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1.
Front Immunol ; 12: 730766, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630410

RESUMO

The SARS-CoV-2 pandemic has spread to all parts of the world and can cause life-threatening pneumonia and other severe disease manifestations known as COVID-19. This health crisis has resulted in a significant effort to stop the spread of this new coronavirus. However, while propagating itself in the human population, the virus accumulates mutations and generates new variants with increased fitness and the ability to escape the human immune response. Here we describe a color-based barcoded spike flow cytometric assay (BSFA) that is particularly useful to evaluate and directly compare the humoral immune response directed against either wild type (WT) or mutant spike (S) proteins or the receptor-binding domains (RBD) of SARS-CoV-2. This assay employs the human B lymphoma cell line Ramos, transfected for stable expression of WT or mutant S proteins or a chimeric RBD-CD8 fusion protein. We find that the alpha and beta mutants are more stably expressed than the WT S protein on the Ramos B cell surface and/or bind with higher affinity to the viral entry receptor ACE2. However, we find a reduce expression of the chimeric RBD-CD8 carrying the point mutation N501Y and E484K characteristic for the alpha and beta variant, respectively. The comparison of the humoral immune response of 12 vaccinated probands with 12 COVID-19 patients shows that after the boost, the S-specific IgG class immune response in the vaccinated group is similar to that of the patient group. However, in comparison to WT the specific IgG serum antibodies bind less well to the alpha variant and only poorly to the beta variant S protein. This is in line with the notion that the beta variant is an immune escape variant of SARS-CoV-2. The IgA class immune response was more variable than the IgG response and higher in the COVID-19 patients than in the vaccinated group. In summary, we think that our BSFA represents a useful tool to evaluate the humoral immunity against emerging variants of SARS-CoV-2 and to analyze new vaccination protocols against these variants.


Assuntos
COVID-19/imunologia , Separação Celular/métodos , Citometria de Fluxo/métodos , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Antivirais/metabolismo , Formação de Anticorpos , Feminino , Humanos , Imunização Secundária , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação/genética , Glicoproteína da Espícula de Coronavírus/genética , Vacinação
2.
RMD Open ; 7(3)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34670840

RESUMO

INTRODUCTION: Several risk factors for severe COVID-19 specific for patients with inflammatory rheumatic and musculoskeletal diseases (RMDs) have been identified so far. Evidence regarding the influence of different RMD treatments on outcomes of SARS-CoV-2 infection is still poor. METHODS: Data from the German COVID-19-RMD registry collected between 30 March 2020 and 9 April 2021 were analysed. Ordinal outcome of COVID-19 severity was defined: (1) not hospitalised, (2) hospitalised/not invasively ventilated and (3) invasively ventilated/deceased. Independent associations between demographic and disease features and outcome of COVID-19 were estimated by multivariable ordinal logistic regression using proportional odds model. RESULTS: 2274 patients were included. 83 (3.6%) patients died. Age, male sex, cardiovascular disease, hypertension, chronic lung diseases and chronic kidney disease were independently associated with worse outcome of SARS-CoV-2 infection. Compared with rheumatoid arthritis, patients with psoriatic arthritis showed a better outcome. Disease activity and glucocorticoids were associated with worse outcome. Compared with methotrexate (MTX), TNF inhibitors (TNFi) showed a significant association with better outcome of SARS-CoV-2 infection (OR 0.6, 95% CI0.4 to 0.9). Immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin) (OR 2.2, 95% CI 1.3 to 3.9), Janus kinase inhibitor (JAKi) (OR 1.8, 95% CI 1.1 to 2.7) and rituximab (OR 5.4, 95% CI 3.3 to 8.8) were independently associated with worse outcome. CONCLUSION: General risk factors for severity of COVID-19 play a similar role in patients with RMDs as in the normal population. Influence of disease activity on COVID-19 outcome is of great importance as patients with high disease activity-even without glucocorticoids-have a worse outcome. Patients on TNFi show a better outcome of SARS-CoV-2 infection than patients on MTX. Immunosuppressants, rituximab and JAKi are associated with more severe course.

