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BACKGROUND: Viral infection outcomes vary widely between individuals, ranging from mild symptoms to severe organ failure and death, and it is clear that host genetic factors play a role in this variability. Type I interferon (IFN) is a critical anti-viral cytokine, and we have previously noted differences in type I IFN levels between world populations. METHODS: In this study, we investigate the interrelationship between regional European genetic ancestry, type I IFN levels, and severe viral infection outcomes. RESULTS: In cohorts of European ancestry lupus patients living in Europe, we noted higher IFN in the Northwestern populations as compared to Southeastern populations. In an independent cohort of European ancestry lupus patients from the United States with varying proportional regional European genetic admixture, we observed the same Northwest vs. Southeast European ancestry IFN gradient. We developed a model to predict type I IFN level based on regional European ancestry (AUC = 0.73, p = 6.1e-6). Examining large databases containing serious viral outcomes data, we found that lower predicted IFN in the corresponding European country was significantly correlated with increased viral infection fatality rate, including COVID-19, viral hepatitis, and HIV [Correlation coefficients: -0.79 (p = 4e-2), -0.94 (p = 6e-3), and -0.96 (p = 8e-2) respectively]. CONCLUSIONS: This association between predicted type I IFN level and viral outcome severity suggests a potential causal relationship, as greater intrinsic type I IFN is beneficial in host defense against viruses. Genetic testing could provide insight into individual and population level risk of fatality due to viruses prior to infection, across a wide range of viral pathogens.
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In genomic medicine, the concept of genetically transitional disease (GTD) refers to cases in which gene mutation is necessary but not sufficient to cause disease. In this Perspective, we apply this novel concept to rheumatic diseases, which have been linked to hundreds of genetic variants via association studies. These variants are in the 'grey zone' between monogenic variants with large effect sizes and common susceptibility alleles with small effect sizes. Among genes associated with rare autoinflammatory diseases, many low-frequency and/or low-penetrance variants are known to increase susceptibility to systemic inflammation. In autoimmune diseases, hundreds of HLA and non-HLA genetic variants have been revealed to be modest- to moderate-risk alleles. These diseases can be reclassified as GTDs. The same concept could apply to many other human diseases. GTD could improve the reporting of genetic testing results, diagnostic yields, genetic counselling and selection of therapy, as well as facilitating research using a novel approach to human genetic diseases.
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Predisposição Genética para Doença , Doenças Reumáticas , Humanos , Doenças Reumáticas/genética , Doenças Reumáticas/diagnóstico , Mutação , Variação Genética , Testes Genéticos/métodosRESUMO
Patients with a history of endometriosis have an increased risk of developing various autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis and celiac disease. There is a potential association between endometriosis and an increased susceptibility for Sjögren's syndrome (SS). SS is a common chronic, inflammatory, systemic, autoimmune, multifactorial disease of complex pathology, with genetic, epigenetic and environmental factors contributing to the development of this condition. It occurs in 0.51% of the population, is characterized by the presence of ocular dryness, lymphocytic infiltrations and contributes to neurological, gastrointestinal, vascular and dermatological manifestations. Endometriosis is an inflammatory, estrogendependent, multifactorial, heterogeneous gynecological disease, affecting ≤10% of reproductiveage women. It is characterized by the occurrence of endometrial tissue outside the uterine cavity, mainly in the pelvic cavity, and is associated with pelvic pain, dysmenorrhea, deep dyspareunia and either subfertility or infertility. It is still unclear whether SS appears as a secondary response to endometriosis, or it is developed due to any potential shared mechanisms of these conditions. The aim of the present review was to explore further the biological basis only of the cooccurrence of these disorders but not their association at clinical basis, focusing on the analysis of the partially shared genetic background between endometriosis and SS, and the clarification of the possible similarities in the underlying pathogenetic mechanisms and the relevant molecular pathways.
