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It is estimated that there are over 500 species of arboviruses worldwide, with more than 150 of them directly associated with human diseases, the majority of which are zoonotic. Among the main arboviruses circulating in Brazil, dengue, Zika, and chikungunya stand out, all transmitted through a common vector, Aedes aegypti. Given this scenario, the development and implementation of more efficient surveillance strategies become urgent. This study aims to compare and evaluate the efficiency of beetroot peel, Beta vulgaris, as an attractant for Ae. aegypti oviposition under field conditions in the municipality of Agrestina, State of Pernambuco, Brazil. Beetroot peel extract is a cheap and accessible source of geosmin, which holds significant potential as an attractant for mosquitoes due to its resemblance to microbial volatiles found in water bodies rich in organic material. During the study period (November 2023 to April 2024), 40 traps were set in each neighborhood, with 20 of each attractant. Two traps were used per property, one following the traditionally used model (beer yeast infusion) and another containing beetroot peel. Overall, in both analyzed neighborhoods (Campo Novo and Cohab), beetroot peel appeared to be a more efficient attractant for the oviposition of culicids. Beetroot peel showed the highest values in egg abundance and in the analyzed indices.
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Physical activity and diet have complementary benefits for attenuating adverse health effects that childhood cancer survivors experience after the end of treatment. This review aimed to explore the impact of combined physical activity and diet interventions on the health status of childhood cancer survivors. A thorough review of the literature was carried out using the Cochrane Library, PubMed, Scielo, LILACS and Web of Science databases for studies published until June 2024. Studies concerning survivors of childhood cancer of any type engaged exclusively in combined diet/physical activity interventions were included in this review. Three manuscripts met the inclusion criteria. The results indicated that combined physical activity plus diet interventions showed beneficial impacts for the intestinal microbiome, percentage of calories from sweet foods, daily consumption of sugary beverages, reduction in sedentary activity, and mood (1 out of 1 study for each of the presented outcomes). Although more rigorous studies are needed, these findings showed promising results regarding the impact of interventions involving both physical activity and diet on childhood cancer survivors.
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BACKGROUND: Stress has been linked to worsening symptoms and increased disease activity in patients with Systemic lupus erythematosus (SLE). Life-events are individual stress points, and there is conflicting evidence regarding their role in SLE activity and disease perception. METHODS: Adult SLE patients were recruited for the study. Clinical and laboratory features of SLE were recorded, and previous diagnosis of anxiety or depression were retrieved from patients' electronic charts. Flares were defined by the Systemic Lupus Erythematosus Disease Activity (SLEDAI) flare Index, and flares during the previous year were documented. During a routine visit, they completed validated Portuguese translations of the 10-item Perceived Stress Scale (PSS-10), Hospital Anxiety and Depression Scale (HADS) and Life Experience Survey (LES) for the previous year. RESULTS: A total of 47 female SLE patients were recruited. Ten patients (21.3%) had experienced recent flares. Patients with recent flares reported fewer life events, with lower positive, negative, and total weightings sums compared to those without recent flares. Although 42.2% of patients perceived pathological levels of stress in the previous month, 48.9% had anxiety symptoms, and 34% were at high risk for an anxiety disorder, these psychometric measures did not differ significantly between the recent flare and no-flare groups. CONCLUSIONS: There is a high prevalence of pathological levels of stress among SLE patients. SLE patients with recent flares report less psychological impact from life events, both positive and negative, independent of other psychological or pharmacological factors.
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Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterised by the progressive loss of specific neuronal cell populations due to multifactorial factors, including neurochemical and immunological disturbances. Consequently, patients can develop cognitive, motor and behavioural dysfunctions, which lead to impairments in their quality of life. Over the years, studies have reported on the neuroprotective properties inherent in phenolic compounds. Therefore, this review highlights the most recent scientific findings regarding phenolic compounds as promising neuroprotective molecules against neurodegenerative diseases.