3.
Front Immunol ; 12: 696810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335609

RESUMO

Changed dietary habits in Western countries such as reduced fiber intake represent an important lifestyle factor contributing to the increase in inflammatory immune-mediated diseases. The mode of action of beneficial fiber effects is not fully elucidated, but short-chain fatty acids (SCFA) and gut microbiota have been implicated. The aim of this study was to explore the impact of dietary fiber on lupus pathology and to understand underlying mechanisms. Here, we show that in lupus-prone NZB/WF1 mice low fiber intake deteriorates disease progression reflected in accelerated mortality, autoantibody production and immune dysregulation. In contrast to our original assumption, microbiota suppression by antibiotics or direct SCFA feeding did not influence the course of lupus-like disease. Mechanistically, our data rather indicate that in low fiber-fed mice, an increase in white adipose tissue mass, fat-inflammation and a disrupted intestinal homeostasis go along with systemic, low-grade inflammation driving autoimmunity. The links between obesity, intestinal leakage and low-grade inflammation were confirmed in human samples, while adaptive immune activation predominantly correlated with lupus activity. We further propose that an accelerated gastro-intestinal passage along with energy dilution underlies fiber-mediated weight regulation. Thus, our data highlight the often-overlooked effects of dietary fiber on energy homeostasis and obesity prevention. Further, they provide insight into how intricately the pathologies of inflammatory immune-mediated conditions, such as obesity and autoimmunity, might be interlinked, possibly sharing common pathways.

4.
Z Rheumatol ; 80(7): 641-646, 2021 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-34196793

RESUMO

The COVID-19 registry ( www.covid19-rheuma.de ) of the German Society of Rheumatology was the first registry for the acquisition and systemic evaluation of viral infections in patients with inflammatory rheumatic diseases (IRD). This has enabled rapid generation of scientific data that will help to improve the care of patients with IRD in the context of the pandemic. In addition to confirming general risk factors, such as patient age and comorbidities (e.g. cardiovascular, chronic lung and kidney diseases), the use of glucocorticoids and the disease activity of the rheumatic disease could be identified as disease-specific independent risk factors for the need of hospitalization due to COVID-19. Evaluations of the continuously growing cohort of patients with IRD and COVID-19 enable recommendations for patient care to be based on better evidence. Cooperation with international rheumatology registries (e.g. European COVID-19 registry for IRD) enables analyses of aggregated cohorts of patients with IRD and COVID-19 for international comparisons and statistically even more reliable statements.


Assuntos
COVID-19 , Doenças Reumáticas , Reumatologia , Humanos , Pandemias , Sistema de Registros , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/epidemiologia , SARS-CoV-2
5.
Front Immunol ; 12: 673912, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34108971

RESUMO

Objectives: ANCA-associated vasculitides (AAV) affect small- and medium-sized blood vessels. In active disease, vessel wall infiltrates are mainly composed of monocytes and macrophages. Immune checkpoint molecules are crucial for the maintenance of self-tolerance and the prevention of autoimmune diseases. After checkpoint inhibitor therapy, the development of autoimmune vasculitis has been observed. However, defects of immune checkpoint molecules in AAV patients have not been identified yet. Methods: Monocytes and monocyte-derived macrophages from AAV patients and healthy age-matched controls were tested for surface expression of immunoinhibitory checkpoint programmed cell death ligand-1 (PD-L1). Using in vitro co-culture approaches, the effect of monocyte PD-L1 expression on CD4+ T cell activation and proliferation was tested. Results: Monocytes from AAV patients displayed lower PD-L1 expression and a defective PD-L1 presentation upon activation, an effect that was correlated with disease activity. Lower PD-L1 expression was due to increased lysosomal degradation of PD-L1 in AAV monocytes. We identified a reduced expression of CMTM6, a protein protecting PD-L1 from lysosomal breakdown, as the underlying molecular defect. PD-L1low AAV monocytes showed increased stimulatory capacity and induced T cell activation and proliferation. Inhibiting lysosomal function corrected this phenotype by increasing PD-L1, thus normalizing the pro-stimulatory behavior of AAV monocytes. Conclusions: This study identifies a defect of the immunoinhibitory checkpoint PD-L1 in monocytes from patients with AAV. Low expression of CMTM6 results in enhanced lysosomal degradation of PD-L1, thus providing insufficient negative signaling to T cells. Correcting this defect by targeting lysosomal function may represent a novel strategy to treat AAV.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Antígeno B7-H1/imunologia , Ativação Linfocitária/imunologia , Proteínas com Domínio MARVEL/metabolismo , Monócitos/imunologia , Proteínas da Mielina/metabolismo , Idoso , Apresentação do Antígeno/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo
6.
Clin Exp Rheumatol ; 39(3): 639-647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33822706