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Artrite Reumatoide , Endometriose , Síndrome de Sjogren , Humanos , Feminino , Síndrome de Sjogren/complicações , Síndrome de Sjogren/genética , Endometriose/complicações , Endometriose/genética , Olho , EpitélioRESUMO
Systemic lupus erythematosus (SLE) is a severe multisystem autoimmune disease that can cause injury in almost every body system. While considered a classic example of autoimmunity, it is still relatively poorly understood. Treatment with immunosuppressive agents is challenging, as many agents are relatively non-specific, and the underlying disease is characterized by unpredictable flares and remissions. This State of The Art Review provides a comprehensive current summary of systemic lupus erythematosus based on recent literature. In basic and translational science, this summary includes the current state of genetics, epigenetics, differences by ancestry, and updates about the molecular and immunological pathogenesis of systemic lupus erythematosus. In clinical science, the summary includes updates in diagnosis and classification, clinical features and subphenotypes, and current guidelines and strategies for treatment. The paper also provides a comprehensive review of the large number of recent clinical trials in systemic lupus erythematosus. Current knowns and unknowns are presented, and potential directions for the future are suggested. Improved knowledge of immunological pathogenesis and the molecular differences that exist between patients should help to personalize treatment, minimize side effects, and achieve better outcomes in this difficult disease.
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Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Imunossupressores/uso terapêutico , AutoimunidadeRESUMO
Type I interferon (IFN-I) is thought to play a role in many systemic autoimmune diseases. IFN-I pathway activation is associated with pathogenic features, including the presence of autoantibodies and clinical phenotypes such as more severe disease with increased disease activity and damage. We will review the role and potential drivers of IFN-I dysregulation in 5 prototypic autoimmune diseases: systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, primary Sjögren syndrome, and systemic sclerosis. We will also discuss current therapeutic strategies that directly or indirectly target the IFN-I system.
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Doenças Autoimunes , Interferon Tipo I , Lúpus Eritematoso Sistêmico , Humanos , Autoimunidade , Interferon Tipo I/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Interferons/metabolismo , Anticorpos , FenótipoRESUMO
Autoimmune diseases vary in the magnitude and diversity of autoantibody profiles, and these differences may be a consequence of different types of breaks in tolerance. Here, we compared the disparate autoimmune diseases autoimmune polyendocrinopathy-candidiasis-ecto-dermal dystrophy (APECED), systemic lupus erythematosus (SLE), and Sjogren's syndrome (SjS) to gain insight into the etiology of breaks in tolerance triggering autoimmunity. APECED was chosen as a prototypical monogenic disease with organ-specific pathology while SjS and SLE represent polygenic autoimmunity with focal or systemic disease. Using protein microarrays for autoantibody profiling, we found that APECED patients develop a focused but highly reactive set of shared mostly anti-cytokine antibodies, while SLE patients develop broad and less expanded autoantibody repertoires against mostly intracellular autoantigens. SjS patients had few autoantibody specificities with the highest shared reactivities observed against Ro-52 and La. RNA-seq B-cell receptor analysis revealed that APECED samples have fewer, but highly expanded, clonotypes compared with SLE samples containing a diverse, but less clonally expanded, B-cell receptor repertoire. Based on these data, we propose a model whereby the presence of autoreactive T-cells in APECED allows T-dependent B-cell responses against autoantigens, while SLE is driven by breaks in peripheral B-cell tolerance and extrafollicular B-cell activation. These results highlight differences in the autoimmunity observed in several monogenic and polygenic disorders and may be generalizable to other autoimmune diseases.
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Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Poliendocrinopatias Autoimunes , Síndrome de Sjogren , Humanos , Autoanticorpos , Doenças Autoimunes/genética , Doenças Autoimunes/complicações , Autoantígenos , Receptores de Antígenos de Linfócitos BRESUMO
BACKGROUND: Systemic lupus erythematosus (SLE) is heterogeneous in organ involvement and disease severity, presenting a broad clinical phenotype. Systemic type I interferon (IFN) activity has been shown to be associated with lupus nephritis, autoantibodies, and disease activity in treated SLE patients; however, these relationships are unknown in treatment-naive patients. We aimed to determine the relationship of systemic IFN activity with clinical phenotypes, disease activity, and damage accrual in treatment-naive SLE patients before and after induction and maintenance therapy. METHODS: Forty treatment-naive SLE patients were enrolled for this retrospective longitudinal observational study to examine the relationship between serum IFN activity and clinical manifestations of EULAR/ACR-2019 criteria domains, disease activity measures, and damage accrual. As controls, 59 other treatment-naive rheumatic disease patients and 33 healthy individuals were recruited. Serum IFN activity was measured by WISH bioassay and presented as an IFN activity score. RESULTS: Treatment-naive SLE patients had significantly higher serum IFN activity than other rheumatic disease patients (score: 97.6 and 0.0, respectively, p < 0.001). High serum IFN activity was significantly associated with fever, hematologic disorders (leukopenia), and mucocutaneous manifestations (acute cutaneous lupus and oral ulcer) of EULAR/ACR-2019 criteria domains in treatment-naive SLE patients. Serum IFN activity at baseline significantly correlated with SLEDAI-2K scores and decreased along with a decrease in SLEDAI-2K scores after induction and maintenance therapy (R2 = 0.112, p = 0.034). SLE patients who developed organ damage (SDI ≥ 1) had higher serum IFN activity at baseline than those who did not (SDI = 0) (150.0 versus 57.3, p= 0.018), but the multivariate analysis did not detect its independent significance (p = 0.132). CONCLUSIONS: Serum IFN activity is characteristically high and is linked to fever, hematologic disorders, and mucocutaneous manifestations in treatment-naive SLE patients. Serum IFN activity at baseline correlates with disease activity and decreases in parallel with a decrease in disease activity after induction and maintenance therapy. Our results suggest that IFN plays an important role in the pathophysiology of SLE and that serum IFN activity at baseline may be a potential biomarker for the disease activity in treatment-naive SLE patients.
