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1.
Microbiol Spectr ; 7(4)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31373269

RESUMO

The group A streptococci are associated with a group of diseases affecting the heart, brain, and joints that are collectively referred to as acute rheumatic fever. The streptococcal immune-mediated sequelae, including acute rheumatic fever, are due to antibody and cellular immune responses that target antigens in the heart and brain as well as the group A streptococcal cross-reactive antigens as reviewed in this article. The pathogenesis of acute rheumatic fever, rheumatic heart disease, Sydenham chorea, and other autoimmune sequelae is related to autoantibodies that are characteristic of autoimmune diseases and result from the immune responses against group A streptococcal infection by the host. The sharing of host and streptococcal epitopes leads to molecular mimicry between the streptococcal and host antigens that are recognized by the autoantibodies during the host response. This article elaborates on the discoveries that led to a better understanding of the pathogenesis of disease and provides an overview of the history and the most current thought about the immune responses against the host and streptococcal cross-reactive antigens in group A streptococcal sequelae.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31140830

RESUMO

Objective: Pediatric autoimmune neuropsychiatric disorder associated with Streptococcus pyogenes infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS) are emerging immune-mediated encephalopathies characterized by sudden onset of seemingly inexplicable complex neuropsychiatric symptoms, including obsessions, compulsions, and heterogeneous tics, which occur in children. Main goal of this study was to report our experience in a large cohort of Italian children affected by either PANDAS or PANS and treated long term with an antibiotic regimen similar to that used for acute rheumatic fever. Patients and Methods: The clinical charts of a cohort of 371 consecutive Italian children, 345 with PANDAS (93.0%) and 26 with PANS (7.0%), were retrospectively evaluated. Antistreptococcal, antinuclear antibodies, and serologic evaluation for a group of common autoantibodies and microbial agents were also assessed. A strict differential diagnosis with other autoimmune diseases displaying neuropsychiatric manifestations was performed. Results: Antistreptolysin O and anti-DNase B antibody titers were tested and were positive in all PANDAS subjects, but negative in PANS. Anti-Mycoplasma pneumoniae antibodies and anti-Epstein-Barr virus Nuclear Antigen antibodies were found positive in 11 (42.3%) and 5 (19.2%) patients with PANS, respectively. Among PANDAS cases, a clear streptococcal infection was clinically evident at the onset of neurological symptoms in only 74 patients (21.4%), whereas the relationship with Streptococcus pyogenes was confirmed by serologic tests in the other 271 (78.6%). All patients fulfilling the diagnostic criteria for PANDAS (n = 345) received amoxicillin/clavulanic acid for 10-21 days at diagnosis, while those who were diagnosed with PANS (n = 26) received treatment according to the causative agent. Thereafter, all PANDAS/PANS patients received prophylaxis with benzathine benzylpenicillin for an overall period of at least 5 years to prevent subsequent potential streptococcal infections. To date, 75.0% of PANDAS patients (n = 258) have shown an improvement of neurologic symptoms, mainly observed within 3-5 months of treatment for PANDAS cases, while 88.4% of PANS patients (n = 23) have improved after 6-12 months. Infection-related relapses of neurologic manifestations were observed in both PANDAS and PANS patients (n = 167 out of 371; 45% of the total cohort) in the long term. Conclusions: Our study has confirmed the usefulness of the preliminary diagnostic criteria for PANDAS and PANS, revealing also the importance of early diagnosis to reduce the risk of evolution toward disabling chronic neurologic sequelae. Long-term antibiotic prophylaxis has resulted in a substantial benefit to reduce neurological symptoms for the majority of PANDAS and PANS patients over a 7-year period.