RESUMO

OBJECTIVES: Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are the most common inflammatory rheumatic diseases (IRD). The aim of this study was to elucidate differences in the outcome of SARS-CoV-2 infection in RA- and SpA-patients. METHODS: Data from the German COVID-19 registry for IRD patients from 30th March to 16th November 2020 were analysed. 208 RA and SpA patients were included in the study, matched for gender and age. RESULTS: 104 SpA patients (40% patients with ankylosing spondylitis, 54% with psoriatic arthritis and 6% with enteropathic arthritis) were compared to 104 RA patients. For both groups, median age was 56 years. TNF-i treatment was reported in 45% of the SpA and in 19% of RA patients (p=0.001). Glucocorticoids were used in 13% of the SpA and in 40% of the RA patients (p=0.001). In both groups, the majority of the patients (97% SpA, 95% RA) recovered from COVID-19. Hospitalisation was needed in 16% of the SpA and in 30% of the RA patients (p=0.05), and oxygen treatment in 10% and 18% respectively (p=ns). Three versus six (p=ns) fatal courses were reported in the SpA versus the RA group. CONCLUSIONS: The study revealed that the hospitalisation rate during COVID-19 infection, but not the mortality, was significantly higher in RA as compared to SpA patients. This could be explained either by different treatment strategies or by different susceptibilities of the two diseases.


Assuntos
Artrite Psoriásica , Artrite Reumatoide , COVID-19 , Espondilartrite , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Humanos , Pessoa de Meia-Idade , SARS-CoV-2 , Espondilartrite/tratamento farmacológico , Espondilartrite/epidemiologia
7.
BMJ Open ; 11(3): e044483, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737437

RESUMO

INTRODUCTION: Systemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease associated with high morbidity and mortality, especially in diffuse cutaneous SSc (dcSSc). Currently, there are several treatments available in early dcSSc that aim to change the disease course, including immunosuppressive agents and autologous haematopoietic stem cell transplantation (HSCT). HSCT has been adopted in international guidelines and is offered in current clinical care. However, optimal timing and patient selection for HSCT are still unclear. In particular, it is unclear whether HSCT should be positioned as upfront therapy or rescue treatment for patients refractory to immunosuppressive therapy. We hypothesise that upfront HSCT is superior and results in lower toxicity and lower long-term medical costs. Therefore, we propose this randomised trial aiming to determine the optimal treatment strategy for early dcSSc by comparing two strategies used in standard care: (1) upfront autologous HSCT versus (2) immunosuppressive therapy (intravenous cyclophosphamide pulse therapy followed by mycophenolate mofetil) with rescue HSCT in case of treatment failure. METHODS AND ANALYSIS: The UPSIDE (UPfront autologous hematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) study is a multicentre, randomised, open-label, controlled trial. In total, 120 patients with early dcSSc will be randomised. The primary outcome is event-free survival at 2 years after randomisation. Secondary outcomes include serious adverse events, functional status and health-related quality of life. We will also evaluate changes in nailfold capillaroscopy pattern, pulmonary function, cardiac MR and high-resolution CT of the chest. Follow-up visits will be scheduled 3-monthly for 2 years and annually in the following 3 years. ETHICS AND DISSEMINATION: The study was approved by the Dutch Central Committee on Research Concerning Human Subjects (NL72607.041.20). The results will be disseminated through patient associations and conventional scientific channels. TRIAL REGISTRATION NUMBERS: NCT04464434; NL 8720.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Esclerodermia Difusa , Ciclofosfamida/uso terapêutico , Humanos , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Esclerodermia Difusa/tratamento farmacológico , Transplante Autólogo
8.
Kidney Int ; 99(6): 1331-1341, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33607177

