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1.
Annu Rev Immunol ; 40: 323-348, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35113729

RESUMO

The diverse biological activity of interleukin-6 (IL-6) contributes to the maintenance of homeostasis. Emergent infection or tissue injury induces rapid production of IL-6 and activates host defense through augmentation of acute-phase proteins and immune responses. However, excessive IL-6 production and uncontrolled IL-6 receptor signaling are critical to pathogenesis. Over the years, therapeutic agents targeting IL-6 signaling, such as tocilizumab, a humanized anti-IL-6 receptor antibody, have shown remarkable efficacy for rheumatoid arthritis, Castleman disease, and juvenile idiopathic arthritis, and their efficacy in other diseases is continually being reported. Emerging evidence has demonstrated the benefit of tocilizumab for several types of acute inflammatory diseases, including cytokine storms induced by chimeric antigen receptor T cell therapy and coronavirus disease 2019 (COVID-19). Here, we refocus attention on the biology of IL-6 and summarize the distinct pathological roles of IL-6 signaling in several acute and chronic inflammatory diseases.


Assuntos
Artrite Reumatoide , COVID-19 , Animais , Artrite Reumatoide/terapia , COVID-19/terapia , Humanos , Imunoterapia Adotiva , Interleucina-6/metabolismo , Transdução de Sinais
2.
Annu Rev Immunol ; 37: 439-456, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31026415

RESUMO

Monocytes are innate blood cells that maintain vascular homeostasis and are early responders to pathogens in acute infections. There are three well-characterized classes of monocytes: classical (CD14+CD16- in humans and Ly6Chi in mice), intermediate (CD14+CD16+ in humans and Ly6C+Treml4+ in mice), and nonclassical (CD14-CD16+ in humans and Ly6Clo in mice). Classical monocytes are critical for the initial inflammatory response. Classical monocytes can differentiate into macrophages in tissue and can contribute to chronic disease. Nonclassical monocytes have been widely viewed as anti-inflammatory, as they maintain vascular homeostasis. They are a first line of defense in recognition and clearance of pathogens. However, their roles in chronic disease are less clear. They have been shown to be protective as well as positively associated with disease burden. This review focuses on the state of the monocyte biology field and the functions of monocytes, particularly nonclassical monocytes, in health and disease.


Assuntos
Artrite Reumatoide/imunologia , Aterosclerose/imunologia , Vasos Sanguíneos/fisiologia , Monócitos/imunologia , Infarto do Miocárdio/imunologia , Animais , Autoimunidade , Hematopoese , Homeostase , Humanos , Inflamação , Camundongos
3.
Immunity ; 56(5): 1046-1063.e7, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-36948194

RESUMO

Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.


Assuntos
Artrite Reumatoide , Imunoglobulinas Intravenosas , Lectinas Tipo C , Receptores de IgG , Animais , Humanos , Camundongos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Membrana Celular/metabolismo , Imunoglobulinas Intravenosas/administração & dosagem , Lectinas Tipo C/metabolismo , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo , Processamento de Proteína Pós-Traducional , Receptores de IgG/metabolismo
4.
Immunol Rev ; 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867408

RESUMO

Rheumatoid arthritis (RA) is considered a multifactorial condition where interaction between the genetic and environmental factors lead to immune dysregulation causing autoreactivity. While among the various genetic factors, HLA-DR4 and DQ8, have been reported to be the strongest risk factors, the role of various environmental factors has been unclear. Though events initiating autoreactivity remain unknown, a mucosal origin of RA has gained attention based on the recent observations with the gut dysbiosis in patients. However, causality of gut dysbiosis has been difficult to prove in humans. Mouse models, especially mice expressing RA-susceptible and -resistant HLA class II genes have helped unravel the complex interactions between genetic factors and gut microbiome. This review describes the interactions between HLA genes and gut dysbiosis in sex-biased preclinical autoreactivity and discusses the potential use of endogenous commensals as indicators of treatment efficacy as well as therapeutic tool to suppress pro-inflammatory response in rheumatoid arthritis.

