RESUMO
Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.
Assuntos
Atresia Biliar/imunologia , Atresia Biliar/terapia , Fígado/imunologia , Animais , Antígenos CD20/metabolismo , Linfócitos B/imunologia , Atresia Biliar/sangue , Atresia Biliar/tratamento farmacológico , Biópsia , Receptor 1 de Quimiocina CX3C/metabolismo , Morte Celular , Linhagem Celular , Proliferação de Células , Transdiferenciação Celular , Criança , Pré-Escolar , Estudos de Coortes , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina G/metabolismo , Lactente , Inflamação/patologia , Células Matadoras Naturais/imunologia , Células de Kupffer/patologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Depleção Linfocítica , Linfopoese , Masculino , Camundongos Endogâmicos BALB C , Fagocitose , RNA/metabolismo , Rituximab/administração & dosagem , Rituximab/farmacologia , Rituximab/uso terapêutico , Rotavirus/fisiologia , Análise de Célula Única , Células Th1/imunologia , Células Th17/imunologiaRESUMO
Increasing clinical data show that the imbalance of host metallome is closely associated with different kinds of disease, however, the intrinsic mechanisms of action of metals in immunity and pathogenesis of disease remain largely undefined. There is lack of multiplexed profiling system to integrate the metalloproteome-immunoproteome information at systemic level for exploring the roles of metals in immunity and disease pathogenesis. In this study, we build up a metal-coding assisted multiplexed proteome assay platform for serum metalloproteomic and immunoproteomic profiling. By taking COVID-19 as a showcase, we unbiasedly uncovered the most evident modulation of iron-related proteins, i.e., Ft and Tf, in serum of severe COVID-19 patients, and the value of Ft/Tf could work as a robust biomarker for COVID-19 severity stratification, which overtakes the well-established clinical risk factors (cytokines). We further uncovered a tight association of transferrin with inflammation mediator IL-10 in COVID-19 patients, which was proved to be mainly governed by the monocyte/macrophage of liver, shedding light on new pathophysiological and immune regulatory mechanisms of COVID-19 disease. We finally validated the beneficial effects of iron chelators as anti-viral agents in SARS-CoV-2-infected K18-hACE2 mice through modulation of iron dyshomeostasis and alleviating inflammation response. Our findings highlight the critical role of liver-mediated iron dysregulation in COVID-19 disease severity, providing solid evidence on the involvement of iron-related proteins in COVID-19 pathophysiology and immunity.
Assuntos
COVID-19 , Ferro , Proteoma , SARS-CoV-2 , COVID-19/imunologia , Humanos , Animais , SARS-CoV-2/imunologia , Camundongos , Ferro/metabolismo , Proteômica/métodos , Transferrina/metabolismo , Metaloproteínas/imunologia , Metaloproteínas/metabolismo , Masculino , Feminino , Biomarcadores/sangue , Biomarcadores/metabolismo , Quelantes de Ferro/uso terapêutico , Quelantes de Ferro/farmacologia , Interleucina-10/imunologia , Interleucina-10/metabolismo , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: In the complex panorama of autoimmune diseases, the characterisation of pivotal contributing autoantibodies that are involved in disease progression remains challenging. This study aimed to employ a global antibody profiling strategy to identify novel antibodies and investigate their association with systemic sclerosis (SSc). METHODS: We implemented this strategy by conducting immunoprecipitation (IP) following on-bead digestion with the sera of patients with SSc or healthy donors, using antigen pools derived from cell lysates. The enriched antigen-antibody complex was proceeded with mass spectrometry (MS)-based quantitative proteomics and over-represented by bioinformatics analysis. The candidate antibodies were then orthogonally validated in two independent groups of patients with SSc. Mice were immunised with the target antigen, which was subsequently evaluated by histological examination and RNA sequencing. RESULTS: The IP-MS analysis, followed by validation in patients with SSc, revealed a significant elevation in anti-PRMT5 antibodies among patients with SSc. These antibodies exhibited robust diagnostic accuracy in distinguishing SSc from healthy controls and other autoimmune conditions, including systemic lupus erythematosus and Sjögren's syndrome, with an area under the curve ranging from 0.900 to 0.988. The elevation of anti-PRMT5 antibodies was verified in a subsequent independent group with SSc using an additional method, microarray. Notably, 31.11% of patients with SSc exhibited seropositivity for anti-PRMT5 antibodies. Furthermore, the titres of anti-PRMT5 antibodies demonstrated a correlation with the progression or regression trajectory in SSc. PRMT5 immunisation displayed significant inflammation and fibrosis in both the skin and lungs of mice. This was concomitant with the upregulation of multiple proinflammatory and profibrotic pathways, thereby underscoring a potentially pivotal role of anti-PRMT5 antibodies in SSc. CONCLUSIONS: This study has identified anti-PRMT5 antibodies as a novel biomarker for SSc.