RESUMO

Data reproducibility and single-center bias are concerns in preclinical research and compromise translation from animal to human. Multicenter preclinical randomized controlled trials (pRCT) may reduce the gap between experimental studies and RCT and improve the predictability of results, for example Jak1/2 inhibition in lupus nephritis. To evaluate this, we conducted the first pRCT in the kidney domain at two Spanish and two German academic sites. Eligible MRL/MpJ-Faslpr mice (female, age13-14 weeks, stress scores of less than two and no visible tumor or signs of infection) were equally randomized to either oral treatment with the Jak1/2 inhibitor baricitinib or vehicle for four weeks. Central blinded histology analysis was performed at an independent fifth site. The primary endpoint was the urinary protein/creatinine ratio. Baricitinib treatment did not significantly affect proteinuria, histological markers of activity and chronicity, or the glomerular filtration rate but significantly improved plasma autoantibody levels and lymphadenopathy. Data heterogeneity was noted across the different centers referring in part to phenotype differences between MRL/MpJ-Faslpr mice bred at different sites, mimicking well patient phenotype diversity in lupus trials. Multicenter pRCT can overcome single-center bias at the cost of increasing variability and reducing effect size. Thus, our pRCT predicts a low effect size of baricitinib treatment on human lupus nephritis in heterogeneous study populations.


Assuntos
Nefrite Lúpica , Animais , Modelos Animais de Doenças , Feminino , Humanos , Janus Quinase 1 , Rim , Nefrite Lúpica/tratamento farmacológico , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos , Reprodutibilidade dos Testes
9.
Int J Mol Sci ; 22(3)2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572654

RESUMO

Altered sialylation patterns play a role in chronic autoimmune diseases such as rheumatoid arthritis (RA). Recent studies have shown the pro-inflammatory activities of immunoglobulins (Igs) with desialylated sugar moieties. The role of neuraminidases (NEUs), enzymes which are responsible for the cleavage of terminal sialic acids (SA) from sialoglycoconjugates, is not fully understood in RA. We investigated the impact of zanamivir, an inhibitor of the influenza virus neuraminidase, and mammalian NEU2/3 on clinical outcomes in experimental arthritides studies. The severity of arthritis was monitored and IgG titers were measured by ELISA. (2,6)-linked SA was determined on IgG by ELISA and on cell surfaces by flow cytometry. Zanamivir at a dose of 100 mg/kg (zana-100) significantly ameliorated collagen-induced arthritis (CIA), whereas zana-100 was ineffective in serum transfer-induced arthritis. Systemic zana-100 treatment reduced the number of splenic CD138+/TACI+ plasma cells and CD19+ B cells, which was associated with lower IgG levels and an increased sialylation status of IgG compared to controls. Our data reveal the contribution of NEU2/3 in CIA. Zanamivir down-modulated the T and B cell-dependent humoral immune response and induced an anti-inflammatory milieu by inhibiting sialic acid degradation. We suggest that neuraminidases might represent a promising therapeutic target for RA and possibly also for other antibody-mediated autoimmune diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Neuraminidase/antagonistas & inibidores , Zanamivir/administração & dosagem , Animais , Artrite Experimental/induzido quimicamente , Colágeno/efeitos adversos , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos C57BL , Orthomyxoviridae/enzimologia , Ácidos Siálicos/metabolismo
10.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572870

RESUMO

As a key anti-inflammatory cytokine, IL-10 is crucial in preventing inflammatory and autoimmune diseases. However, in human and murine lupus, its role remains controversial. Our aim was to understand regulation and immunologic effects of IL-10 on different immune functions in the setting of lupus. This was explored in lupus-prone NZB/W F1 mice in vitro and vivo to understand IL-10 effects on individual immune cells as well as in the complex in vivo setting. We found pleiotropic IL-10 expression that largely increased with progressing lupus, while IL-10 receptor (IL-10R) levels remained relatively stable. In vitro experiments revealed pro- and anti-inflammatory IL-10 effects. Particularly, IL-10 decreased pro-inflammatory cytokines and slowed B cell proliferation, thereby triggering plasma cell differentiation. The frequent co-expression of ICOS, IL-21 and cMAF suggests that IL-10-producing CD4 T cells are important B cell helpers in this context. In vitro and in vivo effects of IL-10 were not fully concordant. In vivo IL-10R blockade slightly accelerated clinical lupus manifestations and immune dysregulation. Altogether, our side-by-side in vitro and in vivo comparison of the influence of IL-10 on different aspects of immunity shows that IL-10 has dual effects. Our results further reveal that the overall outcome may depend on the interplay of different factors such as target cell, inflammatory and stimulatory microenvironment, disease model and state. A comprehensive understanding of such influences is important to exploit IL-10 as a therapeutic target.