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Fármacos Neuroprotetores , Fenóis , Fármacos Neuroprotetores/farmacologia , Animais , Humanos , Fenóis/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças , Doença de Parkinson/tratamento farmacológico , Neuroproteção/efeitos dos fármacosRESUMO
OBJECTIVES: To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE). METHODS: We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission. RESULTS: We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway. CONCLUSIONS: We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective.
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Lúpus Eritematoso Sistêmico , Indução de Remissão , Transcriptoma , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Estudos de CoortesRESUMO
OBJECTIVES: To evaluate the prevalence, magnitude, and potential determinants of work productivity impairment in patients with Behçet's Syndrome (BS), focusing on the role of irreversible organ damage. METHODS: A post-hoc analysis of the BS overall damage index (BODI) prospective validation study was performed. Demographics and clinical features were recorded in all patients. The Work Productivity and Activity Impairment: General Health (WPAI: GH) questionnaire was administered to assess the work limitation and the BODI to measure organ damage. The independent effect of BS features on WPAI: GH outcomes was evaluated by regression analysis. RESULTS: Out of 148 patients, 34.5% were unemployed, with age (OR 1.035) and BODI score (OR 1.313 for 1-unit increase) as the only factors significantly (p< 0.05) associated with the unemployment state. An overall work impairment was reported in about 64.2% of the employed patients. Indeed, 22.7% reported missing work h due to their health (absenteeism), with a mean time loss of 34.4%; whereas 60.2% declared a reduced performance at work because of their health (presenteeism), with a mean productivity impairment of 45.4%. Ocular damage was associated with absenteeism (ß 0.225); female sex (ß 0.260), physician global assessment of disease activity (ß 0.502) and an increased BODI score (ß 0.166 for 1-point increase) with presenteeism; fibromyalgia (ß 0.246), physician global assessment (ß 0.469), and musculoskeletal damage (ß 0.325) with overall work impairment. CONCLUSIONS: Disease activity and organ damage accrual remarkably affect work productivity in BS patients. Achieving remission and preventing damage accrual are crucial and complementary objectives.
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Mucosal vaccination appears to be suitable to protect against SARS-CoV-2 infection. In this study, we tested an intranasal mucosal vaccine candidate for COVID-19 that consisted of a cationic liposome containing a trimeric SARS-CoV-2 spike protein and CpG-ODNs, a Toll-like receptor 9 agonist, as an adjuvant. In vitro and in vivo experiments indicated the absence of toxicity following the intranasal administration of this vaccine formulation. First, we found that subcutaneous or intranasal vaccination protected hACE-2 transgenic mice from infection with the wild-type (Wuhan) SARS-CoV-2 strain, as shown by weight loss and mortality indicators. However, when compared with subcutaneous administration, the intranasal route was more effective in the pulmonary clearance of the virus and induced higher neutralizing antibodies and anti-S IgA titers. In addition, the intranasal vaccination afforded protection against gamma, delta, and omicron virus variants of concern. Furthermore, the intranasal vaccine formulation was superior to intramuscular vaccination with a recombinant, replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 spike glycoprotein (Oxford/AstraZeneca) in terms of virus lung clearance and production of neutralizing antibodies in serum and bronchial alveolar lavage (BAL). Finally, the intranasal liposomal formulation boosted heterologous immunity induced by previous intramuscular vaccination with the Oxford/AstraZeneca vaccine, which was more robust than homologous immunity.
