RESUMO
We evaluated the concentration of AT2R antibodies in 136 patients with primary and secondary glomerular diseases: membranous nephropathy (n = 18), focal and segmental glomerulosclerosis (n = 25), systemic lupus erythematosus (n = 17), immunoglobulin A (IgA) nephropathy (n = 14), mesangial (non-IgA) proliferative nephropathy (n = 6), c-ANCA vasculitis (n = 40), perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) vasculitis (n = 16), and compared it with a healthy control group (22 patients). Serum creatinine levels, proteinuria, serum albumin, and total protein concentrations were prospectively recorded for 2 years. The mean levels of AT2R antibodies in the lupus nephropathy group were significantly higher compared to the control group, 64.12 ± 26.95 units/mL and 9.72 ± 11.88 units/mL, respectively. There was no association between this level and the clinical course of the disease. The AT2R levels in other kinds of glomerular disease were no different from the control group. We found significant correlations between AT1R and AT2R in patients with membranous nephropathy (r = 0.66), IgA nephropathy (r = 0.61), and c-ANCA vasculitis (r = 0.63). Levels of AT2R antibodies in systemic lupus erythematosus are higher compared to other types of glomerulonephritis, vasculitis, and a healthy control group. Levels of AT2R antibodies correlate with AT1R antibodies in the groups of patients with membranous nephropathy, IgA nephropathy, and c-ANCA vasculitis. These kinds of AT2R antibodies have a stimulative effect on AT2R, but we have not found the influence of these antibodies on the clinical course of glomerular diseases.
Assuntos
Autoanticorpos , Receptor Tipo 2 de Angiotensina , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Receptor Tipo 2 de Angiotensina/imunologia , Receptor Tipo 2 de Angiotensina/metabolismo , Autoanticorpos/sangue , Autoanticorpos/imunologia , Idoso , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/sangue , Glomerulonefrite/imunologia , Glomerulonefrite/sangue , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/sangue , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/sangue , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Nefrite Lúpica/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Adulto Jovem , Nefropatias/imunologiaRESUMO
BACKGROUND: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. METHODS: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. RESULTS: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. CONCLUSIONS: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.
Assuntos
Autoanticorpos , Neurônios Dopaminérgicos , Doença de Parkinson , Receptor Tipo 1 de Angiotensina , Animais , Ratos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Autoanticorpos/imunologia , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Oxidopamina/farmacologia , Doença de Parkinson/terapia , Doença de Parkinson/patologia , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Tetrazóis/farmacologia , Tetrazóis/uso terapêuticoRESUMO
PURPOSE: Compared with monotherapy, combination therapy with multiple antihypertensive drugs has demonstrated superior efficacy in the management of hypertension. The aim of this study was to explore the efficacy of multitarget combined vaccines in achieving simultaneous antihypertensive and target organ protection effects. METHODS: Our team has developed ATRQß-001 and ADRQß-004 vaccines targeting Ang II type 1 receptor (AT1R) and α1D-adrenergic receptor (α1D-AR), respectively. In NG-nitroarginine methyl ester ( l -NAME) + abilities spontaneously hypertensive rats (SHRs) model, SHRs were simultaneously inoculated with ATRQß-001 and ADRQß-004 vaccines. Histological and biochemical analyses were performed to evaluate the antihypertensive effects and target organ protection of the ATRQß-001 and ADRQß-004 combined vaccines in comparison with those of the single vaccine. RESULTS: Both ATRQß-001 and ADRQß-004 vaccines induced robust antibody production, resulting in persistent high antibody titers in rats. Notably, the combined administration of both vaccines significantly decreased SBP in SHRs compared with treatment with a single vaccine, both before and after l -NAME administration. Furthermore, the combined vaccine regimen demonstrated superior efficacy in protecting against vascular remodeling, myocardial hypertrophy and fibrosis, and kidney injury in SHRs. Mechanistically, the combined vaccines exhibited significantly downregulated the expression of angiotensin II type 1 receptor (AT1R) and α1D-adrenergic receptor (α1D-AR). Importantly, no apparent immune-related adverse effects were observed in animals immunized with the combined vaccines. CONCLUSION: Preliminary findings from this investigation suggest that co-administration of the novel ATRQß-001 and ADRQß-004 vaccines holds potential as a groundbreaking therapeutic strategy for managing hypertension.
