Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 155
Filtrar
1.
J Exp Med ; 218(5)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33783474

RESUMO

Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >50% of sporadic SLE patients with nephritis manifested reduced DNASE1L3 activity in circulation, which was associated with neutralizing autoantibodies to DNASE1L3. These patients had normal total plasma cfDNA levels but showed accumulation of cfDNA in circulating microparticles. Microparticle-associated cfDNA contained a higher fraction of longer polynucleosomal cfDNA fragments, which bound autoantibodies with higher affinity than mononucleosomal fragments. Autoantibodies to DNASE1L3-sensitive antigens on microparticles were prevalent in SLE nephritis patients and correlated with the accumulation of cfDNA in microparticles and with disease severity. DNASE1L3-sensitive antigens included DNA-associated proteins such as HMGB1. Our results reveal autoantibody-mediated impairment of DNASE1L3 activity as a common nongenetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.

2.
Lupus Sci Med ; 8(1)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33737451

RESUMO

OBJECTIVE: Hydroxychloroquine (HCQ) is a mainstay of therapy in the treatment of SLE. The effect of HCQ on platelets and vascular health is uncertain. We investigated the relationship between HCQ use and dose with platelet activity, platelet transcriptomics and vascular health in patients with SLE. METHODS: Platelet aggregation, platelet mRNA expression and vascular health (sublingual capillary perfused boundary region (PBR), red blood cell filling (RBCF) and brachial artery reactivity testing) were analysed by HCQ use and dose. RESULTS: Among 132 subjects with SLE (age: 39.7±12.9 years, 97% female), 108 were on HCQ. SLE disease activity was similar between subjects on and off HCQ. Platelet aggregation in response to multiple agonists was significantly lower in patients on HCQ. There were inverse relationships between HCQ dose and gene expression pathways of platelet activity. Gene expression of P-selectin (SELP) was inversely correlated with HCQ dose (r=-0.41, p=0.003), which was validated at the protein level. Subjects on HCQ had improved vascular function correlating with HCQ dose as measured by lower PBR (r=-0.52, p=0.007), higher RBCF (r=0.55, p=0.004) and greater brachial artery reactivity (r=0.43, p=0.056). CONCLUSION: HCQ use was associated with decreased platelet activation and activation-related transcripts and improved vascular health in SLE.

3.
Circ Arrhythm Electrophysiol ; 13(10): e008686, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32907357

RESUMO

BACKGROUND: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine is being considered as prophylaxis and treatment of coronavirus disease-19 (COVID-19). Although hydroxychloroquine is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematosus and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy. METHODS: To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal ECGs and hydroxychloroquine blood levels were available in a recently completed study evaluating the efficacy of hydroxychloroquine 400 mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro (anti-Sjögren's Syndrome A/Ro) antibodies. RESULTS: Forty-five ECGs were available for corrected QT interval (QTc) measurement, and levels of hydroxychloroquine were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of hydroxychloroquine and the neonatal QTc (R=0.02, P=0.86) or the mean of hydroxychloroquine values obtained throughout each individual pregnancy and the QTc (R=0.04, P=0.80). In total 5 (11% [95% CI, 4%-24%]) neonates had prolongation of the QTc >2 SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal. CONCLUSIONS: In aggregate, these data provide reassurances that the maternal use of hydroxychloroquine is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01379573.


Assuntos
Antivirais/administração & dosagem , Eletrocardiografia , Coração Fetal/efeitos dos fármacos , Bloqueio Cardíaco/congênito , Frequência Cardíaca/efeitos dos fármacos , Hidroxicloroquina/administração & dosagem , Antivirais/efeitos adversos , Antivirais/sangue , Cardiotoxicidade , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Sangue Fetal/metabolismo , Coração Fetal/fisiopatologia , Idade Gestacional , Bloqueio Cardíaco/diagnóstico , Bloqueio Cardíaco/fisiopatologia , Bloqueio Cardíaco/prevenção & controle , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/sangue , Lactente , Recém-Nascido , Masculino , Valor Preditivo dos Testes , Gravidez , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
4.
Arthritis Res Ther ; 22(1): 191, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807233