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INTRODUCTION/BACKGROUND: Idiopathic Inflammatory Myopathies (IIM) continue to be a major clinical challenge worldwide. The exact aetiopathogenesis of this chronic and disabling disease remains elusive, preventing the development of novel and effective therapeutic strategies and leading to a high incidence of damage. The complexity of treating these diseases is even greater due to the numerous comorbidities that affect these patients. METHODS: Retrospective review of the cohort of patients diagnosed with IIM and followed in a dedicated unit of a tertiary hospital between 1971 and December 2022, with particular attention to damage and comorbidities. Damage was assessed using the Myositis Damage Index. Comorbidities were recorded and analysed as a whole and also assessed using the Charlson Comorbidity Index. Health Assessment Questionnaire (HAQ) Disability Index (DI) was performed by phone call in December 2022, to all patients actively followed-up in the Unit. RESULTS: Analysis of 149 patients with a mean follow-up of 9 years (range 0-51) revealed >90% with damage and comorbidities. Most comorbidities were a consequence of the damage and were particularly related to prolonged steroid therapy. Cardiovascular damage, which occurred either as cardiovascular risk factors or as end-organ sequelae (cardiovascular disease and chronic kidney disease), was the main cause and a major contributor to death. Depression was also high on the list of associated comorbidities. Median HAQ was 2.09 representing high negative impact in quality of life. CONCLUSIONS: Although survival rates have increased in recent decades, patients with IIM carry a high burden of disease with poor quality of life, mainly caused by damage and comorbidities. While comorbidities accumulation is the major factor for poor quality of life, damage severity is the main predictor for mortality. Improved therapeutic strategies are needed to reduce the need for steroids and to introduce routine screening and management of comorbidities as an essential partner of immunosuppressive therapy, leading to comprehensive care of myositis patients and effective improvement of their quality of life.
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Miosite , Qualidade de Vida , Humanos , Miosite/patologia , Estudos de Coortes , Comorbidade , Efeitos Psicossociais da DoençaRESUMO
Advances in RNA-sequencing technologies have led to the identification of molecular biomarkers for several diseases, including neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's diseases and Amyotrophic Lateral Sclerosis. Despite the nature of glaucoma as a neurodegenerative disorder with several similarities with the other above-mentioned diseases, transcriptional data about this disease are still scarce. microRNAs are small molecules (~17-25 nucleotides) that have been found to be specifically expressed in the CNS as major components of the system regulating the development signatures of neurodegenerative diseases and the homeostasis of the brain. In this review, we sought to identify similarities between the functional mechanisms and the activated pathways of the most common neurodegenerative diseases, as well as to discuss how those mechanisms are regulated by miRNAs, using RNA-Seq as an approach to compare them. We also discuss therapeutically suitable applications for these disease hallmarks in clinical future studies.
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Glaucoma , MicroRNAs , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/terapia , RNA-Seq , Homeostase , Glaucoma/genética , Glaucoma/terapia , MicroRNAs/genéticaRESUMO
INTRODUCTION: During pregnancy, the maternal immune system is challenged to tolerate a semi-allogenic fetus. A proinflammatory profile has been linked to adverse pregnancy outcomes and poor placental development. In this study, the authors evaluated the number of circulating Tregs and Th17 cells in a group of patients diagnosed with preeclampsia(PE) and fetal growth restriction(FGR). METHODS: Prospective longitudinal observational study where peripheral blood lymphocyte subsets were analyzed in a cohort of pregnant patients with PE, FGR, and a control group of healthy pregnant women. RESULTS: The diagnosis of PE was associated with a significative higher number of circulating Th17 cells and a significative relative reduction in the Treg cell count. This proinflammatory profile was also expressed in the evolution of the Th17/ CD4+CD25highFOXP3+ Treg ratio. In the FGR group, the Th17 cell count was significantly higher during the third trimester of pregnancy. This proinflammatory profile was also expressed in the evolution of the Th17/ CD4+CD25highFOXP3+ Treg ratio. When we compare the immunological profiles of patients with PE and FGR we observed a higher number of proinflammatory Th17 cells and a significative lower number of Treg cells in PE patients. This is particularly expressed in the differences found between the Th17/ CD4+CD25highFOXP3+ Treg ratios of these two groups. Discussion/Conclusion Our data showed a that a proinflammatory profile and a relative excess of Th17 cells was associated with the diagnosis of PE and FGR. A more exuberant systemic proinflammatory profile present in the PE patients is absent in patients with FGR without preeclampsia.
