of autoantibodies, we investigated the role of these autoantibodies in human ß1AR function. Serum and purified IgG3(+) autoantibodies from patients with onset of cardiomyopathy were tested using human embryonic kidney (HEK) 293 cells expressing human ß1ARs. Unexpectedly, pretreatment of cells with IgG3(+) serum or purified IgG3(+) autoantibodies impaired dobutamine-mediated adenylate cyclase (AC) activity and cyclic adenosine monophosphate (cAMP) generation while enhancing biased ß-arrestin recruitment and Extracellular Regulated Kinase (ERK) activation. In contrast, the ß-blocker metoprolol increased AC activity and cAMP in the presence of IgG3(+) serum or IgG3(+) autoantibodies. Because IgG3(+) autoantibodies are specific to human ß1ARs, non-failing human hearts were used as an endogenous system to determine their ability to bias ß1AR signaling. Consistently, metoprolol increased AC activity, reflecting the ability of the IgG3(+) autoantibodies to bias ß-blocker toward G-protein coupling. Importantly, IgG3(+) autoantibodies are specific toward ß1AR as they did not alter ß2AR signaling. Thus, IgG3(+) autoantibody biases ß-blocker toward G-protein coupling while impairing agonist-mediated G-protein activation but promoting G-protein-independent ERK activation. This phenomenon may underlie the beneficial outcomes observed in patients harboring IgG3(+) ß1AR autoantibodies.


Assuntos
Autoanticorpos/imunologia , Imunoglobulina G/imunologia , Receptores Adrenérgicos beta 1/imunologia , Autoanticorpos/sangue , Cardiomiopatias/imunologia , Cardiomiopatias/fisiopatologia , AMP Cíclico , Células HEK293 , Coração/fisiologia , Humanos , Imunoglobulina G/metabolismo , Receptores Adrenérgicos/imunologia , Receptores Adrenérgicos beta 1/metabolismo , Transdução de Sinais , beta-Arrestinas
4.
Sci Immunol ; 5(51)2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917793

RESUMO

Sympathetic nerves that innervate lymphoid organs regulate immune development and function by releasing norepinephrine that is sensed by immune cells via their expression of adrenergic receptors. Here, we demonstrate that ablation of sympathetic nervous system (SNS) signaling suppresses tumor immunity, and we dissect the mechanism of such immune suppression. We report that disruption of the SNS in mice removes a critical α-adrenergic signal required for maturation of myeloid cells in normal and tumor-bearing mice. In tumor-bearing mice, disruption of the α-adrenergic signal leads to the accumulation of immature myeloid-derived suppressor cells (MDSCs) that suppress tumor immunity and promote tumor growth. Furthermore, we show that these SNS-responsive MDSCs drive expansion of regulatory T cells via secretion of the alarmin heterodimer S100A8/A9, thereby compounding their immunosuppressive activity. Our results describe a regulatory framework in which sympathetic tone controls the development of innate and adaptive immune cells and influences their activity in health and disease.


Assuntos
Células Supressoras Mieloides/imunologia , Sistema Nervoso Simpático/imunologia , Antagonistas Adrenérgicos/uso terapêutico , Animais , Calgranulina A/sangue , Calgranulina B/sangue , Linhagem Celular Tumoral , Feminino , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos BALB C , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Receptores Adrenérgicos/imunologia , Linfócitos T Reguladores/imunologia
5.
J Neuroimaging ; 30(6): 822-827, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32609410

RESUMO

BACKGROUND AND PURPOSE: Recent studies suggest that the autoantibodies against adrenergic/muscarinic receptors might be one of the causes and potential markers of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The purpose of this study was to investigate the structural network changes related to autoantibody titers against adrenergic/muscarinic receptors in ME/CFS by performing a single-subject gray matter similarity-based structural network analysis. METHODS: We prospectively examined 89 consecutive right-handed ME/CFS patients who underwent both brain MRI including 3D T1-wighted images and a blood analysis of autoantibodies titers against ß1 adrenergic receptor (ß1 AdR-Ab), ß2 AdR-Ab, M3 acetylcholine receptor (M3 AchR-Ab), and M4 AchR-Ab. Single-subject gray matter similarity-based structural networks were extracted from segmented gray matter images for each patient. We calculated local network properties (betweenness centrality, clustering coefficient, and characteristic path length) and global network properties (normalized path length λ, normalized clustering coefficient γ, and small-world network value δ). We investigated the correlations between the autoantibody titers and regional gray matter/white matter volumes, the local network properties, and the global network properties. RESULTS: Betweenness centrality showed a significant positive correlation with ß1-AdR-Ab in the right dorsolateral prefrontal cortex. The characteristic path length showed a significant negative correlation with ß2-AdR-Ab in the right precentral gyrus. There were no significant correlations between the antibody titers and the regional gray matter/white matter volumes, and the global network properties. CONCLUSIONS: Our findings suggest that ß1 AdR-Ab and ß2 AdR-Ab are potential markers of ME/CFS.