3.
J Am Heart Assoc ; 8(2): e008968, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30638108

RESUMO

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

5.
Transl Psychiatry ; 8(1): 148, 2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30097568

RESUMO

The identification of brain-targeted autoantibodies in children with autism spectrum disorder (ASD) raises the possibility of autoimmune encephalopathy (AIE). Intravenous immunoglobulin (IVIG) is effective for AIE and for some children with ASD. Here, we present the largest case series of children with ASD treated with IVIG. Through an ASD clinic, we screened 82 children for AIE, 80 of them with ASD. IVIG was recommended for 49 (60%) with 31 (38%) receiving the treatment under our care team. The majority of parents (90%) reported some improvement with 71% reporting improvements in two or more symptoms. In a subset of patients, Aberrant Behavior Checklist (ABC) and/or Social Responsiveness Scale (SRS) were completed before and during IVIG treatment. Statistically significant improvement occurred in the SRS and ABC. The antidopamine D2L receptor antibody, the anti-tubulin antibody and the ratio of the antidopamine D2L to D1 receptor antibodies were related to changes in the ABC. The Cunningham Panel predicted SRS, ABC, parent-based treatment responses with good accuracy. Adverse effects were common (62%) but mostly limited to the infusion period. Only two (6%) patients discontinued IVIG because of adverse effects. Overall, our open-label case series provides support for the possibility that some children with ASD may benefit from IVIG. Given that adverse effects are not uncommon, IVIG treatment needs to be considered cautiously. We identified immune biomarkers in select IVIG responders but larger cohorts are needed to study immune biomarkers in more detail. Our small open-label exploratory trial provides evidence supporting a neuroimmune subgroup in patients with ASD.

6.
J Infect Dis ; 218(2): 324-335, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29236994

RESUMO

Acute rheumatic fever and rheumatic heart disease (ARF/RHD) have long been described as autoimmune sequelae of Streptococcus pyogenes or group A streptococcal (GAS) infection. Both antibody and T-cell responses against immunodominant GAS virulence factors, including M protein, cross-react with host tissue proteins, triggering an inflammatory response leading to permanent heart damage. However, in some ARF/RHD-endemic regions, throat carriage of GAS is low. Because Streptococcus dysgalactiae subspecies equisimilis organisms, also known as ß-hemolytic group C streptococci and group G streptococci (GGS), also express M protein, we postulated that streptococci other than GAS may have the potential to initiate or exacerbate ARF/RHD. Using a model initially developed to investigate the uniquely human disease of ARF/RHD, we have discovered that GGS causes interleukin 17A/interferon γ-induced myocarditis and valvulitis, hallmarks of ARF/RHD. Remarkably the histological, immunological, and functional changes in the hearts of rats exposed to GGS are identical to those exposed to GAS. Furthermore, antibody cross-reactivity to cardiac myosin was comparable in both GGS- and GAS-exposed animals, providing additional evidence that GGS can induce and/or exacerbate ARF/RHD.

7.
Nat Microbiol ; 2(10): 1334-1335, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29046525
8.
Autoimmunity ; 49(8): 563-570, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27562362

RESUMO

Rheumatic fever and rheumatic heart disease (RF/RHD) develop following repeated infection with group A streptococci (GAS). We used the Rat Autoimmune Valvulitis (RAV) model of RF/RHD to demonstrate that repetitive booster immunization with GAS-derived recombinant M protein (rM5) resulted in an enhanced anti-cardiac myosin antibody response that may contribute to the breaking of immune tolerance leading to RF/RHD and increased infiltration of heart valves by mononuclear cells. With each boost, more inflammatory cells were observed infiltrating heart tissue which could lead to severe cardiac damage. We also found evidence that both complement and anti-M protein antibodies in serum from rM5-immunized rats have the potential to contribute to inflammation in heart valves by activating cardiac endothelium. More importantly, we have demonstrated by electrocardiography for the first time in the RAV model that elongation of P-R interval follows repetitive boost with rM5. Our observations provide experimental evidence for cardiac alterations following repeated exposure to GAS M protein with immunological and electrophysiological features resembling that seen in humans following recurrent GAS infection.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Transporte/imunologia , Endocárdio/imunologia , Endocárdio/patologia , Cardiopatia Reumática/etiologia , Cardiopatia Reumática/patologia , Animais , Autoantígenos/imunologia , Autoimunidade , Miosinas Cardíacas/imunologia , Modelos Animais de Doenças , Progressão da Doença , Eletrocardiografia , Endocárdio/metabolismo , Células Endoteliais/metabolismo , Feminino , Imunização , Imunização Secundária , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Ratos , Cardiopatia Reumática/diagnóstico , Cardiopatia Reumática/metabolismo , Streptococcus pyogenes/imunologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
9.
JCI Insight ; 1(9)2016 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-27366791

RESUMO

In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4+IL17+ T cells and Th17-promoting cytokines IL-6, TGF-ß, and IL-23 as well as GM-CSF-secreting CD4+ T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14+ monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17-producing T cells and IL-17-promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3+ Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-ß, IL-6, and IL-23 from myocarditic CD14+ monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option.