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Pré-Eclâmpsia , Linfócitos T Reguladores , Feminino , Humanos , Gravidez , Estudos Prospectivos , Gestantes , Células Th17 , Retardo do Crescimento Fetal , Placenta , Resultado da Gravidez , Fatores de Transcrição ForkheadRESUMO
The guinea pig has been chosen as a research model for otologic or neuropathic studies due to the relative ease of the cochlea, cochlear nerve, and vestibular nerve dissection. Little data have been reported on the normality of these nerves. The vestibular nerve is composed of the superior vestibular, inferior vestibular, and branch nerves. This study aimed to study the microscopic anatomy of the superior vestibular nerve (SVN) of guinea pigs using light microscopy and to search for normality patterns for use in experimental models in basic otologic research. We used eight male albino guinea pigs (Cavia porcellus, English strain), weighing between 400 and 500 g. After anesthetizing, the animals were perfused with a fixative solution of 2.5% glutaraldehyde. Dissection was performed by the access method to the temporal bone, coming to the rock and exposing the cochlea and vestibular nerve. The NVS fragments were removed, postfixed in osmium tetroxide, and embedded in the epoxy plastic resin Poly/Bed 812® (Polysciences Inc., Warrington, PA). Semi-thin transverse serial sections (0.5 µm) were made using a microtome MT6000-XL, RMC, Inc. and stained with toluidine blue. Morphology and morphometry were described and evaluated using the KS 400 application (Kontron 2.0, EchingBei, Munich, Germany) by macro, a computer program specially designed and developed for the study of the VIII nerve. The SVN was found to be devoid of epineurium, with only a thin conjunctive tissue layer. The myelin sheath of guinea pigs is relatively thin compared to the sensory and motor nerves found in mammals. The average fascicular area SVN was 0.19 ± 0.05 mm2 , with the largest area found to be 0.24 mm2 and the lowest was 0.12 mm2 . The average number of fibers was 5,753.00 ± 538 fibers. The density of myelinated fibers reached 32,316.08 ± 11,375.29 fibers/mm2 . Its diameter ranged from 1.0 to 9 µm and its peak was 3 µm. The measured results confirm the results of another study, indicating that the methodology is appropriate and reproducible. These findings are important for the evaluation of injured nerves in experimental models of peripheral neuropathy and basic ear disease.
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Cóclea , Nervo Vestibular , Animais , Cobaias , Nervo Vestibular/anatomia & histologia , Masculino , Bainha de Mielina , Cóclea/inervaçãoRESUMO
Idiopathic inflammatory myopathies (IIM) are a group of chronic autoimmune diseases mainly affecting proximal muscles. Absence of meaningful prognostic factors in IIM has hindered new therapies development. Glycans are essential molecules that regulate immunological tolerance and consequently the onset of autoreactive immune response. We showed that muscle biopsies from patients with IIM revealed a deficiency in the glycosylation pathway resulting in loss of branched N-glycans. At diagnosis, this glycosignature predicted disease relapse and treatment refractoriness. Peripheral CD4+ T cells from active-disease patients shown a deficiency in branched N-glycans, linked to increased IL-6 production. Glycan supplementation, restoring homeostatic glycosylation profile, led to a decrease in IL-6 levels. This study highlights the biological and clinical importance of glycosylation in IIM immunopathogenesis, providing a potential mechanism for IL-6 production. This pinpoints muscle glycome as promising biomarker for personalized follow-up and a potential target for new therapies in a patients' subgroup with an ominous evolution.