Assuntos
Autoanticorpos/imunologia , Córtex Cerebral/diagnóstico por imagem , Síndrome de Fadiga Crônica/diagnóstico por imagem , Receptores Adrenérgicos/imunologia , Receptores Muscarínicos/imunologia , Adolescente , Adulto , Idoso , Síndrome de Fadiga Crônica/imunologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagem , Adulto Jovem
6.
Brain Behav Immun ; 80: 238-246, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30885844

RESUMO

The autonomic nervous system innervates all lymphoid tissues including the spleen therefore providing a link between the central nervous system and the immune system. The only known mechanism of neural inhibition of inflammation in the spleen relies on the production of norepinephrine by splenic catecholaminergic fibers which binds to ß2-adrenergic receptors (ß 2-ARs) of CD4+ T cells. These CD4+ T cells trigger the release of acetylcholine that inhibits the secretion of inflammatory cytokines by macrophages through α7 nicotinic acetylcholine receptor (α7nAchRs) signaling. While the vagal anti-inflammatory pathway has been extensively studied in rodents, it remains to be determined whether it coexists with other neural pathways. Here, we have found that three nerve branches project to the spleen in mice. While two of these nerves are associated with an artery and contain catecholaminergic fibers, the third is located at the apex of the spleen and contain both catecholaminergic and cholinergic fibers. We found that electrical stimulation of the apical nerve, but not the arterial nerves, inhibited inflammation independently of lymphocytes. In striking contrast to the anti-inflammatory pathway mechanism described so far, we also found that the inhibition of inflammation by apical nerve electrical stimulation relied on signaling by both ß 2-ARs and α7nAchRs in myeloid cells, with these two signaling pathways acting in parallel. Most importantly, apical splenic nerve electrical stimulation mitigated clinical symptoms in a mouse model of rheumatoid arthritis further providing the proof-of-concept that such an approach could be beneficial in patients with Immune-mediated inflammatory diseases.


Assuntos
Células Mieloides/imunologia , Receptores Adrenérgicos/imunologia , Receptores Nicotínicos/imunologia , Baço/imunologia , Baço/inervação , Acetilcolina/metabolismo , Animais , Estimulação Elétrica , Feminino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Norepinefrina/metabolismo , Baço/fisiopatologia , Fator de Necrose Tumoral alfa/imunologia , Nervo Vago/imunologia , Estimulação do Nervo Vago
7.
Front Biosci (Elite Ed) ; 11(1): 102-108, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468641

RESUMO

Autoantibodies to beta-1 adrenergic receptor have been reported in adult patients with dilated cardiomyopathy (DCM). Removal of these antibodies has a positive hemodynamic effect. Our aim was to investigate whether these antibodies are present in children with DCM and explore the potential hemodynamic benefit of immunoadsorption (IA). Seventeen children with DCM  were tested for these antibodies. The etiology of DCM was genetic (n=5), myocarditis (n=4), DCM and congenital heart block (n=3), DCM associated to maternal lupus (n=1), DCM and Wolff Parkinson White Syndrome (n=1), and idiopathic (n=3). All patients evidenced ventricular dysfunction. Antibody testing was positive in 8 patients, 7  received IA.  Three patients with high titers had a poor clinical outcome and needed transplantation. Two patients with low titers exhibited a full recovery of heart function. One patient with multiple myocarditis episodes was treated with immunoglobulin IgG and IA ; after 5 years this patient presented a LVEF of 40 percent. Beta-1 adrenergic receptors autoantibodies are present in children with DCM. Immunoadsorption therapy may help improve heart failure in this context.