10.
Pediatr Infect Dis J ; 35(9): 1021-6, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27273689

RESUMO

BACKGROUND: Acute rheumatic fever (ARF) is an autoimmune disorder associated with Streptococcus pyogenes infection. A prevailing hypothesis to account for this disease is that epitopes of self-antigens, such as cardiac myosin react to antibodies against S. pyogenes. The goal of our study was to confirm disease epitopes of cardiac myosin, identify immunodominant epitopes and to monitor the epitope response pattern in acute and convalescent rheumatic fever. METHODS: Enzyme-linked immunosorbant assays were used to determine epitopes immunodominant in acute disease and to track the immune response longitudinally to document any changes in the epitope pattern in convalescent sera. Multiplex fluorescence immunoassay was used to correlate anti-streptolysin O (ASO) and anti-human cardiac myosin antibodies. RESULTS: Disease-specific epitopes in rheumatic fever were identified as S2-1, 4 and 8. Epitopes S2-1, 4, 8 and 9 were found to be immunodominant in acute sera and S2-1, 8, 9, 29 and 30 in the convalescent sera. Frequency analysis showed that 50% of the ARF subjects responded to S2-8. S2-8 responders tended to maintain their epitope pattern throughout the convalescent period, whereas the S2-8 nonresponders tended to spread their responses to other epitopes later in the immune response. There was a significant correlation between anti-cardiac myosin and ASO titers. In addition, S2-8 responders showed elevated ASO titers compared with S2-8 non responders. CONCLUSION: Our studies confirm the existence of S2-1, 4 and 8 as disease-specific epitopes. We provide evidence that cardiac myosin S2-8 responders remain epitope stable in convalescence, whereas S2-8 nonresponders shift to neoepitopes. Multiplex data indicated a correlation between elevated ASO and anti-human cardiac myosin antibody titers. Mapping of cardiac myosin epitopes recognized in rheumatic fever sera may identify immunophenotypes of rheumatic fever.


Assuntos
Autoanticorpos/imunologia , Miosinas Cardíacas/imunologia , Febre Reumática/imunologia , Autoanticorpos/sangue , Miosinas Cardíacas/química , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Hawaii , Humanos , Febre Reumática/sangue , Febre Reumática/fisiopatologia , Streptococcus pyogenes
11.
Nat Rev Dis Primers ; 2: 15084, 2016 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-27188830

RESUMO

Acute rheumatic fever (ARF) is the result of an autoimmune response to pharyngitis caused by infection with group A Streptococcus. The long-term damage to cardiac valves caused by ARF, which can result from a single severe episode or from multiple recurrent episodes of the illness, is known as rheumatic heart disease (RHD) and is a notable cause of morbidity and mortality in resource-poor settings around the world. Although our understanding of disease pathogenesis has advanced in recent years, this has not led to dramatic improvements in diagnostic approaches, which are still reliant on clinical features using the Jones Criteria, or treatment practices. Indeed, penicillin has been the mainstay of treatment for decades and there is no other treatment that has been proven to alter the likelihood or the severity of RHD after an episode of ARF. Recent advances - including the use of echocardiographic diagnosis in those with ARF and in screening for early detection of RHD, progress in developing group A streptococcal vaccines and an increased focus on the lived experience of those with RHD and the need to improve quality of life - give cause for optimism that progress will be made in coming years against this neglected disease that affects populations around the world, but is a particular issue for those living in poverty.


Assuntos
Febre Reumática/complicações , Cardiopatia Reumática/etiologia , Infecções Estreptocócicas/complicações , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Autoimunidade , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Penicilinas/farmacologia , Penicilinas/uso terapêutico , Faringite/etiologia , Prevenção Primária/métodos , Febre Reumática/imunologia , Cardiopatia Reumática/mortalidade , Prevenção Secundária/métodos , Infecções Estreptocócicas/fisiopatologia , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/patogenicidade
12.
J Card Fail ; 22(7): 520-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26941007