Assuntos
Autoanticorpos , Biomarcadores , Proteína-Arginina N-Metiltransferases , Escleroderma Sistêmico , Escleroderma Sistêmico/imunologia , Humanos , Biomarcadores/sangue , Autoanticorpos/sangue , Autoanticorpos/imunologia , Proteína-Arginina N-Metiltransferases/imunologia , Animais , Camundongos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Adulto , Lúpus Eritematoso Sistêmico/imunologia , Imunoprecipitação/métodos , Proteômica/métodosRESUMO
OBJECTIVES: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.
Assuntos
Artrite Reumatoide , Doenças Autoimunes , Linfócitos B Reguladores , Fator de Necrose Tumoral alfa , Animais , Humanos , Camundongos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Doenças Autoimunes/metabolismo , Linfócitos B Reguladores/metabolismo , Fenótipo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS). METHODS: In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration. RESULTS: Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8+CD103+CD69+ cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8+ CD103+ Trm contributed to the secretion of granzyme-B and interferon-γ, CD8+ Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3+CD8+ SG T cells. In the SG of ESS, CD8+CD69+CD103+ Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow. CONCLUSIONS: CD103+CD8+Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.
RESUMO
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints and produces pain, swelling, and stiffness. It has a lifetime prevalence of up to 1% worldwide. An extract of Tripterygium wilfordii Hook F (TwHF), a member of the Celastraceae herbal family widely available in south China, has been used for treatment of RA since 1960s. METHODS: The current consensus practice guidance (CPG) aims to offer guidance on the application of TwHF in the clinical management of active RA. The CPG followed World Health Organisation (WHO)'s recommended process, carried out three systematic reviews to synthesize data from 19 randomised controlled trials (RCT) involving 1795 participants. We utilized Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to evaluate certainty of evidence and derive recommendations. We rigorously followed The Appraisal of Guidelines for Research and Evaluation II (AGREE II) as conduct guides to minimise bias and promote transparency. RESULTS: There was no obvious difference between TwHF monotherapy and methotrexate (MTX) monotherapy on ACR20 (RCT = 2, N = 390, RR = 1.06, 95%CI 0.90-1.26, moderate certainty), ACR50 (RCT = 3, N = 419, RR = 1.03, 95%CI 0.80-1.34, moderate certainty), ACR70 (RCT = 2, N = 390, RR = 1.12, 95%CI 0.69-1.79, low certainty). TwHF monotherapy may be better than salicylazosulfapyridine monotherapy on ACR20 and the effect may be similar on ACR50 and ACR70. Seven RCTs compared MTX combined with TwHF versus MTX monotherapy, and the meta-analysis results favoured combination therapy group on ACR20 (RCT = 3, N = 470, RR = 1.44, 95%CI 1.28-1.62, moderate certainty), ACR50 (RCT = 4, N = 500, RR = 1.88, 95%CI 1.56-2.28, moderate certainty) and ACR70 (RCT = 2, N = 390, RR = 2.12, 95%CI 1.40-3.19, low certainty). We found no obvious difference between groups on critical safety outcomes, including infection (RCT = 3, N = 493, RR = 1.37, 95%CI 0.84-2.23), liver dysfunction (RCT = 5, N = 643, RR = 1.14, 95%CI 0.71-1.85), renal damage (RCT = 3, N = 450, RR = 2.20, 95%CI 0.50-9.72). CONCLUSION: Upon full review of the evidence, the guidance panel reached consensus on recommendations for the use of TwHF in people with active RA, either as monotherapy or as combination therapy with MTX.
Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Antirreumáticos/uso terapêutico , Tripterygium , Consenso , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Doença CrônicaRESUMO
Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.
Assuntos
Autoanticorpos , Lúpus Eritematoso Discoide , Lúpus Eritematoso Sistêmico , Pele , Humanos , Lúpus Eritematoso Discoide/imunologia , Lúpus Eritematoso Discoide/patologia , Feminino , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Autoanticorpos/imunologia , Autoanticorpos/sangue , Pele/patologia , Pele/imunologia , Pele/metabolismo , Adulto , Pessoa de Meia-Idade , Alelos , Antígenos HLA/genética , Antígenos HLA/imunologia , Adulto Jovem , MultiômicaRESUMO
Anti-phospholipid autoantibodies are a group of antibodies that can specifically bind to anionic phospholipids and phospholipid protein complexes. Recent studies have reported elevated serum anti-phospholipid autoantibody levels in patients with antiphospholipid syndrome, systemic lupus erythematosus, rheumatoid arthritis, metabolic disorders, malaria, SARS-CoV-2 infection, obstetric diseases and cardiovascular diseases. However, the underlying mechanisms of anti-phospholipid autoantibodies in disease pathogenesis remain largely unclear. Emerging evidence indicate that anti-phospholipid autoantibodies modulate NETs formation, monocyte activation, blockade of apoptotic cell phagocytosis in macrophages, complement activation, dendritic cell activation and vascular endothelial cell activation. Herein, we provide an update on recent advances in elucidating the effector mechanisms of anti-phospholipid autoantibodies in the pathogenesis of various diseases, which may facilitate the development of potential therapeutic targets for the treatment of anti-phospholipid autoantibody-related disorders.
Assuntos
Síndrome Antifosfolipídica , Lúpus Eritematoso Sistêmico , Humanos , Autoanticorpos , Anticorpos Antifosfolipídeos , MacrófagosRESUMO
As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) is activated by structurally diverse ligands derived from the environment, diet, microorganisms, and metabolic activity. Recent studies have demonstrated that AhR plays a key role in modulating both innate and adaptive immune responses. Moreover, AhR regulates innate immune and lymphoid cell differentiation and function, which is involved in autoimmune pathogenesis. In this review, we discuss recent advances in understanding the mechanism of activation of AhR and its mediated functional regulation in various innate immune and lymphoid cell populations, as well as the immune-regulatory effect of AhR in the development of autoimmune diseases. In addition, we highlight the identification of AhR agonists and antagonists that may serve as potential therapeutic targets for the treatment of autoimmune disorders.
Assuntos
Doenças Autoimunes , Receptores de Hidrocarboneto Arílico , Humanos , Receptores de Hidrocarboneto Arílico/metabolismo , Regulação da Expressão Gênica , Linfócitos/metabolismo , LigantesRESUMO
OBJECTIVE: To investigate the role of programmed cell death protein 1 (PD-1) and its two ligands, PD-L1 and PD-L2, in the pathogenesis of IgG4-related disease (IgG4-RD). METHODS: Patients with IgG4-RD (n = 43) and healthy controls (n = 34) were recruited. Expression levels of PD-1, PD-L1 and PD-L2 in plasma, submandibular gland and T cell subsets were determined by ELISA, immunohistochemistry and flow cytometry. Naïve T cells were stimulated with or without PD-L1/PD-L2 or anti-PD-L1/anti-PD-L2 for 7 days and the proportion of CD4+CD25+ Treg cells was detected by flow cytometry. RESULTS: The expression of PD-1, PD-L1 and PD-L2 in the plasma, submandibular gland and on the surface of Treg cells was increased in IgG4-RD patients. Plasma soluble (s)PD-1 was positively correlated with serum IgG, IgG1, IgG3, IgG4, IgG4-RD responder index and numbers of organs involved, and negatively correlated with serum IgM, IgA, C3 and C4. Plasma sPD-L2 was positively correlated with serum IgG1, and plasma sPD-L1 was positively correlated with sPD-L2 and negatively correlated with C3. Stimulation of PD-L1 but not PD-L2 promoted the differentiation of naïve T cells from IgG4-RD patients into CD4+CD25+ Treg cells. CONCLUSION: Plasma concentrations of sPD-1, sPD-L1 and sPD-L2 were significantly increased in patients with IgG4-RD, and the expression of PD-1 and PD-L2 on Treg cells was upregulated. PD-1-PD-L1 can promote the differentiation of naïve T cells into Treg cells and thus participate in the pathogenesis of IgG4-RD.