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Interferon Tipo I , Lúpus Eritematoso Sistêmico , Doenças Reumáticas , Humanos , Estudos Retrospectivos , Fenótipo , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). The pathogenesis is incompletely understood and diagnostic biomarkers are scarce. We investigated interleukin (IL) 16 as a potential biomarker for LN in a well-characterised cohort of patients with SLE. METHODS: We measured urinary (u-) and plasma (p-) levels of IL-16 in predefined patient groups using ELISA: LN (n=84), active non-renal SLE (n=63), inactive non-renal SLE (n=73) and matched population controls (n=48). The LN group included patients with recent biopsy-confirmed proliferative (PLN, n=47), mesangioproliferative (MES, n=11) and membranous (MLN, n=26) LN. Renal expression of IL-16 was investigated by immunohistochemistry. Associations between IL-16 measurements and clinical parameters and the diagnostic value for LN were explored. RESULTS: p-IL-16 was detected in all investigated cases and high p-IL-16 levels were observed in patients with active SLE. u-IL-16 was detected (dt-u-IL-16) in 47.6% of patients with LN, while only up to 17.8% had dt-u-IL-16 in other groups. In the LN group, 68% of patients with PLN had dt-u-IL-16, while the proportions in the MLN and MES groups were lower (11.5% and 45.5%, respectively). The highest u-IL-16 levels were detected in the PLN group. In the regression model, u-IL-16 levels differentiated PLN from other LN patient subgroups (area under the curve 0.775-0.896, p<0.0001). dt-u-IL-16 had superior specificity but slightly lower sensitivity than elevated anti-double-stranded DNA and low complement C3 or C4 in diagnosing PLN. A high proportion of LN kidney infiltrating cells expressed IL-16. CONCLUSIONS: We demonstrate that detectable u-IL-16 can differentiate patients with PLN from those with less severe LN subtypes and active non-renal SLE. Our findings suggest that u-IL-16 could be used as a screening tool at suspicion of severe LN. Furthermore, the high IL-16 levels in plasma, urine and kidney tissue imply that IL-16 could be explored as a therapeutic target in SLE.
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Interleucina-16/urina , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Biomarcadores , Humanos , Interleucinas/urina , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnósticoRESUMO
Biopsies of inflammatory tissue contain a complex network of interacting cells, orchestrating the immune or autoimmune response. While standard histological examination can identify relationships, it is clear that a great amount of data on each slide is not quantitated or categorized in standard microscopic examinations. To deal with the huge amount of data present in biopsy tissue in an unbiased and comprehensive way, we have developed a deep learning algorithm to identify immune cells in biopsies of inflammatory lesions. We focused on T follicular helper (Tfh) cell subsets and B cells in dermatomyositis biopsy images. We achieved strong performance on detection and classification of cells, including the rare Tfh cell subsets present in the tissue. This algorithm could be used to perform distance mapping between cell types in tissue, and could be easily adapted to other disease states.
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Inteligência Artificial , Aprendizado Profundo , Linfócitos B , Biópsia , Humanos , MicroscopiaRESUMO
Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR = 29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in antiviral immunity.