RESUMO

BACKGROUND: Host autoimmune activity in myocarditis has been proposed to play a role in development of cardiac disease, but evidence of autoimmunity and relationship to outcomes have not been evaluated in pediatric myocarditis. METHODS: We performed a multi-institutional study of children with clinical myocarditis. Newly diagnosed patients were followed for up to 12 months and previously diagnosed patients at a single follow-up for serum levels of autoantibodies to human cardiac myosin, beta-adrenergic receptors 1 and 2, muscarinic-2 receptors, and antibody-mediated protein kinase A (PKA) activation in heart cells in culture. Results were compared with those of healthy control children. RESULTS: Both previously diagnosed patient at follow-up (P = .0061) and newly diagnosed patients at presentation (P = .0127) had elevated cardiac myosin antibodies compared with control subjects. Antibody levels were not associated with recovery status at follow-up in either group. PKA activation was higher at presentation in the newly diagnosed patients who did not recovery normal function (P = .042). CONCLUSIONS: Children with myocarditis have evidence of autoantibodies against human cardiac myosin at diagnosis and follow-up compared with control subjects. Differences in antibody-mediated cell signaling may contribute to differences in patient outcomes, as suggested by elevated antibody-mediated PKA activation in heart cells by the serum from nonrecovered patients.


Assuntos
Autoanticorpos/imunologia , Autoimunidade , Miosinas Cardíacas/imunologia , Proteínas Quinases Dependentes de AMP Cíclico/imunologia , Miocardite/imunologia , Miócitos Cardíacos/imunologia , Autoanticorpos/sangue , Criança , Pré-Escolar , Proteínas Quinases Dependentes de AMP Cíclico/análise , Coração/diagnóstico por imagem , Coração/fisiopatologia , Humanos , Lactente , Miocardite/sangue , Miocardite/diagnóstico por imagem , Miócitos Cardíacos/química
13.
J Interv Card Electrophysiol ; 44(3): 205-12, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26446828

RESUMO

PURPOSE: Previous studies demonstrated that burst pacing and subthreshold infusion of acetylcholine in ß1-adrenergic receptor (ß1AR)-immunized rabbits induced sustained sinus tachycardia. The aim of this study was to examine the anti-arrhythmogenic effect of a newly designed retro-inverso (RI) peptidomimetic inhibitor that specifically targets the ß1AR antibodies in the rabbit. METHODS: Six New Zealand white rabbits were immunized with a ß1AR second extracellular loop peptide to produce sympathomimetic ß1AR antibodies. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization and subsequent treatment with the RI peptide inhibitor. Each rabbit served as its own control. RESULTS: No sustained arrhythmias were induced at preimmune baseline. At 6 weeks after immunization, there was a marked increase in induced sustained tachyarrhythmias, predominantly sinus tachycardia, which was largely suppressed by the RI peptide. The atrial effective refractory period was shortened significantly in immunized rabbits compared to their preimmune state. The RI peptide reversed and prolonged this shortening. ß1AR antibody levels were negatively correlated with the atrial effective refractory period. Postimmune sera-induced ß1AR activation in transfected cells in vitro was also blocked by the RI peptide. CONCLUSIONS: ß1AR-activating autoantibodies are associated with reduction of the atrial effective refractory period and facilitate arrhythmia induction in this model. The RI peptide reversal may have important therapeutic implications in subjects who harbor these autoantibodies.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Arritmias Cardíacas/imunologia , Arritmias Cardíacas/prevenção & controle , Autoanticorpos/imunologia , Peptídeos/administração & dosagem , Receptores Adrenérgicos beta 1/imunologia , Animais , Materiais Biomiméticos/administração & dosagem , Peptídeos/química , Coelhos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Resultado do Tratamento
14.
Hypertension ; 66(4): 830-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26259590

RESUMO

Activating autoantibodies to the angiotensin type 1 receptor (AT1R) are associated with hypertensive disorders. The angiotensin type 2 receptor (AT2R) is known to counter-regulate the actions of AT1R. We investigated whether AT2R autoantibodies produced in immunized rabbits will activate AT2R and suppress the vasopressor responses to angiotensin II and AT1R-activating autoantibodies. Five rabbits immunized with a peptide corresponding to the second extracellular loop of AT2R developed high AT2R antibody titers. Rabbit anti-AT2R sera failed to directly dilate isolated rat cremaster arterioles; however, when co-perfused with angiotensin II or AT1R-activating autoantibodies, the anti-AT2R sera significantly inhibited their contractile effects. Rabbit anti-AT2R sera recognized a predominant sequence near the N-terminus of the AT2R second extracellular loop. A decoy peptide based on this sequence effectively reversed the opposing effect of the anti-AT2R sera on angiotensin II-induced contraction of rat cremaster arterioles. A similar blockade of the anti-AT2R sera effect was observed with the AT2R antagonist PD 123319 and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Rabbit anti-AT2R sera reacted specifically with AT2R. No cross-reactivity with AT1R was observed. Blood pressure did not change in immunized animals. However, the pressor responses to incremental angiotensin II infusions were blunted in immunized animals. Thirteen subjects with primary aldosteronism demonstrated increased AT2R autoantibody levels compared with normal controls. In conclusion, AT2R autoantibodies produced in immunized rabbits have the ability to activate AT2R and counteract the AT1R-mediated vasoconstriction. These autoantibodies provide useful and selective tools for the study of their roles in blood pressure regulation and possible therapeutic intervention.