Assuntos
Hipertensão , Ratos Endogâmicos SHR , Receptor Tipo 1 de Angiotensina , Receptores Adrenérgicos alfa 1 , Animais , Receptor Tipo 1 de Angiotensina/imunologia , Ratos , Masculino , Vacinas Combinadas/imunologia , NG-Nitroarginina Metil Éster/farmacologia , Pressão Sanguínea/efeitos dos fármacosRESUMO
Antibodies to angiotensin II type 1 receptor (AT1R-Abs) are among the most well-studied non-HLA antibodies in renal transplantation. These antibodies have been shown to be common in pediatric kidney transplantation and associated with antibody-mediated rejection (AMR), vascular inflammation, development of human leukocyte donor-specific antibodies (HLA DSA), and allograft loss. As AT1R-Ab testing becomes more readily accessible, evidence to guide clinical practice for testing and treating AT1R-Ab positivity in pediatric kidney transplant recipients remains limited. This review discusses the clinical complexities of evaluating AT1R-Abs given the current available evidence.
Assuntos
Rejeição de Enxerto , Transplante de Rim , Receptor Tipo 1 de Angiotensina , Humanos , Receptor Tipo 1 de Angiotensina/imunologia , Rejeição de Enxerto/imunologia , Criança , Antígenos HLA/imunologia , Autoanticorpos/imunologia , Isoanticorpos/imunologiaRESUMO
BACKGROUND: The role of angiotensin II type 1 receptor antibodies (AT1R-Ab) in pediatric renal transplantation is unclear. Here, we evaluated pre-transplant AT1R-Ab on transplant outcomes in the first 5 years. Secondary analysis compared pre-transplant AT1R-Ab levels by age. METHODS: Thirty-six patients, 2-20 years old, were divided into two groups: pre-transplant AT1R-Ab- (<17 U/ml; n = 18) and pre-transplant AT1R-Ab+ (≥17 U/ml; n = 18). eGFR was determined at 6-month, 1-, 2-, and 4-year post-transplant. Allograft biopsies were performed in the setting of strong HLA-DSA (MFI > 10 000), AT1R-Ab ≥17 U/ml, and/or elevated creatinine. RESULTS: Mean age in pre-transplant AT1R-Ab- was 13.3 years vs. 11.0 in pre-transplant AT1R-Ab+ (p = 0.16). At 6 months, mean eGFR was 111.3 ml/min/1.73 m2 in pre-transplant AT1R-Ab- vs. 100.2 in pre-transplant AT1R-Ab + at 1 year, 103.6 ml/min/1.73 m2 vs. 100.5; at 2 years, 98.9 ml/min/1.73 m2 vs. and 93.7; at 4 years, 72.6 ml/min/1.73 m2 vs. 80.9. 11/36 patients had acute rejection (6 in pre-transplant AT1R-Ab-, 5 in pre-transplant AT1R-Ab + ). There was no difference in rejection rates. All 6 subjects with de novo HLA-DSA and AT1R-Ab ≥17 U/ml at the time of biopsy experienced rejection. Mean age in those with the AT1R-Ab ≥40 U/ml was 10.0 years vs. 13.2 in those <40 U/ml (p = 0.07). CONCLUSION: In our small cohort, pre-transplant AT1R-Ab ≥17 U/ml was not associated with reduced graft function or rejection. The pathogenicity of pre-transplant AT1R-Ab in pediatric kidney transplantation requires further investigation.