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INTRODUCTION: The existence of subphenotypes common to several autoimmune diseases (AIDs) suggests a shared physiopathology - autoimmune tautology. Multiple Autoimmune Syndrome (MAS) - the coexistence of three or more AIDs in one person-, best illustrates that polyautoimmunity is more than a coincidence. OBJECTIVES: Characterize and compare the monoautoimmune and MAS patients. Understand if clustering of AIDs leads to differences in disease severity, autoantibodies expression or genetic polymorphisms that could be markers for polyautoimmunity. METHODS: Currently adult patients were selected from unit cohort. MAS was assumed when ≥3 AIDs were present. 343 patients were included after exclusion criteria: having two AIDs or undetermined diagnosis. Clinical and immunological data were collected from medical files. HLA-DRB1 was genotyped by PCR-SSP methodology and PTPN22(rs2476601) polymorphisms by TaqMan Real Time PCR. Data were analysed using Chi-Square, Fisher's exact tests and logistic regression. Odds ratios (OR) and 95% confidence intervals were calculated. RESULTS: In comparison with control population: ELEVATED FREQUENCIES: HLA-DRB1*03 in study cohort (OR=3.68,p<0.001) and in monoautoimmune SLE (OR=2.79,p<0.001) and SjS (OR=8.27,p<0.001); HLA-DRB1*15 in monoautoimmune SjS (OR=2.39,p = 0.011); HLA-DRB1*16 in MAS SLE (OR=2.67,p = 0.031); PTPN22_T in all groups except monoautoimmune SjS and triple positive systemic MAS. DIMINISHED FREQUENCIES: HLA-DRB1*11 in study cohort (OR=0.57,p = 0.013), in MAS SLE (OR=0.39,p = 0.031) and monoautoimmune SjS (OR=0.10,p = 0.005); HLA-DRB1*13 in study cohort (OR=0.52,p = 0.001) and in monoautoimmune SLE (OR=0.53,p = 0.009) and SjS (OR=0.38,p = 0.031); HLA-DRB1*14 in study cohort (OR=0.32,p = 0.013) and monoautoimmune SLE (OR=0.21,p = 0.021); SLE group: HLA-DRB1*07 frequency was higher in monoautoimmune patients (OR=0.43,p = 0.023). MAS patients had significantly more NPSLE (OR=2.99,p<0.001), subacute cutaneous lesions (OR=2.30,p = 0.037), muscle&tendon (OR=2.00,p = 0.045), and haematological (OR=3.18,p = 0.006) involvement and Raynaud's (OR=2.94,p<0.001). SjS group: MAS patients had more frequently cryoglobulins (OR=2.96,p = 0.030), low complement (OR=2.43,p = 0.030) and Raynaud's (OR=4.38,p<0.001); monoautoimmune patients had more parotid enlargement (OR=0.12,p<0.001). APS group: MAS patients had more non-thrombotic manifestations (OR=4.69,p = 0.020) and Raynaud's (OR=9.12,p<0.001). Triple positive systemic MAS (SLE+SjS+APS) had more frequently severe kidney involvement (OR=11.67,p = 0.021) and CNS thrombosis (OR=4.44,p = 0.009). Anti-U1RNP increased frequency was transversally attributable to MAS. CONCLUSIONS: The coexistence of AIDs contributes to a more severe disease course. We confirmed previously established genetic risk and protection factors and suggest a new protective one - HLA-DRB1*14. HLA-DRB1*07 and anti-U1RNP could be markers for mono and polyautoimmunity, respectively; HLA-DRB1*13 could be a predictor for vascular risk in patients with multiple AIDs. PTPN22(rs2476601) polymorphism could be associated with less severe disease.