Assuntos
Angiotensina II/imunologia , Anticorpos Bloqueadores/fisiologia , Autoanticorpos/imunologia , Hipertensão/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Receptor Tipo 2 de Angiotensina/imunologia , Vasoconstrição/imunologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/fisiopatologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Coelhos , Ratos , Vasoconstrição/efeitos dos fármacos
15.
PLoS One ; 10(3): e0120499, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25793715

RESUMO

Several autoantibodies (anti-dopamine 1 (D1R) and 2 (D2R) receptors, anti-tubulin, anti-lysoganglioside-GM1) and antibody-mediated activation of calcium calmodulin dependent protein kinase II (CaMKII) signaling activity are elevated in children with Sydenham's chorea (SC). Recognizing proposed clinical and autoimmune similarities between SC and PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection), we sought to identify serial biomarker changes in a slightly different population. Antineuronal antibodies were measured in eight children (mean 11.3 years) with chronic, dramatic, recurrent tics and obsessive-compulsive disorder (OCD) associated with a group A ß-hemolytic streptococcal (GABHS) respiratory tract infection, but differing because they lacked choreiform movements. Longitudinal serum samples in most subjects included two pre-exacerbation samples, Exac), one midst Exac (abrupt recurrence of tic/OCD; temporally association with a GABHS infection in six of eight subjects), and two post-Exac. Controls included four groups of unaffected children (n = 70; mean 10.8 years) obtained at four different institutions and published controls. Clinical exacerbations were not associated with a significant rise in antineuronal antibody titers. CaMKII activation was increased at the GABHS exacerbation point in 5/6 subjects, exceeded combined and published control's 95th percentile at least once in 7/8 subjects, and median values were elevated at each time point. Anti-tubulin and anti-D2R titers did not differ from published or combined control group's 95th percentile or median values. Differences in anti-lysoganglioside-GM1 and anti-D1R titers were dependent on the selected control. Variances in antibody titers and CaMKII activation were identified among the institutional control groups. Based on comparisons to published studies, results identify two groups of PANDAS: 1) a cohort, represented by this study, which lacks choreiform movements and elevated antibodies against D2R; 2) the originally reported group with choreiform movements and elevated anti-D2R antibodies, similar to SC. Increased antibody mediated CaMKII activation was found in both groups and requires further study as a potential biomarker.


Assuntos
Anticorpos/metabolismo , Coreia/diagnóstico , Progressão da Doença , Neurônios/metabolismo , Transtorno Obsessivo-Compulsivo/etiologia , Infecções Estreptocócicas/complicações , Tiques/etiologia , Adolescente , Antiestreptolisina/metabolismo , Autoanticorpos/metabolismo , Biomarcadores/sangue , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Estudos de Casos e Controles , Criança , Coreia/sangue , Coreia/imunologia , Doença Crônica , Desoxirribonucleases/metabolismo , Feminino , Humanos , Imunoglobulina G/metabolismo , Estudos Longitudinais , Masculino , Recidiva
16.
Hypertension ; 65(4): 793-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25691619

