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1.
J Clin Invest ; 132(9)2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35499082

RESUMO

The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.


Assuntos
Ferro , Lúpus Eritematoso Sistêmico , Animais , Diferenciação Celular , Epigênese Genética , Humanos , Hidroxibutirato Desidrogenase/genética , Camundongos , Linfócitos T Auxiliares-Indutores
2.
Front Immunol ; 13: 848478, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35479089

RESUMO

Objectives: More than a quarter of single-country systemic lupus erythematosus (SLE) interventional randomized clinical trials (RCTs) were conducted in China. To help develop management guidelines and set benchmarks for future SLE research, a systematic review of current trials is needed. Methods: We searched systematically three databases and four registries to summarize the interventional RCTs in mainland China and identify factors associated with participant loss. The internal validity of trials was assessed using the Cochrane risk-of-bias tool for assessing risk of bias. The odds ratio (OR) was defined as the ratio of the odds of less than 10% loss to follow-up in the presence or absence of different factors. Results: A total of 188 trials met our inclusion criteria, and 15·5% of trials conducted in mainland China ranked low risk of bias. Participant loss was significantly higher among trials that had a defined primary outcome or were registered {primary outcome identification (0·02 [0·00-0·23]) and registration (0·14 [0·03-0·69])}. Trials examining traditional Chinese medicine (TCM) pharmacological treatments had an 8·16-fold (8·16 [1·28-51·98]) higher probability of having low participant loss than trials examining non-TCM pharmacological treatment trials, and trials that did not report masking status had a 15·95-fold (15·95 [2·45-103·88]) higher probability of having low participant loss than open-label trials. In addition, published articles in Chinese also had higher probability of having low participant loss (5·39 [1·10-26·37]). Conclusion: SLE trials conducted in mainland China were of relatively poor quality. This situation, including nonrigorous design, lack of registration, and absence of compliance reporting, needs to be ameliorated. To maintain the fundamental repeatability and comparability of mainland China SLE RCTs, transparency of the clinical trial process and complete reporting of the trial data are crucial and urgently needed.


Assuntos
Lúpus Eritematoso Sistêmico , Projetos de Pesquisa , China/epidemiologia , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Medicina Tradicional Chinesa , Publicações
3.
Expert Opin Drug Discov ; 17(5): 489-500, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35287523

RESUMO

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with substantial phenotypic heterogeneity. Currently, our understanding of the pathogenesis is still limited, and as a result, specific and efficacious therapies are lacking. Various mouse models have been established to serve as powerful tools that will promote a better understanding of the disease and the ability to test novel drugs before clinical application. AREAS COVERED: The authors review the existing mouse models of SLE in terms of pathogenesis and manifestations, as well as their applications in drug discovery and development. The areas of focus include promising novel therapeutics that could benefit patients in the future and the contribution of mouse models used in preclinical studies. EXPERT OPINION: Given the diversity of SLE mouse models with different characteristics, researchers must select a suitable model based on the mechanism involved. The use of multiple models is needed for drug testing studies to evaluate drug efficacy on different genetic backgrounds and other mechanisms to provide a reference for clinical trials.


Assuntos
Lúpus Eritematoso Sistêmico , Animais , Modelos Animais de Doenças , Descoberta de Drogas , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Camundongos
4.
J Autoimmun ; 128: 102811, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35278775