RESUMO

BACKGROUND: Although hydroxychloroquine (HCQ) is a mainstay of treatment for patients with systemic lupus erythematosus (SLE), ocular toxicity can result from accumulated exposure. As the longevity of patients with SLE improves, data are needed to balance the risk of ocular toxicity and the risk of disease flare, especially in older patients with quiescent disease. Accordingly, this study was initiated to examine the safety of HCQ withdrawal in older SLE patients. METHODS: Data were obtained by retrospective chart review at three major lupus centers in New York City. Twenty-six patients who discontinued HCQ and thirty-two patients on HCQ matched for gender, race/ethnicity, and age were included in this study. The primary outcome was the occurrence of a lupus flare classified by the revised version of the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare composite index, within 1 year of HCQ withdrawal or matched time of continuation. RESULTS: Five patients (19.2%) in the HCQ withdrawal group compared to five (15.6%) in the HCQ continuation group experienced a flare of any severity (odds ratio [OR] = 1.28; 95% CI 0.31, 5.30; p = 0.73). There were no severe flares in either group. The results were similar after adjusting for length of SLE, number of American College of Rheumatology criteria, low complement levels, and SELENA-SLEDAI score, and in a propensity score analysis (OR = 1.18; 95% CI 0.23, 6.16; p = 0.84). The analysis of time to any flare revealed a non-significant earlier time to flare in the HCQ withdrawal group (log-rank p = 0.67). Most flares were in the cutaneous and musculoskeletal systems, but one patient in the continuation group developed pericarditis. The most common reason for HCQ withdrawal was retinal toxicity (42.3%), followed by patient's preference (34.6%), other confirmed or suspected adverse effects (15.4%), ophthalmologist recommendation for macular degeneration (3.8%), and rheumatologist recommendation for quiescent SLE (3.8%). CONCLUSIONS: In this retrospective study of older stable patients with SLE on long-term HCQ, withdrawal did not significantly increase the risk of flares.

5.
Arthritis Rheumatol ; 72(12): 1971-1980, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32715660

RESUMO

OBJECTIVE: To characterize patients with systemic lupus erythematosus (SLE) affected by coronavirus disease 2019 (COVID-19) and to analyze associations of comorbidities and medications on infection outcomes. METHODS: Patients with SLE and reverse transcriptase-polymerase chain reaction-confirmed COVID-19 were identified through an established New York University lupus cohort, query of 2 hospital systems, and referrals from rheumatologists. Data were prospectively collected via a web-based questionnaire and review of medical records. Data on baseline characteristics were obtained for all patients with COVID-19 to analyze risk factors for hospitalization. Data were also collected on asymptomatic patients and those with COVID-19-like symptoms who tested negative or were not tested. Statistical analyses were limited to confirmed COVID-19-positive patients. RESULTS: A total of 226 SLE patients were included: 41 with confirmed COVID-19, 19 who tested negative for COVID-19, 42 with COVID-19-like symptoms who did not get tested, and 124 who remained asymptomatic without testing. Of the SLE patients with confirmed COVID-19, hospitalization was required in 24 (59%) and intensive care unit-level of care in 4, and 4 died. Hospitalized patients tended to be older, nonwhite, Hispanic, have higher body mas index (BMI), history of nephritis, and at least 1 comorbidity. An exploratory (due to limited sample size) logistic regression analysis identified race, presence of at least 1 comorbidity, and BMI as independent predictors of hospitalization. CONCLUSION: In general, the variables predictive of hospitalization in our SLE patients were similar to those identified in the general population. Further studies are needed to understand additional risk factors for poor COVID-19 outcomes in patients with SLE.

6.
J Am Coll Cardiol ; 76(3): 292-302, 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32674792

RESUMO

BACKGROUND: Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES: Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS: This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS: By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS: These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).

7.
Artigo em Inglês | MEDLINE | ID: mdl-32433832

RESUMO

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) 2012 SLE classification criteria and the revised American College of Rheumatology (ACR) 1997 criteria are list-based, counting each SLE manifestation equally. We derived a classification rule based on giving variable weights to the SLICC criteria, and compared its performance to the revised ACR 1997, unweighted SLICC 2012 and the newly reported European League Against Rheumatism (EULAR)/ACR 2019 criteria. METHODS: The physician-rated patient scenarios used to develop the SLICC 2012 classification criteria were re-employed to devise a new weighted classification rule using multiple linear regression. The performance of the rule was evaluated on an independent set of expert-diagnosed patient scenarios and compared to the performance of the previously reported classification rules. RESULTS: Weighted SLICC criteria and the EULAR/ACR 2019 criteria had less sensitivity but better specificity compared to the list-based revised ACR 1997 and SLICC 2012 classification criteria. There were no statistically significant differences between any pair of rules with respect to overall agreement with the physician diagnosis. CONCLUSION: The two new weighted classification rules did not perform better than the existing list-based rules in terms of overall agreement on a dataset originally generated to assess the SLICC criteria. Given the added complexity of summing weights, researchers may prefer the unweighted SLICC criteria. However, the performance of a classification rule will always depend on the populations from which the cases and non-cases are derived, and whether the goal is to prioritize sensitivity or specificity.