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Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and Sjögren's syndrome (SS) are heterogeneous autoimmune diseases. Severe manifestations and refractory/intolerance to conventional immunosuppressants demand other options, namely biological drugs, and small molecules. We aimed to define evidence and practice-based guidance for the off-label use of biologics in SLE, APS, and SS. Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice in autoimmune disease management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2021. Preliminary recommendations were drafted by working groups for each disease. A revision meeting with all experts anticipated the consensus meeting held in June 2021. All experts voted (agree, disagree, neither agree nor disagree) during two rounds, and recommendations with at least 75% agreement were approved. A total of 32 final recommendations (20 for SLE treatment, 5 for APS, and 7 for SS) were approved by the experts. These recommendations consider organ involvement, manifestations, severity, and response to previous treatments. In these three autoimmune diseases, most recommendations refer to rituximab, which aligns with the higher number of studies and clinical experience with this biological agent. Belimumab sequential treatment after rituximab may also be used in severe cases of SLE and SS. Second-line therapy with baricitinib, bortezomib, eculizumab, secukinumab, or tocilizumab can be considered in SLE-specific manifestations. These evidence and practice-based recommendations may support treatment decision and, ultimately, improve the outcome of patients living with SLE, APS, or SS.
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Síndrome Antifosfolipídica , Produtos Biológicos , Lúpus Eritematoso Sistêmico , Síndrome de Sjogren , Humanos , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/tratamento farmacológico , Rituximab/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Terapia BiológicaRESUMO
OBJECTIVE: Vasculitis are a very heterogenous group of systemic autoimmune diseases, affecting large vessels (LVV), small vessels or presenting as a multisystemic variable vessel vasculitis. We aimed to define evidence and practice-based recommendations for the use of biologics in large and small vessels vasculitis, and Behçet's disease (BD). METHODS: Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice on autoimmune diseases management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2022. Preliminary recommendations were drafted by working groups for each disease and voted in two rounds, in June and September 2021. Recommendations with at least 75% agreement were approved. RESULTS: A total of 32 final recommendations (10 for LVV treatment, 7 for small vessels vasculitis and 15 for BD) were approved by the experts and several biologic drugs were considered with different supporting evidence. Among LVV treatment options, tocilizumab presents the higher level of supporting evidence. Rituximab is recommended for treatment of severe/refractory cryoglobulinemic vasculitis. Infliximab and adalimumab are most recommended in treatment of severe/refractory BD manifestations. Other biologic drugs can be considered is specific presentations. CONCLUSION: These evidence and practice-based recommendations are a contribute to treatment decision and may, ultimately, improve the outcome of patients living with these conditions.
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Síndrome de Behçet , Produtos Biológicos , Vasculite , Humanos , Síndrome de Behçet/tratamento farmacológico , Vasculite/tratamento farmacológico , Rituximab/uso terapêutico , Terapia Biológica , Produtos Biológicos/uso terapêuticoRESUMO
Autoimmune diseases are life-threatening disorders that cause increasing disability over time. Systemic lupus erythematosus (SLE) and other autoimmune diseases arise when immune stimuli override mechanisms of self-tolerance. Accumulating evidence has demonstrated that protein glycosylation is substantially altered in autoimmune disease development, but the mechanisms by which glycans trigger these autoreactive immune responses are still largely unclear. In this study, we found that presence of microbial-associated mannose structures at the surface of the kidney triggers the recognition of DC-SIGN-expressing γδ T cells, inducing a pathogenic interleukin-17a (IL-17a)-mediated autoimmune response. Mice lacking Mgat5, which have a higher abundance of mannose structures in the kidney, displayed increased γδ T cell infiltration into the kidney that was associated with spontaneous development of lupus in older mice. N-acetylglucosamine supplementation, which promoted biosynthesis of tolerogenic branched N-glycans in the kidney, was found to inhibit γδ T cell infiltration and control disease development. Together, this work reveals a mannose-γδ T cell-IL-17a axis in SLE immunopathogenesis and highlights glycometabolic reprogramming as a therapeutic strategy for autoimmune disease treatment.