RESUMO

BACKGROUND: Although the contribution of aberrant CD4+ T cell signaling to systemic lupus erythematosus (SLE) is well established, its role in cutaneous lupus erythematosus (CLE) skin is largely unknown. Because the rate of systemic manifestations varies in each subtype, resident memory CD4+ T cells in lesions that are responsible for only skin-associated tissue responses may vary in each subtype. However, the role of CD4+ tissue-resident memory T (CD4+ Trm) cells in each CLE subtype remains unclear. OBJECTIVES: To analyze and compare CD4+ Trm cells and absent in melanoma 2 (AIM2) identified by smart RNA sequencing (Smart-seq) in CD4+ Trm cells from patients with acute CLE (ACLE), subacute CLE (SCLE), and localized discoid lupus erythematosus (localized DLE) lesions. METHODS: We performed Smart-seq to investigate differences in dermal CD4+ Trm cells between patients with ACLE and normal controls (NCs). Multicolor immunohistochemistry was utilized to measure the levels of AIM2 in CD4+ Trm cells present in the skin of 134 clinical patients, which included patients with localized DLE (n = 19), ACLE (n = 19), SCLE (n = 16), psoriasis (n = 12), rosacea (n = 17), lichen planus (n = 18), and annular granuloma (n = 15), as well as NCs (n = 18). RESULTS: The Smart-seq data showed higher AIM2 expression in skin CD4+ Trm cells from ACLE lesions than NCs (fold change >10, adjusted P < 0.05). AIM2 expression in CD4+ Trm cells did not vary according to age or sex. AIM2 expression in CD4+ Trm cells was significantly lower in patients with ACLE (6.38 ± 5.22) than localized DLE (179.41 ± 160.98, P < 0.0001) and SCLE (63.43 ± 62.27, P < 0.05). In an overall comparison of ACLE with localized DLE and SCLE, the receiver operating characteristic curve for AIM2 expression in CD4+ Trm cells had a sensitivity of 100.00% and a specificity of 82.86% at a cutoff value of 18.26. In a comparison of ACLE with localized DLE, the sensitivity was 89.47%, and the specificity was 100.00% at a cutoff value of 12.26. In a comparison of ACLE with SCLE, the sensitivity was 100.00%, and the specificity was 75.00% at a cutoff value of 18.26. CONCLUSIONS: The number of CD4+ Trm cells is increased in lesions of SCLE and localized DLE compared to ACLE, suggesting that CD4+ Trm cells may have a more crucial role in persistent lesions of SCLE and localized DLE. In addition, AIM2 expression in CD4+ Trm cells discriminates patients with ACLE from those with localized DLE and SCLE.


Assuntos
Lúpus Eritematoso Cutâneo , Lúpus Eritematoso Discoide , Lúpus Eritematoso Sistêmico , Linfócitos T CD4-Positivos/patologia , Humanos , Lúpus Eritematoso Cutâneo/diagnóstico , Lúpus Eritematoso Cutâneo/metabolismo , Lúpus Eritematoso Cutâneo/patologia , Lúpus Eritematoso Discoide/diagnóstico , Lúpus Eritematoso Discoide/genética , Lúpus Eritematoso Sistêmico/metabolismo , Pele/patologia
5.
Front Immunol ; 13: 813203, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35355990

RESUMO

B cells interact with T follicular helper (Tfh) cells in germinal centers (GCs) to generate high-affinity antibodies. Much less is known about how cognate T-B-cell interactions influence Th cells that enter circulation and peripheral tissues. Therefore, we generated mice lacking MHC-II expressing B cells and, by thoracic duct cannulation, analyzed Th cells in the efferent lymph at defined intervals post-immunization. Focusing on gut-draining mesenteric lymph nodes (MLNs), we show that antigen-specific α4ß7 + gut-homing effector Th cells enter the circulation prior to CXCR5+PD-1+ Tfh-like cells. B cells appear to have no or limited impact on the early generation and egress of gut-homing Th cells but are critical for the subsequent appearance of Tfh-like cells that peak in the lymph before GCs have developed. At this stage, antigen-presenting B cells also reduce the proportion of α4ß7 + Th cells in the MLN and efferent lymph. Furthermore, cognate B-cell interaction drives a broad transcriptional program in Th cells, including IL-4 that is confined to the Tfh cell lineage. The IL-4-producing Tfh-like cells originate from Bcl6+ precursors in the LNs and have gut-homing capacity. Hence, B cells program the efferent lymph Th cell response within a limited window of time after antigenic challenge.


Assuntos
Interleucina-4 , Linfócitos T Auxiliares-Indutores , Animais , Linfócitos B , Centro Germinativo , Camundongos , Receptores CXCR5/genética
6.
Clin Transl Med ; 12(3): e781, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35343082

RESUMO

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that involves T follicular helper (TFH ) cell-mediated humoral immune responses. Absent in melanoma 2 (human AIM2 and murine Aim2) is a well-known component of the inflammasome in the innate immune system. Surprisingly, we observed that in SLE patients, upregulated levels of AIM2 expression were found in peripheral blood and skin lesions, with the highest levels detected in TFH -like cells. In the CD4cre Aim2fl/fl conditional knockout mice, a markedly reduced TFH cell response was observed, with significantly lower levels of serum autoantibodies and proteinuria, as well as profoundly reduced renal IgG deposition in pristane-induced lupus mice. Mechanistically, IL-21 was found to recruit hydroxymethyltransferase ten-eleven translocation 2 (TET2) to the AIM2 promoter, resulting in DNA demethylation and increased transcription of AIM2. In addition, AIM2 could regulate c-MAF expression to enhance IL-21 production, which consequently promoted TFH cell differentiation. Our results have identified a role of AIM2 in promoting the TFH cell response and further revealed that the IL-21-TET2-AIM2-c-MAF signalling pathway is dysregulated in lupus pathogenesis, which provides a potential therapeutic target for SLE.