Assuntos
Autoanticorpos/imunologia , Cardiomiopatia Dilatada/imunologia , Hemodinâmica/genética , Receptores Adrenérgicos/imunologia , Cardiomiopatia Dilatada/terapia , Pré-Escolar , Humanos , Técnicas de Imunoadsorção , Lactente , Recém-Nascido , Resultado do Tratamento
8.
Immunobiology ; 224(2): 220-222, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554740

RESUMO

BACKGROUND: An association between Tako-Tsubo cardiomyopathy (TTC) and underlying malignancies has been observed, suggesting that TTC might be the consequence of paraneoplastic phenomena. This study investigates the presence of autoantibodies against cardiomyocytes as well as adrenergic (ß1, ß2) and muscarinic (M2) receptors in patients with TTC. METHODS AND RESULTS: Serum from 20 TTC patients and 20 controls with ischemic heart disease was obtained. Indirect immunofluorescence testing for intracellular autoantibodies against cardiomyocytes showed a homogenous distribution, as in both groups 9 of 20 sera displayed a characteristic binding pattern of antibodies including vascular walls and intracellular structures. Flow cytometry analysis revealed no difference between TTC and controls in the binding of autoantibodies to the surface antigens of cardiomyocyte HL-1 cells (p = 0.569, t-test). Flow cytometry analysis of nontransfected wild type cells (p = 0.633, t-test), M2 receptor-transfected cells (p = 0.687, t-test), ß1 receptor-transfected cells (p = 0.444, t-test) and ß2 receptor-transfected cells (p = 0.632, t-test) showed similar results for control and TTC sera. Likewise, the binding pattern of TTC patients with a history of neoplasia compared to those without or to controls did not differ significantly (p > 0.05, u-test). CONCLUSION: Findings suggest that the presumed paraneoplastic etiology of TTC cannot be attributed to the formation of these antibodies.


Assuntos
Autoimunidade , Imunidade Humoral , Miócitos Cardíacos/imunologia , Receptores Adrenérgicos/imunologia , Receptores Muscarínicos/imunologia , Cardiomiopatia de Takotsubo/imunologia , Idoso , Animais , Autoanticorpos/imunologia , Autoantígenos , Células CHO , Linhagem Celular , Cricetulus , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Receptores Adrenérgicos/metabolismo , Receptores Muscarínicos/metabolismo , Cardiomiopatia de Takotsubo/metabolismo
9.
Front Immunol ; 9: 736, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29696025

RESUMO

Upper respiratory viral infections are a major etiologic instigator of allergic asthma, and they drive severe exacerbations of allergic inflammation in the lower airways of asthma sufferers. Rhinovirus (RV), in particular, is the main viral instigator of these pathologies. Asthma exacerbations due to RV infections are the most frequent reasons for hospitalization and account for the majority of morbidity and mortality in asthma patients. In both critical care and disease control, long- and short-acting ß2-agonists are the first line of therapeutic intervention, which are used to restore airway function by promoting smooth muscle cell relaxation in bronchioles. While prophylactic use of ß2-agonists reduces the frequency and pathology of exacerbations, their role in modulating the inflammatory response is only now being appreciated. Adrenergic signaling is a component of the sympathetic nervous system, and the natural ligands, epinephrine and norepinephrine (NE), regulate a multitude of autonomic functions including regulation of both the innate and adaptive immune response. NE is the primary neurotransmitter released by post-ganglionic sympathetic neurons that innervate most all peripheral tissues including lung and secondary lymphoid organs. Thus, the adrenergic signaling pathways are in direct contact with both the central and peripheral immune compartments. We present a perspective on how the adrenergic signaling pathway controls immune function and how ß2-agonists may influence inflammation in the context of virus-induced asthma exacerbations.