RESUMO

Activating autoantibodies to the angiotensin II type 1 receptor (AT1R) have been implicated in hypertensive disorders. We investigated whether AT1R antibodies produced in immunized rabbits will activate AT1R and contribute to hypertension by a direct contractile effect on the vasculature and whether they can be blocked by a novel decoy peptide. A multiple antigenic peptide containing the AT1R epitope AFHYESQ, which is the receptor-binding epitope of AT1R-activating autoantibodies, was used to immunize 6 rabbits. AT1R antibody activity was analyzed in AT1R-transfected cells, and their contractile effects were assayed using isolated perfused rat cremaster resistance arterioles. A retro-inverso D-amino acid epitope-mimetic peptide was tested for AT1R antibody inhibition in vitro and in vivo. All immunized animals produced high AT1R antibody titers and developed elevated blood pressure. No changes in measured blood chemistry values were observed after immunization. Rabbit anti-AT1R sera induced significant AT1R activation in transfected cells and vasoconstriction in the arteriole assay, both of which were blocked by losartan and the retro-inverso D-amino acid peptide. A single intravenous bolus injection of the retro-inverso d-amino acid peptide (1 mg/kg) into immunized rabbits dropped the mean arterial pressure from 122±11 to 82±6 mm Hg. Rabbit anti-AT1R sera partially suppressed angiotensin II-induced contraction of isolated rat cremaster arterioles, and the pressor response to angiotensin II infusion was attenuated in immunized animals. In conclusion, AT1R-activating autoantibodies and the retro-inverso d-amino acid peptide, respectively, have important etiologic and therapeutic implications in hypertensive subjects who harbor these autoantibodies.


Assuntos
Autoanticorpos/imunologia , Pressão Sanguínea/fisiologia , Hipertensão/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Vasoconstrição/fisiologia , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Hipertensão/fisiopatologia , Coelhos
17.
J Child Adolesc Psychopharmacol ; 25(1): 76-85, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25658702

RESUMO

BACKGROUND AND OBJECTIVE: Antineuronal antibodies have been implicated in tic and obsessive compulsive disorders (OCD) associated with group A streptococcal infections. We investigated antineuronal autoantibody levels as well as antibody-mediated neuronal cell signaling activity, as previously reported for Sydenham chorea and pediatric autoimmune neuropsychiatric disorder associated with streptococci (PANDAS), to determine immunological profiles for a large cohort of children with tics and/or OCD. METHODS: Study participants (n=311; ages 4-27 years, 66% male) were selected from a larger group of individuals with self-reported neuropsychiatric symptoms (n=742) and included only those with accurate knowledge of group A streptococcal infection status, except for four individuals in whom streptococcal infection status was unknown. Healthy control samples (n=16; ages 5-14 years, 81% male), came from the National Institute of Mental Health and Yale University. In addition to serum donations, participants and/or legal guardians provided neuropsychiatric and related medical histories of symptoms that had lasted >1 year. Antineuronal immunoglobulin G (IgG) titers were measured by standard enzyme-linked immunosorbent assay (ELISA) and compared with mean titers of normal age-matched sera against lysoganglioside, tubulin, and dopamine receptors (D1R and D2R). Antibody-mediated signaling of calcium calmodulin dependent protein kinase II (CaMKII) activity in a human neuronal cell line (SK-N-SH) was tested in serum. RESULTS: Of 311 individuals, 222 (71%) had evidence of group A streptococcal infection, which was associated with tics and/or OCD status (p=0.0087). Sera from individuals with tics and/or OCD (n=261) had evidence of elevated serum IgG antibodies against human D1R (p<0.0001) and lysoganglioside (p=0.0001), and higher serum activation of CaMKII activity (p<0.0001) in a human neuronal cell line compared with healthy controls (n=16). Furthermore, patients with tics and OCD had significantly increased activation of CaMKII activity compared with patients with only tics or only OCD (p<0.033 for each). CONCLUSION: Our study suggested a significant correlation of streptococcal-associated tics and OCD with elevated anti-D1R and antilysoganglioside antineuronal antibodies in serum concomitant with higher activation of CaMKII in human neuronal cells. Youth and young adults with chronic tics and OCD may have underlying infectious/immunologic etiology.


Assuntos
Autoanticorpos/sangue , Neurônios , Transtorno Obsessivo-Compulsivo/sangue , Infecções Estreptocócicas/sangue , Tiques/sangue , Adolescente , Adulto , Linhagem Celular Tumoral , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/etiologia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/diagnóstico , Tiques/diagnóstico , Tiques/etiologia , Adulto Jovem
18.
J Am Soc Hypertens ; 9(1): 15-20, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25537460