Assuntos
Dioxigenases , Lúpus Eritematoso Sistêmico , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Interleucinas/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-maf/genética , Células T Auxiliares Foliculares
7.
J Autoimmun ; 128: 102798, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35182896

RESUMO

To explore bias in lupus erythematosus (LE) randomized clinical trials (RCTs) and to help the development of benchmarks for future trials and management. We searched systematically three databases and three registries to summarize the interventional randomized clinical trials (RCTs) and identify factors associated with participant loss. Trials which examined pharmacological interventions with control group were included and a meta-analysis was carried out by using fixed and random effects models to calculate risk ratio of participant loss in the intervention and control groups. A total of 481 trials with 68,582 participants met our inclusion criteria, organ specific interventional studies along with trials that address quality of life attributes and geopolitical disparities are missing or lagging behind. 90 trials were involved in the meta-analyses, the withdrawal ratio between intervention and control groups was distinctly influenced by national income of the trial-conducted country. In high income countries, the withdrawal ratio was relatively constant, while for trials conducted in low and middle income countries, the results were altered by trial registration, year of start, number of centers, number of participants, and primary outcome identification. Moreover, the comparability of participants was also worrying, trial location and registration status altered basal participant adherence. Our study reveals the unexpectedly huge heterogeneity brought by national income and trial registration in lupus RCTs worldwide. To maintain the fundamental repeatability and referenceability of LE RCTs, rigorously designed single-country trials with diverse inclusion criteria are needed.


Assuntos
Qualidade de Vida , Humanos , Razão de Chances
8.
Artigo em Inglês | MEDLINE | ID: mdl-35064901

RESUMO

Systemic lupus erythematosus (SLE) is a complicated autoimmune disease with female susceptibility. It is characterized by over-activation of the immune system and deposit of autoimmune complex in multiple organs. High heterogeneity, unpredictable disease course of SLE as well as the lack of specific and sensitive biomarkers posed diagnostic challenges to clinicians. Despite the complicated clinical presentation and pathogenesis of SLE, research regarding this disease has made many significant breakthroughs over the past decades. Some new learning can potentially be translated into clinical practice. In addition, new classification criteria to increase diagnostic accuracy were defined in 2019 by the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR). Real-world studies have accumulated evidence for the adoption of this new classification criteria. Abundant classification criteria, improved recognition of organ-specific manifestations, and updated knowledge about lupus autoantibodies enable earlier diagnosis and more personalized medicine. Thus, it is important to update our knowledge about the latest clinical practices for lupus diagnosis. This review provides new insight into the diagnosis of SLE by summarizing recent advances in epidemiology, etiology, classification criteria, clinical manifestations, and study of autoantibodies.

9.
Eur J Immunol ; 52(4): 669-680, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35092307

RESUMO

Immune repertoire (IR) during treatment may be a surrogate biomarker for disease response. Changes of the IR in systemic lupus erythematosus patients in response to immunosuppressive drugs were identified in ten SLE patients. Patients provided peripheral blood mononuclear cells at two time points for sequencing. They were divided into sensitive and nonsensitive groups by their clinical responses to immunosuppressive drugs. After treatment, the BCR expression significantly decreased in patients from the sensitive group while there was no change in patients from the nonsensitive group. IgM comprised a dominant portion of the BCR repertoire and increased slightly in all patients in the sensitive group but decreased in the nonsensitive group. IgA also exhibited opposing changes between the two groups. Shorter CDR3 of TRB and TRG chains occurred in the sensitive group. CDR3 length of IGK decreased significantly in the sensitive group. CDR3 of TCR δ/γ changed distinctly between time points in the sensitive group. Six immune-related genes showed differential expression levels in sensitive and nonsensitive groups. Our study shows that it is BCR repertoire sensitivity to immunosuppressive drugs in SLE patients and sheds light on personalized therapy for SLE.