8.
Lupus Sci Med ; 7(1)2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32371480

RESUMO

OBJECTIVES: To evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4. METHODS: All subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively. Lupus severity was estimated using the Lupus Severity Index (LSI). Statistical analysis consisted of multivariable linear regression and groups comparisons. RESULTS: Abnormal CB-CAPs were more prevalent than low complement values irrespective of LSI levels (62% vs 38%, respectively, p<0.0001). LSI was low (median 5.44, IQR: 4.77-6.93) in patients with no complement abnormality, intermediate in patients with abnormal CB-CAPs (median 6.09, IQR: 5.31-8.20) and high in the group presenting with both abnormal CB-CAPs and low C3 and/or C4 (median 7.85, IQR: 5.51-8.37). Odds of immunosuppressant use was higher in subjects with LSI ≥5.95 compared with subjects with LSI <5.95 (1.60 vs 0.53, p<0.0001 for both). Multivariable regression analysis revealed that higher LSI scores associated with abnormal CB-CAPs-but not low C3/C4-after adjusting for younger age, race and longer disease duration (p=0.0001), which were also independent predictors of disease severity (global R2=0.145). CONCLUSION: Abnormalities in complement activation as measured by CB-CAPs are associated with increased LSI.

9.
Lupus Sci Med ; 7(1): e000396, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341791

RESUMO

Over the 2 months since coronavirus first appeared in China, cases have emerged on every continent, and it is clear that patients with autoimmune diseases might also be affected. Coronavirus disease 2019 (COVID-19) is a highly contagious viral illness with a mortality rate approaching 2%. Here we discuss the challenges that patients with autoimmune diseases might face and the information on using immunomodulatory therapies like chloroquine, tocilizumab and baricitinib to quench the cytokine storm in patients with very severe COVID-19 pneumonia.


Assuntos
Doenças Autoimunes/complicações , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Imunomodulação , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doenças Autoimunes/terapia , Azetidinas/uso terapêutico , Betacoronavirus , Cloroquina/uso terapêutico , Síndrome da Liberação de Citocina , Humanos , Hidroxicloroquina/uso terapêutico , Imunossupressão , Pandemias , Reumatologia , Sulfonamidas/uso terapêutico
10.
Prenat Diagn ; 40(9): 1066-1076, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32282083

RESUMO

Systemic lupus erythematosus (SLE) primarily affects women of childbearing age and is commonly seen in pregnancy. The physiologic and immunologic changes of pregnancy may alter the course of SLE and impact maternal, fetal, and neonatal health. Multidisciplinary counseling before and during pregnancy from rheumatology, maternal fetal medicine, obstetrics, and pediatric cardiology is critical. Transplacental passage of autoantibodies, present in about 40% of women with SLE, can result in neonatal lupus (NL). NL can consist of usually permanent cardiac manifestations, including conduction system and myocardial disease, as well as transient cutaneous, hematologic, and hepatic manifestations. Additionally, women with SLE are more likely to develop adverse pregnancy outcomes such as preeclampsia, fetal growth restriction, and preterm birth, perhaps due to an underlying effect on placentation. This review describes the impact of SLE on maternal and fetal health by trimester, beginning with prepregnancy optimization of maternal health. This is followed by a discussion of NL and the current understanding of the epidemiology and pathophysiology of anti-Ro/La mediated cardiac disease, as well as screening, treatment, and methods for prevention. Finally discussed is the known increase in preeclampsia and fetal growth issues in women with SLE that can lead to iatrogenic preterm delivery.

11.
Arthritis Res Ther ; 22(1): 52, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32188491

RESUMO

BACKGROUND: Lupus patients are at risk for pregnancy loss, and it has been generally accepted that women with SLE should have low disease activity prior to conception. However, there are conflicting results regarding the effect of pregnancy on SLE flares. This study aims to identify predictors of flares during and after pregnancy in SLE patients with inactive or stable disease activity during the first trimester and to characterize and estimate the frequency of post-partum flares in these patients. METHODS: SLE patients in the multicenter, prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study were evaluated for flares during and after pregnancy using the SELENA-SLEDAI Flare Index. Flares during pregnancy were assessed in all 384 patients and post-partum flares in 234 patients with study visits 2-6 months post-partum. Logistic regression models were fit to the data to identify independent risk factors for flare. RESULTS: During pregnancy, 20.8% of patients had mild/moderate flares and 6.25% had severe. Post-partum, 27.7% of patients had mild/moderate flares and 1.7% had severe. The mild flares rarely required treatment. Younger age, low C4 and higher PGA at baseline were independently associated with higher risk of having at least one mild/moderate or severe flare during pregnancy. Older patients were at decreased risk of flare, as well as those with quiescent disease at baseline. No variables evaluated at baseline or the visit most proximal to delivery was significantly associated with risk of flare post-partum. Medications were not associated with flare during or after pregnancy. CONCLUSION: In patients with inactive or stable mild disease activity at the time of conception, lupus disease flares during and after pregnancy are typically mild and occur at similar rates. Flares during pregnancy are predicted by the patients' age and clinical and serological activity at baseline.