Assuntos
Interleucina-10/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Imunidade Adaptativa , Animais , Autoimunidade , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Imunidade Inata , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-10/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Camundongos Endogâmicos NZB , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
11.
Proc Natl Acad Sci U S A ; 118(7)2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33563755

RESUMO

CD20 is a B cell-specific membrane protein and represents an attractive target for therapeutic antibodies. Despite widespread usage of anti-CD20 antibodies for B cell depletion therapies, the biological function of their target remains unclear. Here, we demonstrate that CD20 controls the nanoscale organization of receptors on the surface of resting B lymphocytes. CRISPR/Cas9-mediated ablation of CD20 in resting B cells resulted in relocalization and interaction of the IgM-class B cell antigen receptor with the coreceptor CD19. This receptor rearrangement led to a transient activation of B cells, accompanied by the internalization of many B cell surface marker proteins. Reexpression of CD20 restored the expression of the B cell surface proteins and the resting state of Ramos B cells. Similarly, treatment of Ramos or naive human B cells with the anti-CD20 antibody rituximab induced nanoscale receptor rearrangements and transient B cell activation in vitro and in vivo. A departure from the resting B cell state followed by the loss of B cell identity of CD20-deficient Ramos B cells was accompanied by a PAX5 to BLIMP-1 transcriptional switch, metabolic reprogramming toward oxidative phosphorylation, and a shift toward plasma cell development. Thus, anti-CD20 engagement or the loss of CD20 disrupts membrane organization, profoundly altering the fate of human B cells.


Assuntos
Antígenos CD20/metabolismo , Linfócitos B/imunologia , Antígenos CD19/metabolismo , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Células Cultivadas , Humanos , Ativação Linfocitária , Receptores de Antígenos de Linfócitos B/metabolismo
12.
RMD Open ; 7(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33479021

RESUMO

INTRODUCTION: Whether patients with inflammatory rheumatic and musculoskeletal diseases (RMD) are at higher risk to develop severe courses of COVID-19 has not been fully elucidated. Aim of this analysis was to describe patients with RMD according to their COVID-19 severity and to identify risk factors for hospitalisation. METHODS: Patients with RMD with PCR confirmed SARS-CoV-2 infection reported to the German COVID-19 registry from 30 March to 1 November 2020 were evaluated. Multivariable logistic regression was used to estimate ORs for hospitalisation due to COVID-19. RESULTS: Data from 468 patients with RMD with SARS-CoV-2 infection were reported. Most frequent diagnosis was rheumatoid arthritis, RA (48%). 29% of the patients were hospitalised, 5.5% needed ventilation. 19 patients died. Multivariable analysis showed that age >65 years (OR 2.24; 95% CI 1.12 to 4.47), but even more>75 years (OR 3.94; 95% CI 1.86 to 8.32), cardiovascular disease (CVD; OR 3.36; 95% CI 1.5 to 7.55), interstitial lung disease/chronic obstructive pulmonary disease (ILD/COPD) (OR 2.79; 95% CI 1.2 to 6.49), chronic kidney disease (OR 2.96; 95% CI 1.16 to 7.5), moderate/high RMD disease activity (OR 1.96; 95% CI 1.02 to 3.76) and treatment with glucocorticoids (GCs) in dosages >5 mg/day (OR 3.67; 95% CI 1.49 to 9.05) were associated with higher odds of hospitalisation. Spondyloarthritis patients showed a smaller risk of hospitalisation compared with RA (OR 0.46; 95% CI 0.23 to 0.91). CONCLUSION: Age was a major risk factor for hospitalisation as well as comorbidities such as CVD, ILD/COPD, chronic kidney disease and current or prior treatment with GCs. Moderate to high RMD disease activity was also an independent risk factor for hospitalisation, underlining the importance of continuing adequate RMD treatment during the pandemic.