Assuntos
Leucócitos Mononucleares , Lúpus Eritematoso Sistêmico , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Leucócitos Mononucleares/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
10.
Allergy Asthma Immunol Res ; 14(1): 131-142, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34983113

RESUMO

Immunoglobulin (Ig) E and IgG anti-thyroid autoantibodies (AAbs) play important roles in the immunopathogenesis of chronic spontaneous urticaria (CSU). To date, association of IgE and IgG AAbs with Chinese CSU patients has not been fully investigated. We aimed to explore prevalence rates of IgE and IgG AAbs in Chinese CSU patients and their association with clinical and laboratory parameters. Serum IgE and IgG AAbs against thyroid peroxidase (TPO) and thyroglobulin (TG), total IgE (tIgE) and specific IgEs were measured using enzyme-linked immunosorbent assay, chemiluminescence microparticle immunoassay and immunoblotting. Meta-analyses and literature review were conducted. The meta-analyses indicated that CSU cases were 4.98, 6.90 and 6.68 times more likely to have positive anti-TPO IgE, anti-TPO IgG and anti-TG IgG (all P < 0.001) compared with controls, respectively, and revealed a positive correlation between the prevalence rates of anti-TPO IgE and anti-TPO IgG (r = 0.53, P = 0.025). A total of 1,100 Chinese Han adult CSU patients and 1,100 ethnicity-, age- and sex-matched healthy controls were recruited from 15 centers. Prevalence rates of anti-TPO IgE, anti-TPO IgG, anti-TG IgE or anti-TG IgG in the patients were all significantly higher than those in the controls. Significant correlations were observed between prevalence rates of anti-TPO IgE and anti-TPO IgG (r = 0.297, P < 0.001) as well as between those of anti-TG IgE and anti-TG IgG in the patients (r = 0.137, P < 0.001). Patients with anti-TPO IgE or anti-TPO IgG had significantly lower tIgE levels (P < 0.001). Positive anti-TPO IgE, positive anti-TPO IgG and tIgE < 40 IU/mL were independent predictors of antihistamine-refractory cases. In conclusion, the prevalence rates of IgE and IgG AAbs in Chinese CSU patients are significantly elevated and reciprocally correlated. This study verifies the results of previous case-control studies of CSU patients from other populations and ethnicities.

11.
Clin Rev Allergy Immunol ; 62(2): 273-291, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33449302

RESUMO

There are two major clinical subsets of scleroderma: (i) systemic sclerosis (SSc) is a complex systemic autoimmune disorder characterized by inflammation, vasculopathy, and excessive fibrosis of the skin and multiple internal organs and (ii) localized scleroderma (LoS), also known as morphea, is confined to the skin and/or subcutaneous tissues resulting in collagen deposition and subsequent fibrosis. SSc is rare but is associated with significant morbidity and mortality compared with other rheumatic diseases. Fatal outcomes in SSc often originate from organ complications of the disease, such as lung fibrosis, pulmonary artery hypertension (PAH), and scleroderma renal crisis (SRC). Current treatment modalities in SSc have focused on targeting vascular damage, fibrosis, and regulation of inflammation as well as autoimmune responses. Some drugs previously used in an attempt to suppress fibrosis, like D-penicillamine (D-Pen) or colchicine, have been disappointing in clinical practice despite anecdotal evidence of their advantages. Some canonical medications, including glucocorticoids, immunosuppressants, and vasodilators, have had some success in treating various manifestations in SSc patients. Increasing evidence suggests that some biologic agents targeting collagen, cytokines, and cell surface molecules might have promising therapeutic effects in SSc. In recent years, hematopoietic stem cell transplantation (HSCT), mostly autologous, has made great progress as a promising treatment option in severe and refractory SSc. Due to the complexity and heterogeneity of SSc, there are currently no optimal treatments for all aspects of the disease. As for LoS, local skin-targeted therapy is generally used, including topical application of glucocorticoids or other immunomodulatory ointments and ultraviolet (UV) irradiation. In addition, systemic immunosuppressants are also utilized in several forms of LoS. Here, we comprehensively discuss current treatment options for scleroderma, encompassing old, new, and future potential treatment options. In addition, we summarize data from new clinical trials that have the potential to modify the disease process and improve long-term outcomes in SSc.