Assuntos
Antígeno B7-H1/metabolismo , Doença Relacionada a Imunoglobulina G4/etiologia , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/sangue , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Doença Relacionada a Imunoglobulina G4/sangue , Doença Relacionada a Imunoglobulina G4/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/sangue , Receptor de Morte Celular Programada 1/sangue , Glândula Submandibular/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
BACKGROUND: Recent studies have revealed a role of the ligand for glucocorticoid-induced TNFR family-related protein (GITRL) in mediating functional dysregulations of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of primary Sjögren syndrome (pSS), but the underlying molecular mechanism is largely unclear. In this study, we aimed to elucidate GITRL-mediated signaling pathways in MDSCs during the development of experimental SS (ESS). METHODS: MDSCs were stimulated with recombinant GITRL, the activation of PTEN, AKT and STAT3 in MDSCs was analyzed by Western blot. MDSCs with different treatment were adoptively transferred to ESS mice. ELISA was used to detect the level of autoantibodies. Proportions of Th1 and Th17 cells were examined by flow cytometry. Histological evaluation of glandular destruction was analyzed by hematoxylin and eosin (HE) staining. The interaction of GITR, TRAF3 and PP2A was detected by CoIP. RESULTS: Upon the engagement of GITR on MDSCs, PTEN was activated and led to the inhibition of downstream AKT/STAT3 signaling pathway, therefore, resulting in the impaired immunosuppressive function of MDSCs. In ESS mice, blocking the activity of PTEN could efficiently restore the immunomodulatory effect of MDSCs and alleviate the progression of ESS. Furthermore, TRAF3 was found to bind to GITR, and then recruited PP2A to dephosphorylate PTEN, thus enhancing the activity of PTEN. CONCLUSION: This study elucidated the molecular mechanism underlying the effect of GITRL in regulating the function of MDSCs, which may provide a new therapeutic target for the treatment of pSS.
Assuntos
Células Supressoras Mieloides , Síndrome de Sjogren , Fatores de Necrose Tumoral , Animais , Camundongos , Imunossupressores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator 3 Associado a Receptor de TNF/metabolismo , Fatores de Necrose Tumoral/metabolismoRESUMO
Cutaneous lupus erythematosus (CLE) is a relapsing autoimmune disease, but key elements that drive disease initiation and progression remain elusive. To date, the lack of ideal murine model which resemble human cutaneous lupus makes it extremely challenging for moving mechanistic discoveries and novel therapeutics. Here, we prompt a humanized murine model to develop an inducible rapid-onset murine that performs cutaneous rather than systemic lupus, depending on the successful human immune system reconstruction from active lupus patients and UVB irradiation as for essentially pathogenic triggers. In addition, we demonstrate a newly discovered population of B cell with a unique phenotype, that of the age-associated B cell (ABC, T-bet+ CD11b+), exhibits B cell clusters in humanized cutaneous lupus. In the response of IL-21 and TLR7/9 signals, recruitment of autoreactive B cells to the position of inflammation with subsequent localized antibody production of IgG2a, IgG2b, IgG3, has the potential to exacerbate ongoing inflammation and thus driving lupus-like autoimmunity in a B-cell-dominant fashion. Overall, our model provides a relevant system for exploring the pathophysiology of cutaneous lupus, a suitable model for drug development, as well as updating a potential role of IL-21 and TLR7/9 to be targeted by biologics.