5.
Immunity ; 48(1): 45-58.e6, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29287995

RESUMO

Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rß1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.


Assuntos
Subunidade beta 1 de Receptor de Interleucina-12/metabolismo , Interleucina-23/metabolismo , Receptores de Interleucina/metabolismo , Animais , Calorimetria/métodos , Linhagem Celular , Humanos , Interferometria/métodos , Subunidade p40 da Interleucina-12/metabolismo , Masculino , Camundongos , Ligação Proteica/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
6.
Semin Immunol ; 69: 101814, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37542986

RESUMO

Evidence is emerging that the process of immune aging is a mechanism leading to autoimmunity. Over lifetime, the immune system adapts to profound changes in hematopoiesis and lymphogenesis, and progressively restructures in face of an ever-expanding exposome. Older adults fail to generate adequate immune responses against microbial infections and tumors, but accumulate aged T cells, B cells and myeloid cells. Age-associated B cells are highly efficient in autoantibody production. T-cell aging promotes the accrual of end-differentiated effector T cells with potent cytotoxic and pro-inflammatory abilities and myeloid cell aging supports a low grade, sterile and chronic inflammatory state (inflammaging). In pre-disposed individuals, immune aging can lead to frank autoimmune disease, manifesting with chronic inflammation and irreversible tissue damage. Emerging data support the concept that autoimmunity results from aging-induced failure of fundamental cellular processes in immune effector cells: genomic instability, loss of mitochondrial fitness, failing proteostasis, dwindling lysosomal degradation and inefficient autophagy. Here, we have reviewed the evidence that malfunctional mitochondria, disabled lysosomes and stressed endoplasmic reticula induce pathogenic T cells and macrophages that drive two autoimmune diseases, rheumatoid arthritis (RA) and giant cell arteritis (GCA). Recognizing immune aging as a risk factor for autoimmunity will open new avenues of immunomodulatory therapy, including the repair of malfunctioning mitochondria and lysosomes.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Humanos , Idoso , Envelhecimento , Senescência Celular/fisiologia , Linfócitos T , Inflamação
7.
Proc Natl Acad Sci U S A ; 121(17): e2304199121, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38630712

RESUMO

Although anti-citrullinated protein autoantibodies (ACPAs) are a hallmark serological feature of rheumatoid arthritis (RA), the mechanisms and cellular sources behind the generation of the RA citrullinome remain incompletely defined. Peptidylarginine deiminase IV (PAD4), one of the key enzymatic drivers of citrullination in the RA joint, is expressed by granulocytes and monocytes; however, the subcellular localization and contribution of monocyte-derived PAD4 to the generation of citrullinated autoantigens remain underexplored. In this study, we demonstrate that PAD4 displays a widespread cellular distribution in monocytes, including expression on the cell surface. Surface PAD4 was enzymatically active and capable of citrullinating extracellular fibrinogen and endogenous surface proteins in a calcium dose-dependent manner. Fibrinogen citrullinated by monocyte-surface PAD4 could be specifically recognized over native fibrinogen by a panel of eight human monoclonal ACPAs. Several unique PAD4 substrates were identified on the monocyte surface via mass spectrometry, with citrullination of the CD11b and CD18 components of the Mac-1 integrin complex being the most abundant. Citrullinated Mac-1 was found to be a target of ACPAs in 25% of RA patients, and Mac-1 ACPAs were significantly associated with HLA-DRB1 shared epitope alleles, higher C-reactive protein and IL-6 levels, and more erosive joint damage. Our findings implicate the monocyte cell surface as a unique and consequential site of extracellular and cell surface autoantigen generation in RA.