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COVID-19 , Lúpus Eritematoso Sistêmico , Idoso , Alelos , Antivirais , COVID-19/genética , Predisposição Genética para Doença , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Interferon-alfa/genética , Lúpus Eritematoso Sistêmico/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Dysregulated IFN-1 responses play crucial roles in the development of multiple forms of autoimmunity. Many patients with lupus, systemic sclerosis, Sjogren's syndrome, and dermatomyositis demonstrate enhanced IFN-1 signaling. IFN-1 excess is associated with disease severity and autoantibodies and could potentially predict response to newer therapies targeting IFN-1 pathways. In this review, we provide an overview of the signaling pathway and immune functions of IFN-1s in health and disease. We also review the systemic autoimmune diseases classically associated with IFN-1 upregulation and current therapeutic strategies targeting the IFN-1 system.
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Interferon Tipo I , Lúpus Eritematoso Sistêmico , Escleroderma Sistêmico , Síndrome de Sjogren , Autoimunidade , Humanos , Interferon Tipo I/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: Previous studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN. METHODS: Two hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR. RESULTS: Class III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P = 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1 expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1 expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules. CONCLUSION: Systemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.
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Interferon Tipo I , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Anticorpos Antinucleares , Humanos , Lectinas Tipo C , Nefrite Lúpica/patologia , Glicoproteínas de Membrana , Receptores ImunológicosRESUMO
OBJECTIVE: Axonal/neuronal damage has been shown to be a pathological finding that precedes neuropsychiatric manifestations in SLE. The objective of this study was to determine the presence of axonal dysfunction in childhood-onset SLE patients (cSLE) and to determine clinical, immunological and treatment features associated with its occurrence. METHODS: We included 86 consecutive cSLE patients [median age 17 (range 5-28) years] and 71 controls [median age 18 (5-28) years]. We performed proton magnetic resonance spectroscopic imaging using point resolved spectroscopy sequence over the superior-posterior region of the corpus callosum and signals from N-acetylaspartate (NAA), choline-based (CHO), creatine-containing (Cr), myo-inositol (mI), glutamate, glutamine and lactate were measured and metabolites/Cr ratios were determined. Complete clinical, laboratory and neurological evaluations were performed in all subjects. Serum IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, TNF-α and INF-γ cytokine levels, antiribosomal P protein antibodies (anti-P) and S100ß were measured by ELISA using commercial kits. Data were compared by non-parametric tests. RESULTS: NAA/Cr ratios (P = 0.035) and lactate/Cr ratios (P = 0.019) were significantly decreased in cSLE patients when compared with controls. In multivariate analysis, IFN-γ levels [odds ratio (OR) = 4.1; 95% CI: 2.01, 7.9] and depressive symptoms (OR = 1.9; 95% CI: 1.1, 3.2) were associated with NAA/Cr ratio. Increased CHO/Cr was associated with the presence of cognitive impairment (OR = 3.4; 95% CI: 2.034, 5.078; P < 0.001). mI/Cr ratio correlated with cumulative glucocorticoids dosage (r = 0.361, P = 0.014). CONCLUSION: NAA and CHO ratios may be useful as biomarkers in neuropsychiatric cSLE. Longitudinal studies are necessary to determine whether they predict structural damage.
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Interferon gama , Lúpus Eritematoso Sistêmico , Adolescente , Adulto , Ácido Aspártico/metabolismo , Encéfalo/metabolismo , Criança , Pré-Escolar , Colina/análise , Colina/metabolismo , Humanos , Interferon gama/metabolismo , Ácido Láctico/metabolismo , Lúpus Eritematoso Sistêmico/diagnóstico , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodos , Adulto JovemRESUMO
BACKGROUND: We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. METHODS: Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14++CD16- CL and CD14dimCD16+ NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. RESULTS: The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. CONCLUSIONS: We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.
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Lúpus Eritematoso Sistêmico , Locos de Características Quantitativas , Alelos , Predisposição Genética para Doença/genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Monócitos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity. BACKGROUND: We find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections. TRANSLATIONAL SIGNIFICANCE: We develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.
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T-cell dysregulation has been implicated in the loss of tolerance and overactivation of B cells in systemic lupus erythematosus (SLE). Recent studies have identified T-cell subsets and genetic, epigenetic, and environmental factors that contribute to pathogenic T-cell differentiation, as well as disease pathogenesis and clinical phenotypes in SLE. Many therapeutics targeting T-cell pathways are under development, and although many have not progressed in clinical trials, the recent approval of the calcineurin inhibitor voclosporin is encouraging. Further study of T-cell subsets and biomarkers of T-cell action may pave the way for specific targeting of pathogenic T-cell populations in SLE.