Assuntos
Esclerodermia Localizada , Escleroderma Sistêmico , Fibrose , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Inflamação/complicações , Escleroderma Sistêmico/terapia
12.
Epigenomics ; 14(2): 81-100, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34913398

RESUMO

Aim: To explore potential abnormal epigenetic modifications and immune-cell infiltration in tissues from systemic lupus erythematosus (SLE) patients. Materials & methods: To utilize bioinformatics analysis and 'wet lab' methods to identify and verify differentially expressed genes in multiple targeted organs in SLE. Results: Seven key genes, IFI44, IFI44L, IFIT1, IFIT3, PLSCR1, RSAD2 and OAS2, which are regulated by epigenetics and may be involved in the pathogenesis of SLE, are identified by combined long noncoding RNA-miRNA-mRNA network analysis and DNA methylation analysis. The results of quantitative reverse transcription PCR, immunohistochemistry and DNA methylation analysis confirmed the potential of these genes as biomarkers. Conclusion: This study reveals the potential mechanisms in SLE from epigenetic modifications and immune-cell infiltration, providing diagnostic biomarkers and therapeutic targets for SLE.


Assuntos
Lúpus Eritematoso Sistêmico , MicroRNAs , Biologia Computacional , Metilação de DNA , Epigênese Genética , Epigenômica , Humanos , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética
13.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(11): 1267-1275, 2021 Nov 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34911862

RESUMO

Systemic lupus erythematosus (SLE) is a chronic and autoimmunity-mediated diffuse connective tissue disease. The mainstay of treatments for SLE mainly relies on corticosteroids and immunosuppressants, which have a series of unavoidable side effects. Therefore, it is of fundamental importance to search novel therapeutic targets for better treatment with favorable efficacy and minor side effects. Recent studies shed light on potential therapeutic targets for SLE, mainly covering the followings: B-cell/plasmocyte-related targets [B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), CD20, CD22, CD19/FcγRIIb, Bruton tyrosine kinase (Btk), and proteasome], T cell-related targets [calcineurin, mammalian target of rapamycin (mTOR), regulatory factor X1 (RFX1), and Rho kinase], macrophage-related targets (macrophage migration inhibitory factor), intracellular signaling molecules, cytokines (cereblon, histone deacetylase 6, Janus activated kinase/signal transducer and activator of transcription), co-stimulating factors (CD28/B7, CD40/CD154), IgE autoantibody, and gut microbiome. Among them, belimumab (a humanized monoclonal antibody against B-lymphocyte stimulator) and telitacicept (a recombinant human B-lymphocyte stimulator receptor-antibody fusion protein) have been sequentially approved for the clinical treatment of SLE in China. A variety of new targeted-therapy drugs are in the Phase 2 or Phase 3 clinical trials,among which anifrolumab (a human monoclonal antibody against type I interferon receptor subunit 1) has completed a Phase 3 clinical trial with good responses achieved, although its incidence of herpes zoster is higher than that in the control group. The research progress in both molecular mechanisms and new drug development for different therapeutic targets have greatly promoted our better and in-depth understanding of the pathogenesis of SLE, and have also reflected the complexity and heterogeneity of the disease. Successful development and clinical application of more novel therapies would no doubt usher in a new era of individualized treatment for SLE in the future.


Assuntos
Doença Enxerto-Hospedeiro , Lúpus Eritematoso Sistêmico , Anticorpos Monoclonais/uso terapêutico , Linfócitos B , Humanos , Imunossupressores , Lúpus Eritematoso Sistêmico/tratamento farmacológico
14.
Front Immunol ; 12: 691304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721374