Assuntos
Ácidos Aminossalicílicos , Artrite Reumatoide , Monócitos , Humanos , Desiminases de Arginina em Proteínas , Monócitos/metabolismo , Autoantígenos , Autoanticorpos , Fibrinogênio/metabolismo , Citrulina/metabolismo
8.
Immunol Rev ; 319(1): 142-150, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37507355

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints that affects ~1% of the human population. Joint swelling and bone erosion, hallmarks of RA, contribute to disability and, sometimes, loss of life. Mechanistically, disease is driven by immune dysregulation characterized by circulating autoantibodies, inflammatory mediators, tissue degradative enzymes, and metabolic dysfunction of resident stromal and recruited immune cells. Cell death by apoptosis has been therapeutically explored in animal models of RA due to the comparisons drawn between synovial hyperplasia and paucity of apoptosis in RA with the malignant transformation of cancer cells. Several efforts to induce cell death have shown benefits in reducing the development and/or severity of the disease. Apoptotic cells are cleared by phagocytes in a process known as efferocytosis, which differs from microbial phagocytosis in its "immuno-silent," or anti-inflammatory, nature. Failures in efferocytosis have been linked to autoimmune disease, whereas administration of apoptotic cells in RA models effectively inhibits inflammatory indices, likely though efferocytosis-mediated resolution-promoting mechanisms. However, the nature of signaling pathways elicited and the molecular identity of clearance mediators in RA are understudied. Furthermore, canonical efferocytosis machinery elements also play important non-canonical functions in homeostasis and pathology. Here, we discuss the roles of efferocytosis machinery components in models of RA and discuss their potential involvement in disease pathophysiology.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Animais , Humanos , Fagocitose , Fagócitos , Apoptose
9.
Immunol Rev ; 318(1): 81-88, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37493210

RESUMO

Immune checkpoint inhibitor therapies act through blockade of inhibitory molecules involved in the regulation of T cells, thus releasing tumor specific T cells to destroy their tumor targets. However, immune checkpoint inhibitors (ICI) can also lead to a breach in self-tolerance resulting in immune-related adverse events (irAEs) that include tissue-specific autoimmunity. This review addresses the question of whether the mechanisms that drive ICI-induced irAEs are shared or distinct with those driving spontaneous autoimmunity, focusing on ICI-induced diabetes, ICI-induced arthritis, and ICI-induced thyroiditis due to the wealth of knowledge about the development of autoimmunity in type 1 diabetes, rheumatoid arthritis, and Hashimoto's thyroiditis. It reviews current knowledge about role of genetics and autoantibodies in the development of ICI-induced irAEs and presents new studies utilizing single-cell omics approaches to identify T-cell signatures associated with ICI-induced irAEs. Collectively, these studies indicate that there are similarities and differences between ICI-induced irAEs and autoimmune disease and that studying them in parallel will provide important insight into the mechanisms critical for maintaining immune tolerance.


Assuntos
Autoimunidade , Neoplasias , Humanos , Imunoterapia/métodos , Autoanticorpos , Linfócitos T
10.
Am J Hum Genet ; 110(4): 625-637, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-36924774

RESUMO

Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA.


Assuntos
Artrite Reumatoide , Sinoviócitos , Humanos , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Proliferação de Células/genética , Células Cultivadas , Cromossomos , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Proteínas Repressoras/genética , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Proteína 2 Relacionada a Actina/metabolismo
11.
Immunity ; 47(2): 235-250.e4, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28813657

RESUMO

Mechanisms by which interferon (IFN)-γ activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-γ-mediated gene repression. We used an integrated transcriptomic and epigenomic approach to analyze chromatin accessibility, histone modifications, transcription-factor binding, and gene expression in IFN-γ-primed human macrophages. IFN-γ suppressed basal expression of genes corresponding to an "M2"-like homeostatic and reparative phenotype. IFN-γ repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-γ disassembled a subset of enhancers by inducing coordinate suppression of binding by MAF, lineage-determining transcription factors, and chromatin accessibility. Genes associated with MAF-binding enhancers were suppressed in macrophages isolated from rheumatoid-arthritis patients, revealing a disease-associated signature of IFN-γ-mediated repression. These results identify enhancer inactivation and disassembly as a mechanism of IFN-γ-mediated gene repression and reveal that MAF regulates the macrophage enhancer landscape and is suppressed by IFN-γ to augment macrophage activation.