12.
Mayo Clin Proc ; 95(2): 384-394, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32029091

RESUMO

Systemic lupus erythematosus (SLE) is a chronic, multiorgan, systemic autoimmune disease that is more common in women than men and is typically diagnosed during reproductive age, necessitating sex-specific considerations in care. In women there is no substantive evidence to suggest that SLE reduces fertility, but subfertility may occur as a result of active disease, immunosuppressive drugs, and age-related declines in fertility related to delays in childbearing. Although pregnancy outcomes have improved, SLE still poses risks in pregnancy that contribute to poorer maternal and fetal outcomes. Cyclophosphamide, an important agent for the treatment of severe or life-threatening lupus, may adversely affect fertility, particularly with increases in dose and patient age. Fertility preservation techniques are therefore an important consideration for women and men before cytotoxic treatment. There is mixed evidence as to whether exogenous estrogen in the form of oral contraceptive pills or hormone replacement therapy may increase the risk for the development of SLE, but among women with SLE already diagnosed, combined oral contraceptive pills and hormone replacement therapy do not confer risk for severe flare and remain important in reproductive care. The higher incidence of SLE in women may nonetheless be attributable to effects of endogenous estrogen, as well as failures in X chromosome inactivation, increased Toll-like receptor gene products, and changes in microRNA function. A greater appreciation of the biological underpinnings and consequences of sex differences in SLE may lead to more targeted treatments and improved outcomes for patients with SLE.


Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/epidemiologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Incidência , Masculino , Camundongos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Cuidado Pré-Natal , Prevalência , Fatores Sexuais
14.
Cardiovasc Res ; 116(8): 1446-1457, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31589297

RESUMO

AIMS: Investigating human heart development and applying this to deviations resulting in disease is incomplete without molecular characterization of the cell types required for normal functioning. We investigated foetal human heart single-cell transcriptomes from mid-gestational healthy and anti-SSA/Ro associated congenital heart block (CHB) samples. METHODS AND RESULTS: Three healthy foetal human hearts (19th to 22nd week of gestation) and one foetal heart affected by autoimmune-associated CHB (21st week of gestation) were subjected to enzymatic dissociation using the Langendorff preparation to obtain single-cell suspensions followed by 10× Genomics- and Illumina-based single-cell RNA-sequencing (scRNA-seq). In addition to the myocytes, fibroblasts, immune cells, and other minor cell types, previously uncharacterized diverse sub-populations of endothelial cells were identified in the human heart. Differential gene expression analysis revealed increased and heterogeneous interferon responses in varied cell types of the CHB heart compared with the healthy controls. In addition, we also identified matrisome transcripts enriched in CHB stromal cells that potentially contribute to extracellular matrix deposition and subsequent fibrosis. CONCLUSION: These data provide an information-rich resource to further our understanding of human heart development, which, as illustrated by comparison to a heart exposed to a maternal autoimmune environment, can be leveraged to provide insight into the pathogenesis of disease.

15.
Ann Rheum Dis ; 79(2): 217-224, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31672776

RESUMO

OBJECTIVES: Cardiac manifestations of neonatal lupus (NL) have been associated with significant morbidity and mortality; however, there is minimal information on long-term outcomes of affected individuals. This study was initiated to evaluate the presence of and the risk factors associated with cardiac dysfunction in NL after birth in multiple age groups to improve counselling, to further understand pathogenesis and to provide potential preventative strategies. METHODS: Echocardiogram reports were evaluated in 239 individuals with cardiac NL: 143 from age 0-1 year, 176 from age >1-17 years and 64 from age >17 years. Logistic regression analyses evaluated associations of cardiac dysfunction at each age group with demographic, fetal and postnatal factors, using imputation to address missing data. RESULTS: Cardiac dysfunction was identified in 22.4% at age 0-1 year, 14.8% at age >1-17 years and 28.1% at age >17 years. Dysfunction in various age groups was significantly associated with male sex, black race, lower fetal heart rates, fetal extranodal cardiac disease and length of time paced. In 106 children with echocardiograms at ages 0-1 year and >1-17 years, 43.8% with dysfunction at age 0-1 year were also affected at age >1-17 years, while the others reverted to normal. Of children without dysfunction at age 0-1 year, 8.9% developed new dysfunction between ages >1 and 17 years. Among 34 with echocardiograms at ages >1-17 years and >17 years, 6.5% with normal function at age >1-17 years developed dysfunction in adulthood. CONCLUSIONS: Risk factors in fetal life can influence cardiac morbidity into adulthood.Although limited by a small number of cases, cardiac dysfunction in the first year often normalises by later childhood. New-onset dysfunction, although rare, can occur de novo after the first year.