RESUMO

Background: Increasing evidence suggests that the gut microbiome plays a role in the pathogenesis of allergy and autoimmunity. The association between abnormalities in the gut microbiota and chronic spontaneous urticaria (CSU) remains largely undefined. Methods: Fecal samples were obtained from 39 patients with CSU and 40 healthy controls (HCs). 16S ribosomal RNA (rRNA) gene sequencing (39 patients with CSU and 40 HCs) and untargeted metabolomics (12 patients with CSU and 12 HCs) were performed to analyze the compositional and metabolic alterations of the gut microbiome in CSU patients and HCs. Results: The 16S rRNA gene sequencing results showed a significant difference in the ß-diversity of the gut microbiota, presented as the Jaccard distance, between CSU patients and HCs. No significant differences were found in the α-diversity of the gut microbiota between patients and HCs. At the phylum level, the major bacteria in the gut microbiome of patients with CSU were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. At the genus level, Lactobacillus, Turicibacter, and Lachnobacterium were significantly increased and Phascolarctobacterium was decreased in patients with CSU. PICRUSt and correlation analysis indicated that Lactobacillus, Turicibacter, and Phascolarctobacterium were positively related to G protein-coupled receptors. Metabolomic analysis showed that α-mangostin and glycyrrhizic acid were upregulated and that 3-indolepropionic acid, xanthine, and isobutyric acid were downregulated in patients with CSU. Correlation analysis between the intestinal microbiota and metabolites suggested that there was a positive correlation between Lachnobacterium and α-mangostin. Conclusions: This study suggests that disturbances in the gut microbiome composition and metabolites and their crosstalk or interaction may participate in the pathogenesis of CSU.


Assuntos
Bactérias/metabolismo , Urticária Crônica/metabolismo , Urticária Crônica/microbiologia , Metabolismo Energético , Microbioma Gastrointestinal , Metaboloma , Adolescente , Adulto , Bactérias/genética , Bactérias/imunologia , Estudos de Casos e Controles , Criança , Urticária Crônica/imunologia , Disbiose , Fezes/química , Fezes/microbiologia , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Receptores Acoplados a Proteínas G/metabolismo , Ribotipagem , Adulto Jovem
15.
Clin Rev Allergy Immunol ; 61(3): 424-448, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34529248

RESUMO

Chronic urticaria (CU) is a common skin condition characterized by the recurrence of wheals, with or without angioedema, which lasts for at least 6 weeks. Owing to its pruritus and incurability, this disease adversely affects the patients' physical and mental health and diminishes the quality of life. CU is generally classified into two subtypes based on the relevance of eliciting factors: chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), the latter of which is further divided into several subtypes. To improve the understanding and clinical management of this highly heterogeneous disorder, the EAACI/GA2LEN/EDF/WAO guideline was developed and published in 2018 based on evidence and expert consensus. The diagnostic and treatment algorithms proposed by the guideline have largely facilitated dermatologists in clinical practice. However, several questions remained unsolved and have been widely investigated in the recent years. First, a better understanding of the association between chronic urticaria and its potential underlying causes or eliciting factors such as autoimmunity, infections, coagulation aberrance, and vitamin D deficiency is warranted. This would lead to updates in the diagnostic and treatment procedures of different subtypes of chronic urticaria. Secondly, treatment for recalcitrant cases, especially those resistant to or intolerant of second-generation antihistamines and (or) omalizumab, calls for novel therapeutic measures or strategies. In the present review, we summarized recent advances in the understanding and management of both CSU and CIndU, with special emphasis on their underlying causes or eliciting factors, pathogenic mechanisms, potential targets for intervention, and advances in treatment strategies.


Assuntos
Urticária Crônica , Urticária Crônica/etiologia , Urticária Crônica/patologia , Urticária Crônica/terapia , Humanos
16.
Signal Transduct Target Ther ; 6(1): 341, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521812

RESUMO

Absent in melanoma 2 (AIM2) has been reported to be a component of inflammasomes in innate immune cells. Surprisingly, AIM2 is expressed by B cells, and higher AIM2 expression is observed in the B cells from lupus patients. To date, the inflammasome-independent function of AIM2 in B cells remains unclear. Here, we report increased expression of AIM2 in human tonsil memory and germinal center (GC) B cells and in memory B cells and plasma cells from the circulation and skin lesions of lupus patients. Conditional knockout of AIM2 in B cells reduces the CD19+ B-cell frequency in lymph nodes and spleens, and dampens KLH-induced IgG1-antibody production. In a pristane-induced mouse model of lupus, AIM2 deficiency in B cells attenuates lupus symptoms and reduces the frequency of GC B cells, T follicular helper (Tfh) cells, plasmablast cells, and plasma cells. Furthermore, the loss of AIM2 in human B cells leads to the increased expression of Blimp-1 and reduces the expression of Bcl-6. However, the silencing of Blimp-1 and Bcl-6 has no significant effect on AIM2 expression, indicating that AIM2 might be the upstream regulator for Blimp-1 and Bcl-6. In addition, IL-10 is found to upregulate AIM2 expression via DNA demethylation. Together, our findings reveal that AIM2 is highly expressed in the B cells of lupus patients and promotes B-cell differentiation by modulating the Bcl-6-Blimp-1 axis, providing a novel target for SLE treatment.