Assuntos
Anticorpos , Rejeição de Enxerto , Transplante de Rim , Receptor Tipo 1 de Angiotensina , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Adulto Jovem , Anticorpos/sangue , Estudos de Coortes , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Rim/patologia , Receptor Tipo 1 de Angiotensina/imunologiaRESUMO
COVID-19 shares the feature of autoantibody production with systemic autoimmune diseases. In order to understand the role of these immune globulins in the pathogenesis of the disease, it is important to explore the autoantibody spectra. Here we show, by a cross-sectional study of 246 individuals, that autoantibodies targeting G protein-coupled receptors (GPCR) and RAS-related molecules associate with the clinical severity of COVID-19. Patients with moderate and severe disease are characterized by higher autoantibody levels than healthy controls and those with mild COVID-19 disease. Among the anti-GPCR autoantibodies, machine learning classification identifies the chemokine receptor CXCR3 and the RAS-related molecule AGTR1 as targets for antibodies with the strongest association to disease severity. Besides antibody levels, autoantibody network signatures are also changing in patients with intermediate or high disease severity. Although our current and previous studies identify anti-GPCR antibodies as natural components of human biology, their production is deregulated in COVID-19 and their level and pattern alterations might predict COVID-19 disease severity.
Assuntos
Autoanticorpos/imunologia , COVID-19/imunologia , Receptores Acoplados a Proteínas G/imunologia , Sistema Renina-Angiotensina/imunologia , Autoanticorpos/sangue , Autoimunidade , Biomarcadores/sangue , COVID-19/sangue , COVID-19/classificação , Estudos Transversais , Feminino , Humanos , Aprendizado de Máquina , Masculino , Análise Multivariada , Receptor Tipo 1 de Angiotensina/imunologia , Receptores CXCR3/imunologia , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes.
Assuntos
Autoanticorpos/metabolismo , Doenças Cardiovasculares/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Receptor de Endotelina A/imunologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Colágeno/metabolismo , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Anti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been recognized as non-human leukocyte antigen antibodies associated with allograft rejection and poor allograft outcomes after kidney transplantation. The aim of this study was to assess the risk anti-AT1R-Abs pose for rejection and graft loss among kidney transplant (KT) populations. METHODS: We systematically searched PubMed, Embase and the Cochrane Library databases for relevant articles published from inception until June 2021 to identify all studies concerning the role AT1R-Abs play in the clinical outcome after kidney transplantation. Two reviewers independently identified studies, abstracted outcome data and assessed the quality of the studies. The meta-analysis was summarized using fixed-effects or random-effects models, according to heterogeneity. The major outcomes included delayed graft function, acute rejection, graft loss or patient death after transplantation. RESULTS: Twenty-one eligible studies involving a total of 4023 KT recipients were included in the evaluation. Meta-analysis results showed that the AT1R-Ab-positive KT group had a greater incidence of antibody-mediated rejection {relative risk [RR] 1.94 [95% confidence interval (CI) 1.61-2.33]; P < 0.00001} and graft loss [RR 2.37 (95% CI 1.50-3.75); P = 0.0002] than did the AT1R-Abs-negative KT group. There was no significant statistical difference in delayed graft function rate, T-cell-mediated rejection, mixed rejection, acute cellular rejection, acute rejection and patient death rate between the AT1R-Ab-positive KT and AT1R-Ab-negative KT groups. CONCLUSIONS: Our study shows that the presence of anti-AT1R-Abs was associated with a significantly higher risk of antibody-mediated rejection and graft loss in kidney transplantation. Future studies are still needed to evaluate the importance of routine anti-AT1R monitoring and therapeutic targeting. These results show that assessment of anti-AT1R-Abs would be helpful in determining immunologic risk and susceptibility to immunologic events for recipients.