Assuntos
Ecocardiografia , Cardiopatias/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/congênito , Fatores de Tempo , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Cardiopatias/congênito , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Sistema de Registros , Fatores de Risco , Adulto Jovem
17.
JCI Insight ; 4(20)2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31536480

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell-B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here, we evaluated the phenotypes of CD4+ T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1hiCXCR5-CD4+ T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1hiCXCR5-CD4+ T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5- T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not T follicular helper (Tfh) cells, correlated with both clinical disease activity and the frequency of CD11c+ B cells in SLE patients. PD-1hiCD4+ T cells were found within lupus nephritis kidneys and correlated with B cell numbers in the kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells as a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.


Assuntos
Linfócitos B/imunologia , Interleucinas/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Proto-Oncogênicas c-maf/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Antígeno CD11c/metabolismo , Sistemas CRISPR-Cas/genética , Estudos de Casos e Controles , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/genética , Comunicação Celular/imunologia , Técnicas de Cultura de Células , Separação Celular , Células Cultivadas , Técnicas de Cocultura , Feminino , Citometria de Fluxo , Técnicas de Inativação de Genes , Humanos , Interleucinas/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/sangue , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-maf/genética , RNA-Seq , Receptores CXCR5/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
19.
Mayo Clin Proc ; 94(8): 1436-1443, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31303426

RESUMO

OBJECTIVE: To assess the prevalence of atherosclerotic cardiovascular disease (ASCVD) and its individual phenotypes of coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease by age and sex in a large US cohort of hospitalized patients with systemic lupus erythematosus (SLE). METHODS: A nested case-control study of adults with and without SLE was conducted from the January 1, 2008, through December 31, 2014, National Inpatient Sample. Hospitalized patients with SLE were matched (1:3) by age, sex, race, and calendar year to hospitalized patients without SLE. The prevalences of CAD, PAD, and cerebrovascular disease were evaluated, and associations with SLE were determined after adjustment for common cardiovascular risk factors. RESULTS: Among the 252,676 patients with SLE and 758,034 matched patients without SLE, the mean age was 51 years, 89% were women, and 49% were white. Patients with SLE had a higher prevalence of ASCVD vs those without SLE (25.6% vs 19.2%; OR, 1.45; 95% CI, 1.44-1.47; P<.001). After multivariable adjustment, SLE was associated with a greater odds of ASCVD (adjusted odds ratio [aOR], 1.46; 95% CI, 1.41-1.51). The association between SLE and ASCVD was observed in women and men and was attenuated with increasing age. Also, SLE was associated with increased odds of CAD (aOR, 1.42; 95% CI, 1.40-1.44), PAD (aOR, 1.25; 95% CI, 1.22-1.28), and cerebrovascular disease (aOR, 1.68; 95% CI, 1.65-1.71). CONCLUSION: In hospitalized US patients, SLE was associated with increased ASCVD prevalence, which was observed in both sexes and was greatest in younger patients.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Doença Arterial Periférica/epidemiologia , Adulto , Distribuição por Idade , Estudos de Casos e Controles , Comorbidade , Intervalos de Confiança , Feminino , Seguimentos , Humanos , Pacientes Internados/estatística & dados numéricos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Doença Arterial Periférica/diagnóstico , Prevalência , Estudos Retrospectivos , Índice de Gravidade de Doença , Distribuição por Sexo , Fatores de Tempo , Estados Unidos
20.
Nat Immunol ; 20(7): 902-914, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209404

RESUMO

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.


Assuntos
Rim/imunologia , Nefrite Lúpica/imunologia , Biomarcadores , Biópsia , Análise por Conglomerados , Biologia Computacional/métodos , Células Epiteliais/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunofenotipagem , Interferons/metabolismo , Rim/metabolismo , Rim/patologia , Leucócitos/imunologia , Leucócitos/metabolismo , Nefrite Lúpica/genética , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Anotação de Sequência Molecular , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Célula Única , Transcriptoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...