Assuntos
Proteínas de Ligação a DNA/genética , Lúpus Eritematoso Sistêmico/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Tonsila Faríngea/metabolismo , Tonsila Faríngea/patologia , Animais , Antígenos CD19/genética , Diferenciação Celular/genética , Metilação de DNA/genética , Modelos Animais de Doenças , Centro Germinativo/imunologia , Humanos , Imunidade Inata/genética , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/imunologia , Linfonodos/metabolismo , Linfonodos/patologia , Camundongos , Baço/imunologia , Baço/metabolismo , Terpenos/toxicidade
17.
Ann Transl Med ; 9(13): 1062, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34422974

RESUMO

BACKGROUND: Although lupus can be diagnosed by first impression, medical history, physical examination, pathological analysis and laboratory tests, the accurate classification of cutaneous lupus erythematosus (LE) is still a major challenge in the clinic, which might mislead the selection of treatments and miss the right time for the administration of therapies. The goal of this study was to establish a novel kit to assist with the diagnosis and classification of cutaneous lupus. METHODS: Sixty-five patients from three hospitals were included in this study, including 50 patients with LE and other similar skin diseases. We invited two dermatology specialists to make an accurate diagnosis of the subtypes of lupus based on the patient's clinical features, laboratory examination tests, pathology manifestation analysis, medical treatments and follow-up records. Then, we used their diagnosis results as a standard to which we successively compared the consistency of each step of our diagnosis processes, including impression diagnosis, pathology diagnosis, the combined consideration of the former two diagnostic analyses, and the results of an in situ immune cell detection kit to assist in arriving at a judgement. RESULTS: By Cohen's kappa analysis, we found that the results of the in situ immune cell detection kit had the highest consistency with the diagnoses of the two specialists, both for the diagnosis (k=0.921) and for the classification of cutaneous lupus (k=0.940). In addition, this kit enhanced the LE classification accuracy by 36.3% compared with the diagnostic accuracy of impression diagnosis combined with only pathological analysis. CONCLUSIONS: This skin in situ immune cell detection kit may assist doctors in achieving a higher diagnostic performance and price ratio and enhance their diagnostic efficiency.

18.
Int Rev Immunol ; : 1-25, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34445929

RESUMO

B cells play a crucial role in antigen presentation, antibody production and pro-/anti-inflammatory cytokine secretion in adaptive immunity. Several translational factors including transcription factors and cytokines participate in the regulation of B cell development, with the cooperation of epigenetic regulations. Autoimmune diseases are generally characterized with autoreactive B cells and high-level pathogenic autoantibodies. The success of B cell depletion therapy in mouse model and clinical trials has proven the role of B cells in pathogenesis of autoimmune diseases. The failure of B cell tolerance in immune checkpoints results in accumulated autoreactive naïve B (BN) cells with aberrant B cell receptor signaling and dysregulated B cell response, contributing to self-antibody-mediated autoimmune reaction. Dysregulation of translational factors and epigenetic alterations in B cells has been demonstrated to correlate with aberrant B cell compartment in autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren's syndrome, multiple sclerosis, diabetes mellitus and pemphigus. This review is intended to summarize the interaction of translational factors and epigenetic regulations that are involved with development and differentiation of B cells, and the mechanism of dysregulation in the pathogenesis of autoimmune diseases.