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Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Animais , Camundongos , Autoimunidade , Manose , Interleucina-17/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismoRESUMO
BACKGROUND: This study aimed to investigate the trajectory of damage accrual, associated factors, and impact on health-related quality of life (HR-QoL) in a multicenter cohort of patients with Behçet's syndrome (BS) over 2 years of follow-up. METHODS: Patients recruited in the BS Overall Damage Index (BODI) validation study were prospectively monitored for 2 years and assessed for damage accrual, defined as an increase ≥1 in the BODI score, and HR-QoL was evaluated by the SF-36 questionnaire. Logistic and multiple linear regression models were built to determine factors associated with damage accrual and impairment in the different SF-36 domains. RESULTS: During follow-up, 36 out of 189 (19.0%) patients had an increase ≥1 in the BODI score with a mean (SD) difference of 1.7 (0.8) (p <0.001). The incidence rate of damage accrual was stable over time, regardless of the disease duration. Out of 61 new BODI items, 25 (41.0%) were considered related to glucocorticoid (GC) use. In multivariate analysis, duration of GC therapy (OR per 1-year 1.15, 95% CI 1.07-1.23; p <0.001) and occurrence of ≥1 disease relapse (OR 3.15, 95% CI 1.09-9.12; p 0.038) were identified as predictors of damage accrual, whereas the use of immunosuppressants showed a protective effect (OR 0.20, 95% CI 0.08-0.54, p<0.001). Damage accrual was independently associated with the impairment of different physical domains and, to a greater extent, in emotional domains of the SF-36 questionnaire. Female sex, higher disease activity, and fibromyalgia were also significantly associated with impairment in HR-QoL. CONCLUSION: In BS, organ damage accrues over time, also in long-standing disease, resulting in an impairment of the perceived physical and mental health. Adequate immunosuppressive treatment, preventing disease flares and minimizing exposure to GCs have a crucial role in lowering the risk of damage accrual.
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Síndrome de Behçet , Qualidade de Vida , Humanos , Feminino , Seguimentos , Síndrome de Behçet/epidemiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Progressão da Doença , Imunossupressores/uso terapêuticoRESUMO
INTRODUCTION: Behçet's disease (BD) is a systemic vasculitis of unknown cause. The spectrum of the disease ranges from mucocutaneous manifestations to other organ diseases with relevant morbidity. Associations between disease severity and male sex, earlier age at onset, and the presence of erythema nodosum have been described. OBJECTIVES: To evaluate clinical factors associated with manifestations of severe disease in a single-center cohort. METHODS: A longitudinal, prospective, unicentric cohort study with patients followed in a specialized outpatient clinic between 1981 and 2020. Severe BD was defined as a Krause total clinical severity score >4 points. RESULTS: We included 243 patients, of whom 31% were male, with an average follow-up time of 14.6 years. Regarding organ manifestations, all patients had mucous manifestations (N=243, 100%), 133 (55%) skin, 104 (43%) joint, 71 (29%) ocular, 48 (20%) vascular, 47 (19%) neurological, 22 (9%) gastrointestinal and 1 (0.4%) cardiac involvement by BD. One hundred fifty-six (64%) patients were classified as having severe BD. Severe BD was more frequent in men (OR=2.004, p=0.024), increasing with age (OR=1.021 per year, p=0.037), in the presence of skin manifestations (OR=4.711, p<0.001), specifically erythema nodosum (OR=8.381, p<0.001), and pseudofolliculitis (OR=2.910, p<0.001). In the multivariate model, variables independently associated with severe BD were male gender (Adjusted OR=1.961, p=0.047), erythema nodosum (Adjusted OR=8.561, p<0.001) and pseudofolliculitis (Adjusted OR=2.372, p=0.007). DISCUSSION: Male gender, erythema nodosum, and pseudofolliculitis were independently associated with severe BD forms and therefore should serve as warning signs to the clinician.
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Síndrome de Behçet , Eritema Nodoso , Idade de Início , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiologia , Estudos de Coortes , Eritema Nodoso/diagnóstico , Eritema Nodoso/epidemiologia , Eritema Nodoso/etiologia , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown etiology. The role of genetic risk factors has been the focus of numerous studies probing for associations of genetic variants with IPF. We aimed to determine whether single-nucleotide polymorphisms (SNPs) of four candidate genes are associated with IPF susceptibility and survival in a Portuguese population. A retrospective case-control study was performed with 64 IPF patients and 74 healthy controls. Ten single-nucleotide variants residing in the MUC5B, TOLLIP, SERPINB1, and PLAU genes were analyzed. Single- and multi-locus analyses were performed to investigate the predictive potential of specific variants in IPF susceptibility and survival. Multifactor dimensionality reduction (MDR) was employed to uncover predictive multi-locus interactions underlying IPF susceptibility. The MUC5B rs35705950 SNP was significantly associated with IPF: T allele carriers were significantly more frequent among IPF patients (75.0% vs 20.3%, P < 1.0 × 10-6). Genotypic and allelic distributions of TOLLIP, PLAU, and SERPINB1 SNPs did not differ significantly between groups. However, the MUC5B-TOLLIP T-C-T-C haplotype, defined by the rs35705950-rs111521887-rs5743894-rs5743854 block, emerged as an independent protective factor in IPF survival (HR = 0.37, 95% CI 0.17-0.78, P = 0.009, after adjustment for FVC). No significant multi-locus interactions correlating with disease susceptibility were detected. MUC5B rs35705950 was linked to an increased risk for IPF, as reported for other populations, but not to disease survival. A haplotype incorporating SNPs of the MUC5B-TOLLIP locus at 11p15.5 seems to predict better survival and could prove useful for prognostic purposes and IPF patient stratification. KEY MESSAGES : The MUC5B rs35705950 minor allele is associated with IPF risk in the Portuguese. No predictive multi-locus interactions of IPF susceptibility were identified by MDR. A haplotype defined by MUC5B and TOLLIP SNPs is a protective factor in IPF survival. The haplotype may be used as a prognostic tool for IPF patient stratification.
Assuntos
Fibrose Pulmonar Idiopática , Serpinas , Humanos , Estudos de Casos e Controles , Predisposição Genética para Doença , Fibrose Pulmonar Idiopática/genética , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Serpinas/genéticaRESUMO
INTRODUCTION: LupusQoL is a questionnaire specifically designed to assess health-related quality of life (HRQoL) in SLE patients. We report on the translation and cross-cultural adaptation of LupusQoL into European Portuguese. METHODS: Translation and cultural adaptation were performed according to standard protocol described by the original developers. LupusQoL-PT was administered to patients during a routine visit from an outpatient clinic at a university hospital in Portugal. Content structure was validated using factorial analysis. Cronbach's alpha coefficient was computed for internal consistency. Sociodemographic were questioned during the visit and clinical data were collected during the visit and from the clinical files. Pearson's correlation, T-test, Mann-Whitney and one-way ANOVA were applied to test internal and external validation. RESULTS: Seventy-nine SLE patients (78 woman: 1 man) were evaluated. Most had Low disease activity (mean SLEDAI-2k = 3.49; standard deviation 4.80), 19% had moderate to severe activity and 38% had damage accrual (mean SDI = 0.75; standard deviation 1.05). Cronbach's alpha coefficient was at least 0.812, confirming good internal consistency. Correlation coefficient and test-retest correlation between the eight domains of LupusQoL-PT were strong in almost every domain (p < 0.01). External convergent analysis showed strong correlation between LupusQoL-PT and Medical Outcome Study Short Form 36-item version 2 and visual analogic scale. Current disease activity was negative correlated with "Body Image" domain. There was no correlation between other LupusQoL-PT domains and SLEDAI-2k on divergent validity. Patients with previous neuropsychiatric and DMARDs treatment had lower HRQoL in emotional domains, while patients with renal damage accrual had HRQoL impact in both physical and emotional domains. Portuguese SLE patients had lower HRQoL than French and Italian validation cohorts' patients, and higher than Spanish cohorts. CONCLUSION: LupusQoL-PT has shown adequate metric properties and should be considered an appropriate tool to evaluate HRQoL in Portuguese SLE patients.