Assuntos
Envelhecimento/imunologia , Linfócitos B/fisiologia , Interleucinas/fisiologia , Lúpus Eritematoso Cutâneo/etiologia , Adolescente , Adulto , Animais , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina G/biossíntese , Lúpus Eritematoso Cutâneo/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Receptor 7 Toll-Like/fisiologia , Receptor Toll-Like 9/fisiologia , Adulto JovemRESUMO
Although the expansion of myeloid-derived suppressor cells (MDSCs) has been reported in autoimmune disorders, it is largely unclear how MDSCs contribute to the development of primary Sjögren syndrome (pSS). In this study, we found significantly increased MDSCs with gradually diminished suppressive capacity during disease development in mice with experimental Sjögren syndrome (ESS). The ligand for glucocorticoid-induced TNFR family-related protein (GITRL) was increased along ESS progression, whereas the increased GITRL was found to attenuate the immunosuppressive function of MDSCs. Moreover, blocking GITR signal in MDSCs significantly restored their immunosuppressive function and alleviated ESS progression in mice. In pSS patients, expanded MDSCs were found to express low levels of arginase. Significantly increased serum GITRL levels were closely correlated with patients with higher Sjögren syndrome disease activity index. Furthermore, treatment with recombinant GITRL markedly reduced the immunosuppressive function of human MDSCs. Together, our studies have demonstrated a critical role of GITRL in modulating the suppressive function of MDSCs, which may facilitate the validation of GITRL as a therapeutic target for the treatment of pSS.
Assuntos
Células Supressoras Mieloides/imunologia , Síndrome de Sjogren/imunologia , Fatores de Necrose Tumoral/imunologia , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Síndrome de Sjogren/metabolismo , Fatores de Necrose Tumoral/metabolismoRESUMO
The structural elucidation of chiral molecules with more than one stereocenter is usually a tricky problem. In this paper, efficient 1H NMR spectroscopic approaches for assigning the erythro and threo configurations of 1-oxygenated 1,2-diarylpropan-3-ols were developed. By analysis of the chemical shift differences of diastereotopic methylene H2-3 (Δδ3) in CDCl3 or the chemical shift differences of H-1 and H-2 (Δδ1,2) in methanol-d4, deuterated dimethyl sulfoxide, and acetone-d6, the configurations of 1-oxygenated 1,2-diarylpropan-3-ols can be rapidly and conveniently determined.
Assuntos
1-Propanol/química , Dimetil Sulfóxido/química , Oxigênio/química , Espectroscopia de Ressonância Magnética/métodos , EstereoisomerismoRESUMO
BACKGROUND: Lipocalin-2 (LCN2) is an indicator of the severity of lupus nephritis (LN) and plays a pivotal role in immune responses, but it is not known if its effect on LN pathogenesis derives from regulating the immune imbalance of T lymphocyte subsets. METHODS: The expression of LCN2 in T cells and kidneys was assessed in renal biopsies from patients with LN. We investigated the relationship between LCN2 levels and development of LN and systemic illness by injecting anti-LCN2 antibodies into MRL/lpr mice and analyzing pristane-treated LCN2-/- mice. RESULTS: LCN2 is highly expressed in CD4+ T cells and in renal tissues, and is associated with severe renal damage in patients with LN and in mice with experimental lupus. LCN2 promotes IFN-γ overexpression in CD4+ T cells through the IL-12/STAT4 pathway in an autocrine or paracrine manner. Both neutralization of LCN2 in MRL/lpr mice and genetic depletion of LCN2 in pristane-induced lupus mice greatly ameliorate nephritis. The frequency and number of splenic and renal Th1 cells decrease in proportion to LN disease activity. Conversely, administration of LCN2 exacerbates the disease with significantly higher renal activity scores and increased numbers of Th1 cells. CONCLUSIONS: LCN2 plays a crucial role in Th1 cell differentiation, and may present a potential therapeutic target for LN.