Assuntos
Anticorpos , Transplante de Rim , Receptor Tipo 1 de Angiotensina , Função Retardada do Enxerto , Rejeição de Enxerto , Humanos , Receptor Tipo 1 de Angiotensina/imunologiaRESUMO
The stimulation of AT1R (Angiotensin II Receptor Type 1) by Angiotensin II has, in addition to the effects on the renin-angiotensin system, also pro-inflammatory effects through stimulation of ADAM17 and subsequent production of INF-gamma and Interleukin-6. This pro-inflammatory action stimulate the cytokine storm that characterizes the most severe forms of SARS-CoV-2 infection. We studied the effect of AT1Rab on the AT1R on 74 subjects with SARS-CoV-2 infection with respiratory symptoms requiring hospitalization. We divided the patients into 2 groups: 34 with moderate and 40 with severe symptoms that required ICU admission. Hospitalized subjects showed a 50% reduction in the frequency of AT1Rab compared to healthy reference population. Of the ICU patients, 33/40 (82.5%) were AT1Rab negative and 16/33 of them (48.5%) died. All 7 patients positive for AT1Rab survived. These preliminary data seem to indicate a protective role played by AT1R autoantibodies on inflammatory activation in SARS-CoV-2 infection pathology.
Assuntos
Autoanticorpos/imunologia , COVID-19/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoantígenos/imunologia , Feminino , Hospitalização , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2/imunologiaRESUMO
Objectives: 1) To detect functionally active antibodies(abs) to the angiotensin II type-1-receptor (AT1R) by a novel luminometric assay. 2) To assess their prevalence in systemic sclerosis (SSc), other collagen disorders, as well as in further chronic inflammatory disorders including autoimmune, toxic and chronic viral diseases. 3) To compare these abs with anti-AT1R antibodies by ELISA as well as with antibodies to endothelin-type-A receptors (ETA1) and to topoisomerase I (topo-I) with respect to their specificity and clinical relevance. Methods: Sera from 98 SSc-patients, 110 patients with other chronic inflammatory rheumatic disorders, 97 patients with autoimmune liver diseases, 57 patients with toxic or chronic viral liver diseases and 36 healthy controls were analyzed. A luminometric bioassay was established with Huh-7-cells constitutively expressing the AT1R. Patients' sera were also tested by commercially available ELISA for anti-AT1R, -ETA1- and by an in-house ELISA for anti-topo-I-abs. Results: Fifty-two percent of the SSc-patients had functionally active anti-AT1R-abs with stimulatory (34%) or inhibitory capacity (18%). They were present also in up to 59% of patients with other rheumatic diseases but only 22% of healthy individuals (sensitivity 52%, specificity 53%). The functionally active antibodies detected by the luminometric assay did not correlate with anti-AT1R-, -ETA1- or -topo-I-abs measured by ELISA, but there was a strong correlation between anti-topo-I-, AT1R-, and -ETA1-ab reactivity measured by ELISA. Sensitivities of 55%, 28% and 47% and specificities of 66%, 87%, and 99% were calculated for these anti-AT1R-, -ETA1-, and anti-topo-I-abs, respectively. Functionally active abs did not correlate with disease severity or any organ manifestation. In contrast, abs to topo-I, AT1R, and ETA1 were associated with digital ulcers, pulmonary- and esophageal manifestation. Conclusions: Functionally active anti-AT1R-abs can be detected in SSc-patients but do not correlate with disease activity. They are not specific for this disease and occur also in other autoimmune disorders and even viral or toxic diseases. Also, the vascular antibodies detected by ELISA are not SSc-specific but correlated with disease manifestations. In contrast, anti-topo-I-abs were confirmed to be a highly specific biomarker for both, diagnosis and organ manifestations of SSc.