RESUMO

Autoantibodies to the angiotensin II type 1 receptor (AT1R) have been reported in patients with primary aldosteronism, including aldosterone producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH). Sera from 25 primary aldosteronism subjects (12 with IAH and 13 with APA) and 15 normotensive control subjects were assayed for AT1R autoantibodies by enzyme-linked immunosorbent assay and an AT1R-transfected cell-based bioassay. Nine of 12 IAH subjects (75%) and six of 13 APA subjects (46%) were positive for AT1R autoantibodies in the bioactivity assay. The mean AT1R autoantibody activity for the IAH and APA subjects was significantly greater than controls (P < .001 and P < .01, respectively), and this in vitro activity was suppressed by the AT1R blocker losartan. None of the controls had significant AT1R autoantibody activity. Enzyme-linked immunosorbent assay values were less sensitive but were positive in some subjects with IAH and APA. The mean arterial pressure of these primary aldosteronism subjects correlated modestly with AT1R autoantibody activity. These data confirm the presence of active AT1R autoantibodies in a high percentage of subjects with primary aldosteronism irrespective of their underlying etiology. These observations have both pathophysiological and clinical implications.


Assuntos
Autoanticorpos/imunologia , Hiperaldosteronismo/imunologia , Receptor Tipo 1 de Angiotensina/metabolismo , Adulto , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Losartan/farmacologia , Masculino , Pessoa de Meia-Idade , Prevalência
19.
J Child Adolesc Psychopharmacol ; 25(1): 3-13, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25325534

RESUMO

On May 23 and 24, 2013, the First PANS Consensus Conference was convened at Stanford University, calling together a geographically diverse group of clinicians and researchers from complementary fields of pediatrics: General and developmental pediatrics, infectious diseases, immunology, rheumatology, neurology, and child psychiatry. Participants were academicians with clinical and research interests in pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) in youth, and the larger category of pediatric acute-onset neuropsychiatric syndrome (PANS). The goals were to clarify the diagnostic boundaries of PANS, to develop systematic strategies for evaluation of suspected PANS cases, and to set forth the most urgently needed studies in this field. Presented here is a consensus statement proposing recommendations for the diagnostic evaluation of youth presenting with PANS.


Assuntos
Doenças Autoimunes/diagnóstico , Transtorno Obsessivo-Compulsivo/diagnóstico , Guias de Prática Clínica como Assunto/normas , Infecções Estreptocócicas/diagnóstico , Doença Aguda , Doenças Autoimunes/terapia , Criança , Humanos , Transtorno Obsessivo-Compulsivo/terapia , Infecções Estreptocócicas/terapia , Síndrome
20.
Endocrine ; 49(2): 457-63, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25500789

RESUMO

We have previously demonstrated that activating autoantibodies to ß1-adrenergic receptor (ß1AR) and M2 muscarinic receptor (M2R) facilitate atrial fibrillation (AF) in patients with Graves' disease (GD). The objectives of this expanded study were to examine the prevalence of ß1AR, ß2AR, and M2R autoantibodies in hyperthyroidism subjects. Sera from 81 patients including 31 with GD and AF, 36 with GD and sinus rhythm, 9 with toxic multinodular goiter, 5 with subacute thyroiditis, and 10 control subjects were examined for these autoantibodies by ELISA. Sera from 20 ELISA-positive GD subjects, 10 with AF and 10 with sinus rhythm, were assayed for autoantibody bioactivity using cell-based bioassays. In patients with GD and AF, 45, 65, and 77 % were ELISA positive for ß1AR, M2R, and ß2AR autoantibodies, respectively. In patients with GD and sinus rhythm, 17, 39, and 75 % were ELISA positive for ß1AR, M2R, and ß2AR autoantibodies, respectively. ß1AR and M2R autoantibodies were co-present in 39 % of patients with GD and AF compared to 14 % in GD with sinus rhythm (p = 0.026). Patients with toxic multinodular goiter or subacute thyroiditis had a low prevalence of autoantibodies. The mean ß1AR and M2R autoantibody activity was elevated in both GD groups but higher in those with AF than those with sinus rhythm. ß2AR autoantibody activity was also increased in both groups. In conclusion, ß1AR, ß2AR, and M2R autoantibodies were elevated in GD. ß1AR and M2R autoantibodies appear to be related to concurrent AF, while ß2AR autoantibodies were equally prevalent in those with a sinus tachycardia and those with AF.


Assuntos
Fibrilação Atrial/sangue , Autoanticorpos/sangue , Doença de Graves/sangue , Receptor Muscarínico M2/imunologia , Receptores Adrenérgicos beta 1/imunologia , Receptores Adrenérgicos beta 2/imunologia , Taquicardia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/etiologia , Feminino , Doença de Graves/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Taquicardia/etiologia
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