19.
J Autoimmun ; 123: 102707, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34364171

RESUMO

Cutaneous lupus erythematosus (CLE) is an inflammatory, autoimmune disease encompassing a broad spectrum of subtypes including acute, subacute, chronic and intermittent CLE. Among these, chronic CLE can be further classified into several subclasses of lupus erythematosus (LE) such as discoid LE, verrucous LE, LE profundus, chilblain LE and Blaschko linear LE. To provide all dermatologists and rheumatologists with a practical guideline for the diagnosis, treatment and long-term management of CLE, this evidence- and consensus-based guideline was developed following the checklist established by the international Reporting Items for Practice Guidelines in Healthcare (RIGHT) Working Group and was registered at the International Practice Guideline Registry Platform. With the joint efforts of the Asian Dermatological Association (ADA), the Asian Academy of Dermatology and Venereology (AADV) and the Lupus Erythematosus Research Center of Chinese Society of Dermatology (CSD), a total of 25 dermatologists, 7 rheumatologists, one research scientist on lupus and 2 methodologists, from 16 countries/regions in Asia, America and Europe, participated in the development of this guideline. All recommendations were agreed on by at least 80% of the 32 voting physicians. As a consensus, diagnosis of CLE is mainly based on the evaluation of clinical and histopathological manifestations, with an exclusion of SLE by assessment of systemic involvement. For localized CLE lesions, topical corticosteroids and topical calcineurin inhibitors are first-line treatment. For widespread or severe CLE lesions and (or) cases resistant to topical treatment, systemic treatment including antimalarials and (or) short-term corticosteroids can be added. Notably, antimalarials are the first-line systemic treatment for all types of CLE, and can also be used in pregnant patients and pediatric patients. Second-line choices include thalidomide, retinoids, dapsone and MTX, whereas MMF is third-line treatment. Finally, pulsed-dye laser or surgery can be added as fourth-line treatment for localized, refractory lesions of CCLE in cosmetically unacceptable areas, whereas belimumab may be used as fourth-line treatment for widespread CLE lesions in patients with active SLE, or recurrence of ACLE during tapering of corticosteroids. As for management of the disease, patient education and a long-term follow-up are necessary. Disease activity, damage of skin and other organs, quality of life, comorbidities and possible adverse events are suggested to be assessed in every follow-up visit, when appropriate.


Assuntos
Lúpus Eritematoso Cutâneo/diagnóstico , Lúpus Eritematoso Cutâneo/terapia , Guias de Prática Clínica como Assunto , Humanos , Lúpus Eritematoso Cutâneo/classificação
20.
Am J Clin Dermatol ; 22(6): 877-889, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34374027

RESUMO

BACKGROUND: Atopic dermatitis is a chronic, inflammatory condition causing a substantial burden to patients and caregivers. SHR0302 is an oral, highly selective, Janus kinase 1 inhibitor under investigation for inflammatory skin diseases. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of SHR0302 in Chinese patients with moderate to severe atopic dermatitis. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, multicenter, phase II trial was conducted in China between October 2019 and August 2020. PARTICIPANTS: Patients (n = 105) aged 18-75 years with moderate to severe dermatitis and nonresponsive or intolerant to topical or conventional systemic treatments were included. INTERVENTIONS: Patients were randomly assigned in a ratio of 1:1:1 to receive SHR0302 4 mg once daily, SHR0302 8 mg once daily, or placebo for 12 weeks. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the proportion of patients achieving Investigator's Global Assessment (IGA) response (IGA of 0 [clear] or 1 [almost clear] with improvement of ≥2 grades) at week 12. Secondary efficacy assessments included Eczema Area and Severity Index (EASI) and pruritus Numerical Rating Scale (NRS) scores. RESULTS: At week 12, IGA response was achieved in nine patients (25.7%; 90% confidence interval [CI] 13.6-37.9%; p = 0.022) in the SHR0302 4 mg group, 19 patients (54.3%; 90% CI 40.4-68.1%; p < 0.001) in the SHR0302 8 mg group, and two patients (5.7%; 90% CI 0.0-12.2%) in the placebo group. EASI75 was achieved in 51.4% (p = 0.013), 74.3% (p < 0.001), and 22.9% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively, while an NRS ≥3-point improvement occurred in 65.7% (p < 0.001), 74.3% (p < 0.001), and 22.9% of patients, respectively. Treatment-emergent adverse events were reported in 60.0%, 68.6%, and 51.4% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively. The adverse events were mild in most cases. Three serious adverse events were reported, all being worsening of atopic dermatitis. No serious infection was reported. CONCLUSIONS AND RELEVANCE: Oral SHR0302 was effective and well tolerated in Chinese adult patients with moderate to severe atopic dermatitis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04162899; URL: https://clinicaltrials.gov/ . Date first registered: 14 November 2019.


Assuntos
Dermatite Atópica/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/administração & dosagem , Ácidos Sulfúricos/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Dermatite Atópica/diagnóstico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Inibidores de Janus Quinases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Ácidos Sulfúricos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
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