Assuntos
Artrite Reumatoide/imunologia , Montagem e Desmontagem da Cromatina , Interferon gama/metabolismo , Macrófagos/imunologia , Proteínas Proto-Oncogênicas c-maf/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Citocinas/metabolismo , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-maf/genética , Transcriptoma
12.
Immunity ; 46(2): 220-232, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28228280

RESUMO

Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1ß. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.


Assuntos
Comunicação Autócrina/imunologia , Fibroblastos/imunologia , Regulação da Expressão Gênica/imunologia , Fator Inibidor de Leucemia/imunologia , Receptores de OSM-LIF/imunologia , Artrite Reumatoide/imunologia , Células Cultivadas , Citocinas/biossíntese , Perfilação da Expressão Gênica , Humanos , Inflamação/imunologia , Interleucina-6/imunologia , Fator de Transcrição STAT4/imunologia , Membrana Sinovial/imunologia , Transcriptoma
13.
Proc Natl Acad Sci U S A ; 120(33): e2303385120, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37549284

RESUMO

Excessive cell-free DNA (cfDNA) in the serum and synovium is considered a causative factor of rheumatoid arthritis (RA). Thus, cfDNA scavenging by using cationic polymers has been an effective therapeutic avenue, while these stratagems still suffer from systemic toxicity and unstable capture of cfDNA. Here, inspired by the biological charge-trapping effects and active degradation function of enzyme-containing organelles in vivo, we proposed a cationic peptide dendrimer nanogel with deoxyribonuclease I (DNase I) conjugation for the treatment of RA. Benefitting from their naturally derived peptide components, the resultant nanogels were highly biocompatible. More attractively, by tailoring them with a larger size and higher surface charge density, these cationic nanogels could achieve the fastest targeting capability, highest accumulation amounts, longer persistence time, and superior DNA scavenging capacity in inflamed joints. Based on these features, we have demonstrated that the organelle mimicking cationic nanogels could significantly down-regulate toll-like receptor (TLR)-9 signaling pathways and attenuate RA symptoms in collagen-induced arthritis mice. These results make the bioinspired DNase I conjugated cationic nanogels an ideal candidate for treating RA and other immune dysregulation diseases.


Assuntos
Artrite Reumatoide , Ácidos Nucleicos Livres , Camundongos , Animais , Nanogéis/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Peptídeos/uso terapêutico , Desoxirribonuclease I
14.
Proc Natl Acad Sci U S A ; 120(19): e2218019120, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-37141171

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to systemic and articular bone loss by activating bone resorption and suppressing bone formation. Despite current therapeutic agents, inflammation-induced bone loss in RA continues to be a significant clinical problem due to joint deformity and lack of articular and systemic bone repair. Here, we identify the suppressor of bone formation, Schnurri-3 (SHN3), as a potential target to prevent bone loss in RA. SHN3 expression in osteoblast-lineage cells is induced by proinflammatory cytokines. Germline deletion or conditional deletion of Shn3 in osteoblasts limits articular bone erosion and systemic bone loss in mouse models of RA. Similarly, silencing of SHN3 expression in these RA models using systemic delivery of a bone-targeting recombinant adenoassociated virus protects against inflammation-induced bone loss. In osteoblasts, TNF activates SHN3 via ERK MAPK-mediated phosphorylation and, in turn, phosphorylated SHN3 inhibits WNT/ß-catenin signaling and up-regulates RANKL expression. Accordingly, knock-in of a mutation in Shn3 that fails to bind ERK MAPK promotes bone formation in mice overexpressing human TNF due to augmented WNT/ß-catenin signaling. Remarkably, Shn3-deficient osteoblasts are not only resistant to TNF-induced suppression of osteogenesis, but also down-regulate osteoclast development. Collectively, these findings demonstrate SHN3 inhibition as a promising approach to limit bone loss and promote bone repair in RA.