Assuntos
Asma/imunologia , Receptores Adrenérgicos/imunologia , Viroses/imunologia , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Animais , Asma/tratamento farmacológico , Humanos , Transdução de Sinais , Viroses/tratamento farmacológico
11.
Scand Cardiovasc J ; 51(5): 243-247, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28738696

RESUMO

Orthostatic intolerance is defined as the provocation of symptoms upon standing, commonly caused by neurogenic orthostatic hypotension (OH) and postural tachycardia syndrome (POTS), the etiology for which has not been fully uncovered yet. Many reports have described the occurrence of dysautonomia, orthostatic intolerance and POTS following febrile illness, presumably viral and post-vaccine. Furthermore, patients with dysautonomia have higher rates of autoimmune disorders such as Hashimoto thyroiditis and SLE. Recent evidence has shown the presence of adrenergic and cholinergic receptor antibodies in patients with POTS and orthostatic hypotension. In patients with cholinergic receptor antibodies, higher titers correlate with the disease severity. Few reports have shown that immunomodulation therapy resulted in significant improvement in symptoms. In this article, we review the available literature correlating autoimmunity with orthostatic intolerance syndromes. Future studies are warranted to evaluate the prevalence of such antibodies and examine different treatment modalities in this sub group of patients.


Assuntos
Autoanticorpos/imunologia , Autoimunidade , Pressão Sanguínea , Intolerância Ortostática/imunologia , Postura , Receptores Adrenérgicos/imunologia , Receptores Colinérgicos/imunologia , Animais , Humanos , Intolerância Ortostática/fisiopatologia , Fatores de Risco
12.
Sci Rep ; 7: 43962, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28262783

RESUMO

Smoking is a dominant risk factor for chronic obstructive pulmonary disease (COPD) and emphysema, but not every smoker develops emphysema. Immune responses in smokers vary. Some autoantibodies have been shown to contribute to the development of emphysema in smokers. ß2-adrenergic receptors (ß2-ARs) are important targets in COPD therapy. ß2-adrenergic receptor autoantibodies (ß2-AAbs), which may directly affect ß2-ARs, were shown to be increased in rats with passive-smoking-induced emphysema in our current preliminary studies. Using cigarette-smoke exposure (CS-exposure) and active-immune (via injections of ß2-AR second extracellular loop peptides) rat models, we found that CS-exposed rats showed higher serum ß2-AAb levels than control rats before alveolar airspaces became enlarged. Active-immune rats showed increased serum ß2-AAb levels, and exhibited alveolar airspace destruction. CS-exposed-active-immune treated rats showed more extensive alveolar airspace destruction than rats undergoing CS-exposure alone. In our current clinical studies, we showed that plasma ß2-AAb levels were positively correlated with the RV/TLC (residual volume/total lung capacity) ratio (r = 0.455, p < 0.001) and RV%pred (residual volume/residual volume predicted percentage, r = 0.454, p < 0.001) in 50 smokers; smokers with higher plasma ß2-AAb levels exhibited worse alveolar airspace destruction. We suggest that increased circulating ß2-AAbs are associated with smoking-related emphysema.


Assuntos
Autoanticorpos/sangue , Enfisema/diagnóstico , Enfisema/patologia , Receptores Adrenérgicos/imunologia , Fumar/efeitos adversos , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos
13.
Kardiologiia ; 56(6): 50-57, 2016 06.
Artigo em Russo | MEDLINE | ID: mdl-28290848

RESUMO

AIM: to assess clinical and prognostic value of circulating cardiospecific autoantibodies (AAB) and CD4+ T-regulatory cells in patients with myocarditis. MATERIAL AND METHODS: We included into this study 47 patients with lymphocytic myocarditis verified by analysis of histological and immunohistochemical data. Comparison group consisted of 30 practically healthy persons. Content of marker cardiotropic AAT were measured with the help of standardized immune enzyme test-systems. Number of circulating CD4+CD25+ and CD4+CD25+FoxP3+ T-lymphocytes were evaluated by flow cytometry. RESULTS: Among factors determining prognosis of patients with lymphocytic myocarditis factors of key significance were the presence of clinically overt heart failure at the disease debut, and degree of reduction of left ventricular ejection fraction. Distinctive feature of active myocarditis was elevation of titer of AABs to sarcomeric, cytoskeleton, and cytoplasmic proteins of cardiomyocytes, as well as elevated level of AABs to various epitopes of adenine nucleotide translocator. Elevated level of AAB to 1-adrenoreceptors was an independent predictor of unfavorable outcome in patients with lymphocytic myocarditis. Increased population of circulating CD4+CD25+ T-regulatory cells was as sociated with elevated concentration of of natriuretic peptide. CONCLUSION: Abnormalities in the system of autoimmunity play key role not only in pathogenesis but also in prognosis of inflammatory myocardial diseases. Changes of profile of circulating cardiospecific AABs and T-regulatory cells can bear a protective function.