Assuntos
Autoanticorpos/sangue , DNA Topoisomerases Tipo I/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Escleroderma Sistêmico/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Bioensaio/métodos , Biomarcadores/sangue , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Endotelina A/imunologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologia , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: The role of an alloimmune response against non-self-antigens is established in organ transplantation. HLA incompatibilities are mainly responsible for this recognition between donor and recipient, but they may also be involved in the reactivity against other alloantigens expressed on the allograft resulting from an autoimmune response developed against selfantigens. OBJECTIVE: Our study aimed to determine the presence of non-anti-HLA antibodies (anti-AT1R and anti-ETAR) in sera from patients with end-stage renal disease, who underwent kidney transplantation in pre- and post-transplantation samples to study their influence on the development and evolution of acute humoral rejections and DSAs. METHODS: Antibodies (Abs) against two G protein-coupled receptors (GPCRs), angiotensin II type 1 receptor (AT1R) and endothelin-1 type A receptor (ETAR), have been detected in the sera of transplant recipients, who experience allograft dysfunction, patients with coronary heart disease, marginal hypertension and refractory, vascular lesions, myocardial hypertrophy and chronic inflammatory diseases, such as atherosclerosis or sclerosis. RESULTS: Kidney graft recipients were monitored for anti-ETAR, -AT1R, and -HLA Abs in pre-and post-transplant evolution, and anti-AT1R and/or -ETAR Abs were detected in 24% of recipients (22.4% with anti-AT1R Abs and 9.8% with anti-ETAR Abs). Due to acute humoral rejection, Graft loss was detected in 6.4% of patients with anti-GPCRs non-HLA Abs, and 3.2% had DSA anti-HLA Abs. In this research, we have described how the function of the anti-GPCRs autoAbs and how these Abs that activate GPCRs could influence graft outcome. CONCLUSION: In conclusion, there is a high association of non-HLA anti-GPCRs Abs levels with reduced kidney function after transplantation, especially in the presence of DSA anti-HLA Abs. Although more studies are needed, anti-AT1R and anti-ETAR antibodies may be helpful biomarkers that allow the risk of graft loss to be assessed.
Assuntos
Anticorpos/química , Falência Renal Crônica/terapia , Transplante de Rim/métodos , Receptor Tipo 1 de Angiotensina/imunologia , Receptor de Endotelina A/imunologia , Adulto , Idoso , Anticorpos/imunologia , Anticorpos/farmacologia , Feminino , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Humanos , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , Doadores de Tecidos , Transplante Homólogo , Resultado do TratamentoRESUMO
Preeclampsia is a complex hypertensive disorder in pregnancy which can be lethal and is responsible for more than 70,000 maternal deaths worldwide every year. Besides the higher risk of unfavorable obstetric outcomes in women with preeclampsia, another crucial aspect that needs to be considered is the association between preeclampsia and the postpartum cardiovascular health of the mother. Currently, preeclampsia is classified as one of the major risk factors of cardiovascular disease (CVD) in women, which doubles the risk of venous thromboembolic events, stroke, and ischemic heart disease. In order to comprehend the pathophysiology behind the linkage between preeclampsia and the development of postpartum CVD, a thorough understanding of the abnormal uteroplacental vascular remodeling in preeclampsia is essential. Therefore, this review aims to summarize the current knowledge of the defective process of spiral artery remodeling in preeclampsia and how the resulting placental damage leads to excessive angiogenic imbalance and systemic inflammation in long term CVD. Key molecular factors in the pathway-including novel findings of microRNAs-will be discussed with suggestions of future management strategies of preventing CVD in women with a history of preeclampsia.
Assuntos
Doenças Cardiovasculares/etiologia , Placenta/irrigação sanguínea , Pré-Eclâmpsia/fisiopatologia , Útero/irrigação sanguínea , Autoanticorpos/sangue , Autoanticorpos/imunologia , Feminino , Humanos , MicroRNAs , Período Pós-Parto , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Gravidez , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Remodelação VascularRESUMO
BACKGROUND: Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies. METHODS AND FINDINGS: We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. None of the 13 patients without history of SARS-CoV-2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS-CoV-2 had levels of ACE2 antibodies above the cutoff threshold. In contrast, 26/32 (81%) in the convalescent group and 14/15 (93%) of patients acutely hospitalized had detectable ACE2 antibodies. Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies. We measured the capacity of the samples to inhibit ACE2 enzyme activity. Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies. CONCLUSIONS: Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC.