Assuntos
Artrite Reumatoide , Reabsorção Óssea , Camundongos , Humanos , Animais , beta Catenina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Osso e Ossos/metabolismo , Osteoblastos/metabolismo , Osteogênese/genética , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Reabsorção Óssea/metabolismo , Inflamação/metabolismo , Osteoclastos/metabolismo
15.
Proc Natl Acad Sci U S A ; 120(25): e2218668120, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37307481

RESUMO

A longstanding goal has been to find an antigen-specific preventive therapy, i.e., a vaccine, for autoimmune diseases. It has been difficult to find safe ways to steer the targeting of natural regulatory antigen. Here, we show that the administration of exogenous mouse major histocompatibility complex class II protein bounding a unique galactosylated collagen type II (COL2) peptide (Aq-galCOL2) directly interacts with the antigen-specific TCR through a positively charged tag. This leads to expanding a VISTA-positive nonconventional regulatory T cells, resulting in a potent dominant suppressive effect and protection against arthritis in mice. The therapeutic effect is dominant and tissue specific as the suppression can be transferred with regulatory T cells, which downregulate various autoimmune arthritis models including antibody-induced arthritis. Thus, the tolerogenic approach described here may be a promising dominant antigen-specific therapy for rheumatoid arthritis, and in principle, for autoimmune diseases in general.


Assuntos
Artrite Reumatoide , Doenças Autoimunes , Animais , Camundongos , Vacinas de Subunidades Antigênicas , Linfócitos T Reguladores , Anticorpos
16.
J Biol Chem ; 300(2): 105591, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38141769

RESUMO

Long noncoding RNAs (lncRNAs) are specifically expressed in different diseases and regulate disease progression. To explore the functions of rheumatoid arthritis (RA)-specific lncRNA, we determined the lncRNA expression profile of fibroblast-like synoviocytes (FLS) obtained from patients with RA and osteoarthritis (OA) using a LncRNA microarray and identified up-regulated LncNFYB in RA as a potential therapeutic target. Using gain- and loss-of-function studies, LncNFYB was proven to promote FLS proliferation and cell cycle progress but not affect their invasion, migration, and apoptotic abilities. Further investigation discovered that LncRNA could combine with annexin A2 (ANXA2) and enhance the level of phospho-ANXA2 (Tyr24) in the plasma membrane area, which induced the activation of ERK1/2 to promote proliferation. These findings provide new insights into the biological functions of LncNFYB on modification of FLS, which may be exploited for the therapy of RA.


Assuntos
Anexina A2 , Artrite Reumatoide , Sistema de Sinalização das MAP Quinases , RNA Longo não Codificante , Sinoviócitos , Humanos , Anexina A2/genética , Anexina A2/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/fisiopatologia , Proliferação de Células/genética , Células Cultivadas , Ativação Enzimática/genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/fisiopatologia , Fosforilação/genética , Ligação Proteica/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Sinoviócitos/citologia , Sinoviócitos/metabolismo
17.
Eur J Immunol ; 54(1): e2350633, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37799110

RESUMO

In COVID-19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre-existing autoimmune conditions can therefore be at increased risk of severe COVID-19 and/or associated sequelae, yet SARS-CoV-2 infection in this group has been little studied. Here, we performed single-cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS-CoV-2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell-cell communication that substantially shape the immune response under SARS-CoV-2 infection. While enrichment of HLA-DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type-I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS-CoV-2 in patients with pre-existing autoimmunity, highlighting important considerations for disease treatment and follow-up.