Assuntos
Autoimunidade , Miocardite , Adulto , Autoanticorpos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocardite/imunologia , Miocardite/fisiopatologia , Prognóstico , Receptores Adrenérgicos/imunologia , Função Ventricular Esquerda
14.
J Am Heart Assoc ; 3(1): e000755, 2014 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-24572257

RESUMO

BACKGROUND: Patients with postural tachycardia syndrome (POTS) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS. We tested the hypothesis that they harbor functional autoantibodies to adrenergic receptors (AR). METHODS AND RESULTS: Fourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR autoantibody-mediated contractility using a perfused rat cremaster arteriole assay. A receptor-transfected cell-based assay was used to detect the presence of ß1AR and ß2AR autoantibodies. Data were normalized and expressed as a percentage of baseline. The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P<0.001) when coexisting ß2AR dilative activity was blocked; and this was suppressed by α1AR blockade with prazosin. POTS sera acted as a partial α1AR antagonist significantly shifting phenylephrine contractility curves to the right. All POTS sera increased ß1AR activation (130±3% of baseline, P<0.01) and a subset had increased ß2AR activity versus healthy subjects. POTS sera shifted isoproterenol cAMP response curves to the left, consistent with enhanced ß1AR and ß2AR agonist activity. Autoantibody-positive POTS sera demonstrated specific binding to ß1AR, ß2AR, and α1AR in transfected cells. CONCLUSIONS: POTS patients have elevated α1AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1AR for vasoconstriction and concurrent ßAR-mediated tachycardia. Coexisting ß1AR and ß2AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.


Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/imunologia , Autoimunidade , Hemodinâmica , Síndrome da Taquicardia Postural Ortostática/imunologia , Receptores Adrenérgicos/imunologia , Agonistas Adrenérgicos/farmacologia , Adulto , Animais , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/fisiopatologia , Bioensaio , Biomarcadores/sangue , Células CHO , Estudos de Casos e Controles , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Oklahoma , Síndrome da Taquicardia Postural Ortostática/sangue , Síndrome da Taquicardia Postural Ortostática/diagnóstico , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , Ratos , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/genética , Receptores Adrenérgicos alfa 1/imunologia , Receptores Adrenérgicos beta 1/imunologia , Receptores Adrenérgicos beta 2/imunologia , Tennessee , Transfecção , Vasoconstrição , Vasodilatação , Adulto Jovem
15.
Cancer Biomark ; 13(3): 145-54, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23912486

RESUMO

The importance of adrenergic pathways in cancer has long been suspected, but now there is mounting epidemiological, preclinical, and clinical evidence of its importance in gynecologic cancers. To date, most of these effects are mediated primarily through the beta 2 adrenergic receptor activation of the tumor cell cyclic AMP-protein kinase A signaling pathway. This review will discuss the current knowledge about the neuroendocrine stress response in gynecologic tumor biology.


Assuntos
Neoplasias dos Genitais Femininos/metabolismo , Receptores Adrenérgicos/metabolismo , Animais , Feminino , Neoplasias dos Genitais Femininos/imunologia , Humanos , Receptores Adrenérgicos/imunologia , Transdução de Sinais
16.
J Leukoc Biol ; 94(2): 247-57, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23633414

RESUMO

Preeclampsia syndrome is characterized by inadequate placentation, because of deficient trophoblastic invasion of the uterine spiral arteries, leading to placental hypoxia, secretion of proinflammatory cytokines, the release of angiogenic and antiangiogenic factors and miRNAs. Although immune-system alterations are associated with the origin of preeclampsia, other factors, including proinflammatory cytokines, neutrophil activation, and endothelial dysfunction, are also related to the pathophysiology of this syndrome. The pathophysiology of preeclampsia may involve several factors, including persistent hypoxia at the placental level and the release of high amounts of STBMs. DAMP molecules released under hypoxic conditions and STBMs, which bind TLRs, may activate monocytes, DCs, NK cells, and neutrophils, promoting persistent inflammatory conditions in this syndrome. The development of hypertension in preeclamptic women is also associated with endothelial dysfunction, which may be mediated by various mechanisms, including neutrophil activation and NET formation. Furthermore, preeclamptic women have higher levels of nonclassic and intermediate monocytes and lower levels of lymphoid BDCA-2(+) DCs. The cytokines secreted by these cells may contribute to the inflammatory process and to changes in adaptive-immune system cells, which are also modulated in preeclampsia. The changes in T cell subsets that may be seen in preeclampsia include low Treg activity, a shift toward Th1 responses, and the presence of Th17 lymphocytes. B cells can participate in the pathophysiology of preeclampsia by producing autoantibodies against adrenoreceptors and autoantibodies that bind the AT1-R.


Assuntos
Pré-Eclâmpsia/imunologia , Imunidade Adaptativa , Proteínas Angiogênicas/fisiologia , Autoanticorpos/biossíntese , Hipóxia Celular , Micropartículas Derivadas de Células , Citocinas/metabolismo , Células Dendríticas/imunologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Imunidade Inata , Inflamação , Leucócitos/imunologia , MicroRNAs/genética , NF-kappa B/metabolismo , Ativação de Neutrófilo , Estresse Oxidativo , Placenta/fisiopatologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Receptor Tipo 1 de Angiotensina/imunologia , Receptores Adrenérgicos/imunologia , Subpopulações de Linfócitos T/imunologia , Trofoblastos/patologia
17.
PLoS One ; 8(3): e57983, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23483958

RESUMO

BACKGROUND: Pre-eclampsia is the leading cause of maternal and neonatal morbidity and mortality with incompletely understood etiopathogenesis. The purpose of the current study is to determine whether there is a relationship between the presence of autoantibodies against ß1, ß2 and α1 adrenoreceptors and severe pre-eclampsia. METHODOLOGY/PRINCIPAL FINDINGS: Synthetic peptides corresponding to amino acid sequences of the second extracellular loops of ß1, ß2 and α1 adrenoreceptors were synthesized as antigens to test 34 patients with severe pre-eclampsia, 36 normal pregnancy women and 40 non-pregnant controls for the presence of autoantibodies using enzyme-linked immunosorbent assay. The respective frequencies of autoantibodies against ß1, ß2 and α1 adrenoreceptors were 50.0% (17/34), 52.9% (18/34) and 55.9% (19/34) in patients with severe pre-eclampsia, 19.4% (7/36) (p = 0.011), 19.4% (7/36) (p = 0.006) and 17.6% (6/36) (p = 0.001) in normal pregnancy women and 10% (4/40), 7.5% (3/40) and 10% (4/40) (p<0.001) in non-pregnant controls. Titers of these autoantibodies were also significantly increased in patients with severe pre-eclampsia. By logistic regression analysis, the presence of these three autoantibodies significantly increased the risk of neonatal death (odds ratio, 13.5; 95% confidence interval, 1.3-141.3; p = 0.030) and long-term neonatal hospitalization (odds ratio, 5.0; 95% confidence interval, 1.3-19.1; p = 0.018). The risk of hypertension and fetal distress were also associated with the presence of these three autoantibodies. CONCLUSIONS/SIGNIFICANCE: This novel pilot study demonstrated for the first time that the presence of autoantibodies against ß1, ß2 and α1 adrenoreceptors are increased in patients with severe pre-eclampsia. Pregnant women who are positive for the three autoantibodies are at increased risks of neonatal mortality and morbidity. We posit that these autoantibodies may be involved in the pathogenesis of severe pre-eclampsia.


Assuntos
Autoanticorpos/imunologia , Pré-Eclâmpsia/imunologia , Receptores Adrenérgicos/imunologia , Adulto , Índice de Apgar , Peso ao Nascer , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Recém-Nascido , Tamanho do Órgão , Projetos Piloto , Placenta/patologia , Gravidez , Complicações na Gravidez/imunologia , Resultado do Tratamento
19.
Brain Behav Immun ; 27(1): 101-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23046723