Assuntos
Autoanticorpos/sangue , COVID-19/imunologia , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/sangue , Angiotensina II/sangue , Angiotensina II/imunologia , Enzima de Conversão de Angiotensina 2/genética , Autoanticorpos/imunologia , Autoanticorpos/isolamento & purificação , COVID-19/sangue , COVID-19/virologia , Feminino , Humanos , Masculino , Peptidil Dipeptidase A/sangue , Receptor Tipo 1 de Angiotensina/sangue , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/imunologia , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/isolamento & purificaçãoRESUMO
Lung transplant patients have the lowest long-term survival rates compared to other solid organ transplants. The complications after lung transplantation such as primary graft dysfunction (PGD) and ultimately chronic lung allograft dysfunction (CLAD) are the main reasons for this limited survival. In recent years, lung-specific autoantibodies that recognize non-HLA antigens have been hypothesized to contribute to graft injury and have been correlated with PGD, CLAD, and survival. Mounting evidence suggests that autoantibodies can develop during pulmonary disease progression before lung transplant, termed pre-existing autoantibodies, and may participate in allograft injury after transplantation. In this review, we summarize what is known about pulmonary disease autoantibodies, the relationship between pre-existing autoantibodies and lung transplantation, and potential mechanisms through which pre-existing autoantibodies contribute to graft injury and rejection.
Assuntos
Autoanticorpos/imunologia , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias/etiologia , Bronquiolite Obliterante/imunologia , Glicosilação , Humanos , Pneumopatias/etiologia , Pneumopatias/imunologia , Doenças Pulmonares Intersticiais/imunologia , Complicações Pós-Operatórias/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Receptor de Endotelina A/imunologia , Transplante HomólogoRESUMO
The renin-angiotensin system (RAS) plays a major role in COVID-19. Severity of several inflammation-related diseases has been associated with autoantibodies against RAS, particularly agonistic autoantibodies for angiotensin type-1 receptors (AA-AT1) and autoantibodies against ACE2 (AA-ACE2). Disease severity of COVID-19 patients was defined as mild, moderate or severe following the WHO Clinical Progression Scale and determined at medical discharge. Serum AA-AT1 and AA-ACE2 were measured in COVID-19 patients (n = 119) and non-infected controls (n = 23) using specific solid-phase, sandwich enzyme-linked immunosorbent assays. Serum LIGHT (TNFSF14; tumor necrosis factor ligand superfamily member 14) levels were measured with the corresponding assay kit. At diagnosis, AA-AT1 and AA-ACE2 levels were significantly higher in the COVID-19 group relative to controls, and we observed significant association between disease outcome and serum AA-AT1 and AA-ACE2 levels. Mild disease patients had significantly lower levels of AA-AT1 (p < 0.01) and AA-ACE2 (p < 0.001) than moderate and severe patients. No significant differences were detected between males and females. The increase in autoantibodies was not related to comorbidities potentially affecting COVID-19 severity. There was significant positive correlation between serum levels of AA-AT1 and LIGHT (TNFSF14; rPearson = 0.70, p < 0.001). Both AA-AT1 (by agonistic stimulation of AT1 receptors) and AA-ACE2 (by reducing conversion of Angiotensin II into Angiotensin 1-7) may lead to increase in AT1 receptor activity, enhance proinflammatory responses and severity of COVID-19 outcome. Patients with high levels of autoantibodies require more cautious control after diagnosis. Additionally, the results encourage further studies on the possible protective treatment with AT1 receptor blockers in COVID-19.