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Lúpus Eritematoso Sistêmico , Linfócitos T , Linfócitos B , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológicoRESUMO
BACKGROUND: Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. METHODS: Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. RESULTS: Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 (Cdkn1a) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. CONCLUSIONS: Maladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.
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Senescência Celular/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Isquemia/fisiopatologia , Rim/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Quinases Ativadas por p21/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Doença Crônica , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p19/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Dasatinibe/farmacologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/fisiologia , Transição Epitelial-Mesenquimal , Expressão Gênica , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Humanos , Isquemia/etiologia , Rim/irrigação sanguínea , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteopontina/genética , Inibidores de Proteínas Quinases/farmacologia , Obstrução da Artéria Renal/complicações , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Análise de Sequência de RNA , Análise de Célula Única , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia , Regulação para Cima , Quinases Ativadas por p21/genéticaRESUMO
BACKGROUND: The objective of the study was to explore the disease pathways activated in the inflammatory foci of skin lesions in cutaneous lupus erythematosus (CLE) and dermatomyositis (DM). METHODS: Skin biopsies acquired from active CLE and DM lesions, patient (PC), and also healthy controls (HC) were investigated. Biopsy sections were examined by a pathologist, inflammatory foci were laser micro-dissected and captured, and proteins within captured tissue were detected in an unbiased manner by mass spectrometry. Protein pathway analysis was performed by the string-db.org platform. Findings of interest were confirmed by immunohistochemistry (IHC). RESULTS: Proteome investigation identified abundant expression of interferon-regulated proteins (IRP) as a common feature of CLE and DM. Interleukin (IL)-16 was the only abundant cytokine differentially expressed in CLE compared to DM. Caspase-3, an enzyme that cleaves IL-16 into its active form, was detected in low levels. Significantly higher proportion of IL-16- and caspase-3-positive cells was identified in CLE lesions in comparison with DM, PC, and HC. Proteomic results indicate more abundant complement deposition in CLE skin lesions. CONCLUSIONS: Using unbiased mass spectrometry investigation of CLE and DM inflammatory infiltrates, we confirmed that high IRP expression is a common feature of both CLE and DM, while IL-16 is the only differentially expressed cytokine in CLE. IHC confirmed high expression of IL-16 and caspase-3 in CLE. Our novel molecular findings indicate that IL-16 detection could be useful in differential diagnostics between the two conditions that can display similar histopathological appearance. IL-16 could be of interest as a future therapeutic target for CLE.
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Dermatomiosite , Interleucina-16 , Lúpus Eritematoso Cutâneo , Dermatomiosite/genética , Humanos , Interleucina-16/genética , Lúpus Eritematoso Cutâneo/genética , Proteoma , Proteômica , PeleRESUMO
Systemic lupus erythematosus (SLE) is a complex and heterogeneous systemic autoimmune disease associated with innate and adaptive immune dysregulation. SLE occurs primarily in females of childbearing age, with increased prevalence and severity in minority populations. Despite improvements in treatment modalities, SLE patients frequently experience periods of heightened disease activity and flare that can lead to permanent organ damage, increased morbidity, and early mortality. Such outcomes impair quality of life and inflict a significant socioeconomic burden. Predicting changes in SLE disease activity could allow for closer monitoring and preemptive treatment, but existing clinical, demographic and serologic markers have been only modestly predictive. Novel, proactive approaches to clinical disease management are thus critically needed. Panels of blood biomarkers can detect a breadth of immune pathway dysregulation that captures SLE heterogeneity and disease activity. Alterations in the balance of pro-inflammatory and regulatory soluble mediators have been associated with changes in clinical disease activity and are detectable several weeks prior to clinical flare occurrence. A soluble mediator score has been highly predictive of impending flare in both European American and African American SLE patients, and this score does not require a priori knowledge of specific pathway activation in the patient. We review current concepts of disease activity and flare in SLE, focusing on the potential of novel blood biomarkers to characterize and predict changes in disease activity. Measuring the disordered immune response in SLE in this way promises to improve disease management and prevent organ damage in SLE.