RESUMO

Elevated blood pressure (BP) and infiltration of the vasculature by monocytes contribute to vascular pathology; but, monocyte migratory characteristics based on differing inflammatory potential under adrenergic activation remains unclear. We compared nonclassical (CD14(+)CD16(++); HLA-DR(+)), intermediate (CD14(++)CD16(+); HLA-DR(++)), and classical (CD14(++)CD16(-); HLA-DR(+/-)) monocyte trafficking and their LPS-stimulated TNF production in response to a physical stressor (20-min treadmill exercise at 65-70% VO(2peak)) in participants with high prehypertension (PHT), mild PHT or normal BP (NBP). To determine adrenergic receptor (AR) sensitivity, pre-exercise cells were also treated with isoproterenol (Iso). When cells were stimulated with LPS, the CD16 molecules were downregulated, and monocyte subsets were differentiated based on HLA-DR expression. Monocyte subpopulations (as % of total monocytes) and intracellular TNF production were evaluated by flow cytometry. TNF production in all subsets decreased post-exercise and with ex-vivo incubation with Iso, irrespective of BP (p<0.001), with nonclassical and intermediate monocytes being a major source of TNF production. Overall, % nonclassical monocytes increased, % intermediate did not change, whereas % classical decreased post-exercise (p<0.001). However, % increase in nonclassical monocytes under exercise-induced adrenergic activation was blunted in high PHT individuals (p<0.05), but not in individuals with mild PHT and NBP. These findings extend our previous reports by showing that the mobilization of proinflammatory monocytes under physical stress is attenuated with even mild BP elevation. This may be indicative of monocytic AR desensitization and/or greater adhesion of "proinflammatory" monocytes to the vascular endothelium in hypertension with potential clinical implications of vascular pathology.


Assuntos
Exercício Físico/fisiologia , Lipopolissacarídeos/farmacologia , Monócitos , Pré-Hipertensão/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto , Estudos de Casos e Controles , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Regulação para Baixo , Teste de Esforço , Feminino , Citometria de Fluxo , Proteínas Ligadas por GPI/efeitos dos fármacos , Proteínas Ligadas por GPI/imunologia , Antígenos HLA-DR/imunologia , Humanos , Isoproterenol/farmacologia , Receptores de Lipopolissacarídeos/imunologia , Lipopolissacarídeos/imunologia , Masculino , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/imunologia , Receptores de IgG/efeitos dos fármacos , Receptores de IgG/imunologia , Simpatomiméticos/farmacologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos
20.
Br J Pharmacol ; 166(3): 847-57, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22220626

RESUMO

Antibodies against cholinergic and adrenergic receptors (adrenoceptors) are frequent in serum of patients with chronic heart failure. Their prevalence is associated with Chagas' disease, idiopathic dilated cardiomyopathy (DCM), and ischaemic heart disease. Among the epitopes targeted are first and second extracellular loops of the ß-adrenergic (ß-adrenoceptor) and M2 muscarinic receptor. ß(1)-adrenoceptor autoantibodies affect radioligand binding and cardiomyocyte function similar to agonists. Corresponding rodent immunizations induce symptoms compatible with chronic heart failure that are reversible upon removal of the antibodies, transferable via the serum and abrogated by adrenergic antagonists. In DCM patients, prevalence and stimulatory efficacy of ß(1)-adrenoceptor autoantibodies are correlated to the decline in cardiac function, ventricular arrhythmia and higher incidence of cardiac death. In conclusion, such autoantibodies seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion. However, the pharmacology of this interaction is poorly understood. It is unclear how the autoantibodies trigger changes in receptor activity and second messenger coupling and how that is related to the pathogenesis and severity of the associated diseases. Here, we summarize the available evidence regarding these issues and discuss these findings in the light of recent knowledge about the conformational activation of the human ß(2)-adrenoceptor and the properties of bona fide cardiopathogenic autoantibodies derived from immune-adsorption therapy of DCM patients. These considerations might contribute to the conception of therapy regimen aimed at counteracting or neutralizing cardiopathogenic receptor autoantibodies.


Assuntos
Autoanticorpos/sangue , Sistema Nervoso Autônomo/imunologia , Cardiopatias/imunologia , Receptores Adrenérgicos/imunologia , Receptores Colinérgicos/imunologia , Antagonistas Adrenérgicos/administração & dosagem , Antagonistas Adrenérgicos/efeitos adversos , Antagonistas Adrenérgicos/uso terapêutico , Regulação Alostérica/imunologia , Animais , Autoanticorpos/imunologia , Cardiopatias/sangue , Cardiopatias/tratamento farmacológico , Humanos , Contração Miocárdica/imunologia
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