Assuntos
COVID-19/diagnóstico , Glucocorticoides/efeitos adversos , Doenças Musculoesqueléticas/complicações , Doenças Reumáticas/complicações , SARS-CoV-2/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , COVID-19/epidemiologia , COVID-19/terapia , COVID-19/virologia , Estudos de Casos e Controles , Comorbidade , Feminino , Alemanha/epidemiologia , Glucocorticoides/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculoesqueléticas/tratamento farmacológico , Sistema de Registros , Respiração Artificial/métodos , Estudos Retrospectivos , Doenças Reumáticas/tratamento farmacológico , Fatores de Risco
13.
Rheumatology (Oxford) ; 60(3): 1300-1312, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32940712

RESUMO

OBJECTIVES: To test the ability of an established traditional cardiovascular (CV) risk prediction score [Systematic COronary Risk Evaluation (SCORE)] and its EULAR modified version (mSCORE) to identify antisynthetase syndrome (ASyS) patients at high CV risk and to examine for the first time associations of CV and cerebrovascular surrogate markers with clinical and immunological ASyS parameters. METHODS: SCORE/mSCORE and the gold standard marker of aortic stiffness [carotid-femoral pulse wave velocity (cfPWV)] were examined in ASyS patients and healthy controls. Moreover, sonography of the common- (CCA) and internal- (ICA) carotid arteries was performed in subsets of both groups, evaluating carotid intima-media thickness (cIMT), plaques and Doppler sonographic cerebrovascular surrogates [resistance (RI) and pulsatility (PI) indices]. RESULTS: We recruited 66 ASyS patients and 88 controls. According to mSCORE, 10% of the patients had high CV risk. However, cfPWV and carotid sonography revealed an increased CV risk in 21.2% and subclinical carotid atherosclerosis (SCA) in 85.7% of the patients, respectively. cfPWV and cIMT were higher in patients compared with controls (Padj=0.021 and Padj=0.003, respectively). In the ASyS group, cfPWV and cIMT correlated significantly with age (r = 0.679; P<0.001 and r = 0.664; P<0.001, respectively). Moreover, cfPWV correlated with BMI (Padj=0.001) and diabetes (Padj=0.043). CCA-RI and CCA-PI showed significant associations with creatine phosphokinase (r = 0.629; P=0.012 and r = 0.574; P=0.032, respectively) and ICA-RI and ICA-PI were higher in patients with lung involvement (both; P=0.039). CONCLUSION: ASyS patients had higher aortic stiffness and SCA compared with controls, even after adjustment for confounders. SCORE/mSCORE performed poorly in identifying high-risk patients compared with cfPWV and carotid sonography. Thus, cfPWV and carotid sonography may improve CV and cerebrovascular screening in ASyS.

14.
Rheumatology (Oxford) ; 60(6): 2672-2677, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-33175957

RESUMO

OBJECTIVE: The prevalence of fatigue is high in patients with systemic lupus erythematosus (SLE). In this study, we used latent class analysis to reveal patterns of fatigue, anxiety, depression and organ involvement in a large international cohort of SLE patients. METHODS: We used the Lupus BioBank of the upper Rhein to analyse patterns of fatigue using latent class analysis (LCA). After determining the optimal number of latent classes, patients were assigned according to model generated probabilities, and characteristics of classes were compared. RESULTS: A total of 502 patients were included. Significant fatigue, anxiety and depression were reported by 341 (67.9%), 159 (31.7%) and 52 (10.4%) patients, respectively. LCA revealed a first cluster (67.5% of patients) with low disease activity [median (25th-75th percentile interquartile range) Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI: 2 (0-4)], significant fatigue (55.5%, P < 0.0001), low anxiety (11.8%, P < 0.0001) and depression (0.9%, P < 0.0001). Cluster 2 (25.3%) also comprised patients with low disease activity [SELENA-SLEDAI: 2 (0-6)], but those patients had a very high prevalence of fatigue (100%, P < 0.0001), anxiety (89%, P < 0.0001) and depression (38.6%, P < 0.0001). Cluster 3 (7.2%) comprised patients with high disease activity [SELENA-SLEDAI: 12 (8-17), P < 0.0001] and high fatigue (72.2%, P < 0.0001) with low levels of anxiety (16.7%, P < 0.0001) and no depression (0%, P < 0.0001). CONCLUSION: LCA revealed three patterns of fatigue with important practical implications. Based on these, it is crucial to distinguish patients with active disease (in whom remission will be achieved) from those with no or mild activity but high levels of fatigue, depression and anxiety, for whom psychological counselling should be prioritized.

15.
Front Immunol ; 11: 535784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193306

RESUMO

Human CD21low B cells are expanded in autoimmune (AI) diseases and display a unique phenotype with high expression of co-stimulatory molecules, compatible with a potential role as antigen-presenting cells (APCs). Thus, we addressed the co-stimulatory capacity of naïve-like, IgM-memory, switched memory and CD27negIgDneg memory CD21low B cells in allogenic co-cultures with CD4 T cells. CD21low B cells of patients with AI disorders expressed high levels of not only CD86, CD80, and HLA-DR (memory B cells) but also PD-L1 ex vivo and efficiently co-stimulated CD4 T cells of healthy donors (HD), as measured by upregulation of CD25, CD69, inducible co-stimulator (ICOS), and programmed cell death protein 1 (PD-1) and induction of cytokines. While the co-stimulatory capacity of the different CD21low B-cell populations was over all comparable to CD21pos counterparts of patients and HD, especially switched memory CD21low B cells lacked the increased capacity of CD21pos switched memory B-cells to induce high expression of ICOS, IL-2, IL-10, and IFN-γ. Acknowledging the limitation of the in vitro setting, CD21low B cells do not seem to preferentially support a specific Th effector response. In summary, our data implies that CD21low B cells of patients with AI diseases can become competent APCs and may, when enriched for autoreactive B-cell receptors (BCR), potentially contribute to AI reactions as cognate interaction partners of autoreactive T cells at sites of inflammation.


Assuntos
Apresentação do Antígeno , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Receptores de Complemento 3d/imunologia , Idoso , Doenças Autoimunes/patologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/patologia , Citocinas/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
17.
Front Immunol ; 11: 2086, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983161

RESUMO

Immunosuppressive therapies increase the susceptibility of patients to infections. The current pandemic with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compels clinicians to develop recommendations for successful clinical management and surveillance of immunocompromised patients at high risk for severe disease progression. With only few case studies published on SARS-CoV-2 infection in patients with rheumatic diseases, we report a 25-year-old male who developed moderate coronavirus disease 2019 (COVID-19) with fever, mild dyspnea, and no major complications despite having received high-dose prednisolone, cyclophosphamide, and rituximab for the treatment of highly active, life-threatening eosinophilic granulomatosis with polyangiitis (EGPA).


Assuntos
Betacoronavirus/genética , Síndrome de Churg-Strauss/complicações , Síndrome de Churg-Strauss/tratamento farmacológico , Infecções por Coronavirus/complicações , Ciclofosfamida/uso terapêutico , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Imunossupressores/uso terapêutico , Pneumonia Viral/complicações , Adulto , Antivirais/uso terapêutico , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Quimioterapia Combinada , Glucocorticoides/uso terapêutico , Humanos , Hospedeiro Imunocomprometido , Masculino , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Prednisolona/uso terapêutico , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rituximab/uso terapêutico , SARS-CoV-2 , Resultado do Tratamento
18.
RMD Open ; 6(2)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32878994

RESUMO

OBJECTIVES: Patients with inflammatory rheumatic diseases (IRD) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be at risk to develop a severe course of COVID-19. The influence of immunomodulating drugs on the course of COVID-19 is unknown. To gather knowledge about SARS-CoV-2 infections in patients with IRD, we established a registry shortly after the beginning of the pandemic in Germany. METHODS: Using an online questionnaire (www.COVID19-rheuma.de), a nationwide database was launched on 30 March 2020, with appropriate ethical and data protection approval to collect data of patients with IRD infected with SARS-CoV-2. In this registry, key clinical and epidemiological parameters-for example, diagnosis of IRD, antirheumatic therapies, comorbidities and course of the infection-are documented. RESULTS: Until 25 April 2020, data from 104 patients with IRD infected with SARS-CoV-2 were reported (40 males; 63 females; 1 diverse). Most of them (45%) were diagnosed with rheumatoid arthritis, 59% had one or more comorbidities and 42% were treated with biological disease-modifying antirheumatic drugs. Hospitalisation was reported in 32% of the patients. Two-thirds of the patients already recovered. Unfortunately, 6 patients had a fatal course. CONCLUSIONS: In a short time, a national registry for SARS-CoV2-infected patients with IRD was established. Within 4 weeks, 104 cases were documented. The registry enables to generate data rapidly in this emerging situation and to gain a better understanding of the course of SARS-CoV2-infection in patients with IRD, with a distinct focus on their immunomodulatory therapies. This knowledge is valuable for timely information of physicians and patients with IRD, and shall also serve for the development of guidance for the management of patients with IRD during this pandemic.