Assuntos
Enzima de Conversão de Angiotensina 2/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , COVID-19/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Idoso , Autoanticorpos/imunologia , COVID-19/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/imunologia , SARS-CoV-2Assuntos
Autoanticorpos/sangue , Hipertensão/imunologia , Pré-Eclâmpsia/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Ecocardiografia , Feminino , Coração/diagnóstico por imagem , Coração/fisiopatologia , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Incidência , Pré-Eclâmpsia/diagnóstico por imagem , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Risco , Fatores de Tempo , Ultrassonografia Pré-Natal , Regulação para Cima , Adulto JovemRESUMO
RATIONALE: Anti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been demonstrated to increase the risk of antibody-mediated rejection. We report a case of AT1R-Ab mediated rejection which caused early critical cortical infarction. PATIENT CONCERNS: A 52-year-old man with end-stage kidney disease underwent preemptive kidney transplantation (KT) from his wife. He had no immunologic risk except ABO incompatibility. Proper desensitization treatment were applied prior to KT. On postoperative day 1, he showed stable clinical course with adequate urine output, but there was no decrease in serum creatinine level and imaging studies showed hypoperfusion in the transplanted kidney. DIAGNOSES: Allograft biopsy revealed total cortical infarction with severe necrotizing vasculitis, but the medullary area was preserved. Serum AT1R-Ab concentration was elevated from 10.9âU/mL before KT to 19.1âU/mL on 7âdays after KT. INTERVENTIONS: He was treated with plasmapheresis, intravenous immunoglobulin, rituximab, high-dose methylprednisolone, and bortezomib. OUTCOMES: The treatment showed a partial response, and he was discharged with 7.3âmg/dL creatinine level. At 4âmonths, his creatinine plateaued at 5.5âmg/dL and AT1R-Ab decreased to 3.6âU/mL. LESSONS: This case highlights the risk of early active antibody-mediated rejection by preformed AT1R-Ab, suggesting its ability to exhibit atypical histopathologic findings, such as total cortical infarction.
Assuntos
Rejeição de Enxerto/imunologia , Infarto/imunologia , Isoanticorpos/sangue , Necrose do Córtex Renal/imunologia , Transplante de Rim/efeitos adversos , Receptor Tipo 1 de Angiotensina/imunologia , Aloenxertos/irrigação sanguínea , Aloenxertos/imunologia , Aloenxertos/patologia , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/terapia , Teste de Histocompatibilidade , Humanos , Fatores Imunológicos/administração & dosagem , Infarto/sangue , Infarto/diagnóstico , Infarto/terapia , Isoanticorpos/imunologia , Córtex Renal/irrigação sanguínea , Córtex Renal/imunologia , Córtex Renal/patologia , Necrose do Córtex Renal/sangue , Necrose do Córtex Renal/diagnóstico , Necrose do Córtex Renal/terapia , Falência Renal Crônica/cirurgia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Plasmaferese , Cônjuges , Fatores de TempoRESUMO
Background: Lung histopathology demonstrates vasculopathy in a subset of deceased COVID19 patients, which resembles histopathology observed in antibody-mediated lung transplant rejection. Autoantibodies against angiotensin II type 1 receptor (AT1R) and Endothelin receptor Type A (ETAR) have been demonstrated in antibody-mediated rejection and may also be associated with severe COVID19 infection. Objective To assess AT1R and ETAR auto-antibodies in COVID19 patients and controls, and explore their association with disease course. Methods: 65 hospitalized patients with COVID19 infection were included. Clinical and laboratory findings were retrospectively assessed. Patients with unfavorable disease course, admitted at the intensive care unit and/or deceased during hospital admission (n=33) were compared to admitted COVID19 patients with favorable disease course (n=32). The presence of antinuclear antibodies (ANA) and auto-antibodies against AT1R or ETAR in peripheral blood were compared between COVID19 with unfavorable and favorable disease course and age matched controls (n=20). Results: The presence of ANA was not significantly different between COVID19 patients with unfavorable (n=7/33; 21%) and favorable disease course (n=6/32; 19%) (p= 0.804) and controls (n=3/20; 15%). Auto-antibodies against AT1R were significantly increased in unfavorable disease course (median 14.59 U/mL, IQR 11.28 - 19.89) compared to favorable disease course (median 10.67 U/mL, IQR 8.55 - 13.0, p< 0.01). ETAR antibody titers were also significantly increased in unfavorable disease course (median 7.21, IQR 5.0 - 10.45) as compared to favorable disease course (median 4.0, IQR 3.0 - 6.0, p <0.05). Conclusion: Auto-antibodies against AT1R and ETAR are significantly increased in COVID19 patients with an unfavorable disease course.