Assuntos
Doenças Autoimunes , COVID-19 , Humanos , SARS-CoV-2 , Leucócitos Mononucleares , Multiômica , Autoimunidade , Análise de Célula Única
18.
Eur J Immunol ; : e2350823, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38922875

RESUMO

Osteoclast-mediated bone erosion and deformation represent significant pathological features in rheumatoid arthritis (RA). Myeloid-derived suppressor cells (MDSCs) and B cells have emerged as key contributors to the progression of RA. Nevertheless, their involvement, especially the interaction in RA osteoclastogenesis remains elusive. In this study, our results revealed a marked expansion of MDSCs in RA patients, and importantly, their abundance was positively correlated with radiographic damage evaluated by the Sharp/van der Heijde score. Notably, MDSCs derived from both RA patients and arthritic mice exhibited a heightened propensity to differentiate into osteoclasts compared with those from healthy individuals. Intriguingly, we observed that B cells from RA patients could augment the osteoclastogenic potential of MDSCs, which was also observed in arthritic mice. The impact of B cells on MDSC-mediated osteoclastogenesis was found to be most pronounced in switched memory B cells, followed by CD21low B cells and naïve B cells. MDSCs from B-cell-deficient mice exhibited diminished capacity to differentiate into osteoclasts, accompanied by distinct gene expression profiles associated with osteoclastogenesis. Taken together, our findings suggested that MDSCs were important osteoclast precursors primed by B cells in RA, serving as novel therapeutic targets for the persistent disease.

19.
Eur J Immunol ; 54(4): e2350659, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38314895

RESUMO

Like rheumatoid arthritis (RA) in humans, collagen-induced arthritis (CIA) in mice is associated with not only MHC class II genetic polymorphism but also, to some extent, with other loci including genes encoding Fc gamma receptors (FCGRs) and complement C5. In this study, we used a cartilage antibody-induced arthritis (CAIA) model in which arthritis develops within a 12-h timeframe, to determine the relative importance of FCGRs and C5 (Hc). In CAIA, inhibiting or deleting FCGR3 substantially hindered arthritis development, underscoring the crucial role of this receptor. Blocking FCGR3 also reduced the levels of FCGR4, and vice versa. When employing an IgG1 arthritogenic cocktail that exclusively interacts with FCGR2B and FCGR3, joint inflammation was promptly initiated in Fcgr2b-- mice but not in Fcgr3-- mice, suggesting that FCGR3 is sufficient for CAIA development. Regarding complement activation, Fcgr2b++.Hc** mice with C5 mutated were fully resistant to CAIA, whereas Fcgr2b--.Hc** mice developed arthritis rapidly. We conclude that FCGR3 is essential and sufficient for CAIA development, particularly when induced by IgG1 antibodies. The human ortholog of mouse FCGR3, FCGR2A, may be associated with RA pathogenesis. FCGR2B deficiency allows for rapid arthritis progression and overrides the resistance conferred by C5 deficiency.


Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Camundongos , Cartilagem/patologia , Complemento C5/genética , Imunoglobulina G , Receptores de IgG/genética
20.
FASEB J ; 38(10): e23636, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38752683

RESUMO

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common forms of arthritis with undefined etiology and pathogenesis. Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ), which act as sensors for cellular mechanical and inflammatory cues, have been identified as crucial players in the regulation of joint homeostasis. Current studies also reveal a significant association between YAP/TAZ and the pathogenesis of OA and RA. The objective of this review is to elucidate the impact of YAP/TAZ on different joint tissues and to provide inspiration for further studying the potential therapeutic implications of YAP/TAZ on arthritis. Databases, such as PubMed, Cochran Library, and Embase, were searched for all available studies during the past two decades, with keywords "YAP," "TAZ," "OA," and "RA."


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Artrite Reumatoide , Osteoartrite , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Fatores de Transcrição/metabolismo , Animais , Artrite Reumatoide/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Sinalização YAP/metabolismo , Osteoartrite/metabolismo , Osteoartrite/etiologia , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Articulações/metabolismo , Articulações/patologia , Transativadores/metabolismo , Transativadores/genética
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