Assuntos
Antirreumáticos/uso terapêutico , Produtos Biológicos/uso terapêutico , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Sistema de Registros , Doenças Reumáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Psoriásica/complicações , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Betacoronavirus , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/mortalidade , Feminino , Alemanha , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Hospitalização , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/mortalidade , Polimialgia Reumática/complicações , Polimialgia Reumática/tratamento farmacológico , Prognóstico , Doenças Reumáticas/complicações , SARS-CoV-2 , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Índice de Gravidade de Doença , Espondilite Anquilosante/complicações , Espondilite Anquilosante/tratamento farmacológico , Adulto Jovem
19.
J Immunol ; 205(8): 2016-2025, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32907998

RESUMO

An expansion of CD21low B cells has been described in a variety of diseases associated with persistent immune stimulation as in chronic infection, immunodeficiency, or autoimmunity. Different developmental stages of CD21low B cells have been highlighted in specific diseases; however, a systematic comparison of distribution, phenotype, and signaling capacity of these populations has not yet been performed to delineate the pivotal character of this unusual B cell population. Screening of more than 200 patients with autoimmune disease demonstrated that the prevalence of patients with expanded CD21low B cells varies between diseases. The expansion was frequent in patients with systemic lupus erythematosus, in which it correlated to relative B cell lymphopenia and duration of disease. Different proportions of distinct developmental stages of CD21low B cells co-occur in nearly all patients with autoimmune disease. Although in most patients, naive-like and CD27- switched memory B cells were the most prominent CD21low subpopulations, there was no detectable association of the pattern with the underlying disease. Despite their distinct developmental stage, all CD21low B cells share a common core phenotype including the increased expression of inhibitory receptors, associated with an elevated constitutive phosphorylation of proximal signaling molecules downstream of the BCR but impaired Ca2+ mobilization and NF-κB activation after BCR stimulation. Further, this was accompanied by impaired upregulation of CD69, although CD86 upregulation was preserved. Beyond maturation-associated differences, the common core characteristics of all CD21low B cell populations suggests either a common ancestry or a shared sustained imprint by the environment they originated in.


Assuntos
Subpopulações de Linfócitos B/imunologia , Sinalização do Cálcio/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Memória de Curto Prazo , Receptores de Complemento 3d/imunologia , Transdução de Sinais/imunologia , Adulto , Subpopulações de Linfócitos B/patologia , Feminino , Humanos , Masculino , Receptores de Antígenos de Linfócitos B/imunologia
20.
Cells ; 9(7)2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32640727

RESUMO

Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenesis of chronic inflammatory diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). Ideally, therapeutic NF-KappaB inhibition should only take place in those cell types that are involved in disease pathogenesis to maintain physiological cell functions in all other cells. In contrast, unselective NF-kappaB inhibition in all cells results in multiple adverse effects, a major hindrance in drug development. Hitherto, various substances exist to inhibit different steps of NF-kappaB signaling. However, powerful tools for cell-type specific NF-kappaB inhibition are not yet established. Here, we review the role of NF-kappaB in inflammatory diseases, current strategies for drug delivery and NF-kappaB inhibition and point out the "sneaking ligand" approach. Sneaking ligand fusion proteins (SLFPs) are recombinant proteins with modular architecture consisting of three domains. The prototype SLC1 binds specifically to the activated endothelium and blocks canonical NF-kappaB activation. In vivo, SLC1 attenuated clinical and histological signs of experimental arthritides. The SLFP architecture allows an easy exchange of binding and effector domains and represents an attractive approach to study disease-relevant biological targets in a broad range of diseases. In vivo, SLFP treatment might increase therapeutic efficacy while minimizing adverse effects.


Assuntos
NF-kappa B/metabolismo , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , NF-kappa B/antagonistas & inibidores , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
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