Assuntos
Autoanticorpos/sangue , COVID-19/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Receptor de Endotelina A/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/sangue , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Países Baixos , Receptor Tipo 1 de Angiotensina/sangue , Receptor de Endotelina A/sangue , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de DoençaRESUMO
Autoantibody against the angiotensin II type I receptor (AT1-AA) has been found in the serum of patients with diabetes mellitus (DM). However, it remains unclear whether AT1-AA induces ß-cell apoptosis and participates in the development of DM. In this study, an AT1-AA-positive rat model was set up by active immunization, and AT1-AA IgG was purified. INS-1 cells were treated with AT1-AA, and cell viability, apoptosis, and autophagy-related proteins were detected by Cell Counting Kit-8 assay, flow cytometry, and western blot analysis, respectively. Results showed that existence of AT1-AA impaired the islet function and increased the apoptosis of pancreatic islet cells in rats, and the autophagy level in rat pancreatic islet tissues tended to increase gradually with the prolongation of immunization time. AT1-AA markedly reduced INS-1 cell viability, promoted cell apoptosis, and decreased insulin secretion in vitro. In addition, the autophagy level was gradually increased along with the prolongation of AT1-AA treatment time. Meanwhile, it was determined that treatment with autophagy inhibitor 3-methyladenine and angiotensin II type 1 receptor (AT1R) blocker telmisartan could improve insulin secretion and apoptosis in vitro and in vivo. In conclusion, it is deduced that upregulation of autophagy contributed to the AT1-AA-induced ß-cell apoptosis and islet dysfunction, and AT1R mediated the signal transduction.
Assuntos
Apoptose/efeitos dos fármacos , Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Células Secretoras de Insulina/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Adenina/análogos & derivados , Adenina/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Apoptose/imunologia , Autoanticorpos/isolamento & purificação , Autofagia/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Imunização/métodos , Imunoglobulina G/isolamento & purificação , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/imunologia , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Telmisartan/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
Intruduction and aim: Angiotensin II type 1 receptor antibodies (AT1R-Ab) are associated with graft rejection and poor graft outcomes in kidney transplantation (KT). We aimed to assess the frequency of preformed AT1R-Ab and their impact on graft function and survival at 1 year after KT in a low immunological risk cohort. METHODS: We performed a prospective, observational cohort study in 67 adult KT recipients, transplanted between 2018 and 2019. A cut-off value >10 U/ml was used for AT1R-Ab detection. RESULTS: The frequency of preformed AT1R-Ab was 10.4% and the median value of their level was 8.4 U/ml (IQR: 6.8-10.4). Donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) were absent, no case of biopsy-proven rejection was reported and the incidence of graft failure was 7.5%. Estimated glomerular filtration rate (eGFR) was significantly reduced in the AT1R-Ab group [35 (29.8-55.2) vs 56.1 (41.3-66.5) ml/min, p = 0.02] at 1 year after KT. After multivariate linear regression analysis, preformed AT1R-Ab were found as an independent determinant of eGFR at 1 year after KT (ß: -15.395; 95% CI: -30.49 - -0.30; p = 0.04). By Cox multivariate regression analysis, preformed AT1R-Ab were not associated with graft failure (HR: 1.36; 95% CI:0.10-14.09; p = 0.80). CONCLUSION: Preformed AT1R-Ab are an independent determinant of graft function but do not impact graft survival at 12 months after transplantation in a prospective low immunological risk cohort of KT recipients.