Assuntos
Lipocalina-2/metabolismo , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Células Th1/metabolismo , Animais , Estudos de Casos e Controles , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Humanos , Nefrite Lúpica/etiologia , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr , Células Th1/patologiaRESUMO
The pandemic of COVID-19 has caused global social impact and high health risk. Clinical observations have suggested that elevated levels of inflammatory mediators are associated with disease severities in COVID-19 patients, in which the immunological profiles indicate the hyperactivation of innate immune cells and dysregulated adaptive immune responses. The increasing prevalence and disease progression of COVID-19 has emerged as a pressing challenge for the management of rheumatic patients with immune dysregulations. Here we review the immune dysregulations in COVID-19 and discuss the management of COVID-19 patients with rheumatic diseases.
Assuntos
COVID-19 , Sistema Imunitário/fisiopatologia , Doenças Reumáticas , COVID-19/imunologia , COVID-19/fisiopatologia , Humanos , Pandemias , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/terapiaRESUMO
Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder affecting exocrine glands of the body, prevalently lacrimal and salivary glands. The pSS pathogenesis has been thought to be B-cell-centric and several clinical trials have been carried out in order to clarify the therapeutic role of B-cell depletion in patients with pSS. Unfortunately, however, B-cell depletion with rituximab has failed in demonstrating any significant results in pSS patients. Besides the contribution of B cells in the pathogenesis of pSS, effector Tfh, Th17 and Th22 cells, follicular dendritic cells (DCs), innate cells (ICs) and several cytokines, chemokines and miRNA have been proved to participate to the development of this systemic disease. Understanding these molecular processes may help guide research into resistant diseases and highly targeted therapeutic strategies. This review aims to discuss important pathogenetic mechanisms involved in the initiation and perpetuation of pSS behind the established role of B cells.
Assuntos
MicroRNAs , Síndrome de Sjogren , Linfócitos B , Humanos , Rituximab , Glândulas Salivares , Síndrome de Sjogren/tratamento farmacológicoRESUMO
Chemical investigations of the 75% EtOH extract of the leaves of Tripterygium wilfordii obtained five undescribed naturally occurring sesquiterpenes with dihydro-ß-agarofuran skeleton, tripteresters A-E (1-5), along with eight known analogues (6-13). Their chemical structures were elucidated by a combination of spectroscopic the comprehensive spectroscopic analyses, electronic circular dichroism (ECD) exciton chirality, and quantum chemical calculations ECD. In the bioactivity assay, their neuroprotective properties against hydrogen peroxide (H2O2)-induced oxidative damage in human neuroblastoma SH-SY5Y cells were investigated, and compounds 4, 8, and 12 revealed moderate protective activity at a concentration of 12.5 µM.
Assuntos
Descoberta de Drogas , Peróxido de Hidrogênio/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos/farmacologia , Tripterygium/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Peróxido de Hidrogênio/farmacologia , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Extensive studies have suggested a central role of B cells in the autoimmune pathogenesis, as loss of B cell tolerance results in increased serum levels of autoantibodies, enhanced effector T cell response and tissue damages. Here, we provide an overview of dysregulated B cell responses in the development of autoimmunity. In addition to their presence in the target organs, autoreactive B cells can promote the formation of ectopic lymphoid structures and differentiate into plasma cells that produce large amounts of autoantibodies and cytokines. In animal models that recapitulate the key features of human autoimmune disease, mechanistic studies have indicated two categories of autoantibodies: (1) serological markers for disease diagnosis and prognosis; (2) effector molecules that induce organ hypofunction or damage directly in an epitope-specific manner, or indirectly by activating other immune cell subsets. Moreover, B cell-derived cytokines usually promote the autoreactive T cell response during autoimmune development, but there is compelling evidence that a subpopulation of B cells negatively regulates immune responses, also known as regulatory B cells via secreting anti-inflammatory cytokines (IL-10, IL-35, etc.) or a contact-dependent fashion. Although B cell depletion could eliminate most circulating B cells in the periphery, the clinical outcomes of B cell depletion therapy for autoimmune diseases vary among individuals due to differential activation or survival signals for B cells provided by tissue microenvironment. Thus, therapeutic combinations that target immune checkpoints and B cell activation may represent a promising strategy for the effective treatment of human autoimmune diseases.
Assuntos
Doenças Autoimunes , Linfócitos B , Animais , Autoanticorpos , Autoimunidade , Humanos , Linfócitos TRESUMO
Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways.