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1.
Annu Rev Immunol ; 41: 533-560, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-36854182

RESUMO

Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy.


Assuntos
Interferons , Lúpus Eritematoso Sistêmico , Humanos , Animais , Interferons/uso terapêutico , Linfócitos B , Linfócitos T Auxiliares-Indutores , Autoanticorpos
2.
Cell ; 184(17): 4464-4479.e19, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34384544

RESUMO

Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.


Assuntos
Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Mitocôndrias/metabolismo , Células Mieloides/metabolismo , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Criança , Pré-Escolar , Eritroblastos/metabolismo , Eritroblastos/ultraestrutura , Eritrócitos/metabolismo , Eritropoese , Humanos , Mitofagia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo
3.
Immunity ; 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39378884

RESUMO

Opsonization of red blood cells that retain mitochondria (Mito+ RBCs), a feature of systemic lupus erythematosus (SLE), triggers type I interferon (IFN) production in macrophages. We report that monocytes (Mos) co-produce IFN and mature interleukin-1ß (mIL-1ß) upon Mito+ RBC opsonization. IFN expression depended on cyclic GMP-AMP synthase (cGAS) and RIG-I-like receptors' (RLRs) sensing of Mito+ RBC-derived mitochondrial DNA (mtDNA) and mtRNA, respectively. Interleukin-1ß (IL-1ß) production was initiated by the RLR antiviral signaling adaptor (MAVS) pathway recognition of Mito+ RBC-derived mtRNA. This led to the cytosolic release of Mo mtDNA, which activated the inflammasome. Importantly, mIL-1ß secretion was independent of gasdermin D (GSDMD) and pyroptosis but relied on IFN-inducible myxovirus-resistant protein 1 (MxA), which facilitated the incorporation of mIL-1ß into a trans-Golgi network (TGN)-mediated secretory pathway. RBC internalization identified a subset of blood Mo expressing IFN-stimulated genes (ISGs) that released mIL-1ß and expanded in SLE patients with active disease.

4.
bioRxiv ; 2023 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-37577613

RESUMO

Systemic Lupus Erythematosus (SLE) is characterized by autoreactive B cell activation, upregulation of Type I Interferon (IFN) and widespread inflammation. Mitochondrial nucleic acids (NAs) are increasingly recognized as triggers of IFN 1 . Thus, defective removal of mitochondria from mature red blood cells (Mito + RBCs), a feature of SLE, contributes to IFN production by myeloid cells 2 . Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1ß (IL-1ß) in SLE patients with active disease. We show that ISG expression requires the interaction between Mito + RBC-derived mitochondrial DNA (mtDNA) and cGAS, while IL-1ß production entails Mito + RBC-derived mitochondrial RNA (mtRNA) triggering of RIG-I-like receptors (RLRs). This leads to the cytosolic release of Mo-derived mtDNA that activates the NLRP3 inflammasome. Importantly, IL-1ß release depends on the IFN-inducible myxovirus resistant protein 1 (MxA), which enables the translocation of this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. Our study highlights a novel and synergistic pathway involving IFN and the NLRP3 inflammasome in SLE.

5.
Arthritis Rheumatol ; 75(7): 1246-1261, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36648920

RESUMO

OBJECTIVE: This study was undertaken to identify blood markers of juvenile dermatomyositis (DM) disease activity (DA), which are needed to improve disease management. METHODS: The study comprised a total of 123 juvenile DM patients and 53 healthy controls. Results of laboratory tests (aldolase, creatinine kinase, lactate dehydrogenase [LDH], aspartate aminotransferase) and clinical measures of DA in patients with juvenile DM, including the Manual Muscle Testing in 8 muscles (MMT-8), Childhood Myositis Assessment Scale (CMAS), and disease activity scores (DAS) (total DAS for juvenile DM, the muscle DAS, and the skin DAS), were recorded when available. Surface phenotype of peripheral blood mononuclear cells was assessed using flow cytometry. Whole blood transcriptional profiles were studied using either RNA-sequencing or microarrays. Differential gene expression was determined using DESeq and compared by pathway and gene ontology analyses. RESULTS: Conventional memory (CD27+IgD-) B cells expressing low CXCR5 levels (CXCR5low/- CM B cells) were significantly increased in frequency and absolute numbers in 2 independent cohorts of juvenile DM patients compared with healthy controls. The frequency of CD4+ Th2 memory cells (CD45RA-CXCR5-CCR6-CXCR3-) was also increased in juvenile DM, especially in patients who were within <1 year from diagnosis. The frequency of CXCR5low/- CM B cells correlated with serum aldolase levels and with a blood interferon-stimulated gene transcriptional signature. Furthermore, both the frequency and absolute numbers of CXCR5low/- CM B cells correlated with clinical and laboratory measures of muscle DA (MMT-8, CMAS, aldolase, and LDH). CONCLUSION: These findings suggest that both CM B cells lacking the CXCR5 follicular marker and CXCR5- Th2 cells represent potential biomarkers of DA in juvenile DM and may contribute to its pathogenesis.


Assuntos
Dermatomiosite , Humanos , Dermatomiosite/metabolismo , Leucócitos Mononucleares , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Aldeído Liases/metabolismo
6.
J Immunol ; 185(12): 7317-29, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21078913

RESUMO

Invariant NKT (iNKT) cells play an effector/adjuvant function during antimicrobial and antitumoral immunity and a regulatory role to induce immune tolerance and prevent autoimmunity. iNKT cells that differentially modulate adaptive immunity do not bear a unique phenotype and/or specific cytokine secretion profile, thus opening questions on how a single T cell subset can exert opposite immunological tasks. In this study, we show that iNKT cells perform their dual roles through a single mechanism of action relying on the cognate interaction with myeloid dendritic cells (DCs) and leading to opposite effects depending on the presence of other maturation stimuli simultaneously acting on DCs. The contact of murine purified iNKT cells with immature autologous DCs directly triggers the tolerogenic maturation of DCs, rendering them able to induce regulatory T cell differentiation and prevent autoimmune diabetes in vivo. Conversely, the interaction of the same purified iNKT cells with DCs, in the presence of simultaneous TLR4 stimulation, significantly enhances proinflammatory DC maturation and IL-12 secretion. The different iNKT cell effects are mediated through distinct mechanisms and activation of different molecular pathways within the DC: CD1d signaling and activation of the ERK1/2 pathway for the tolerogenic action, and CD40-CD40L interaction and NF-κB activation for the adjuvant effect. Our data suggest that the DC decision to undergo proinflammatory or tolerogenic maturation results from the integration of different signals received at the time of iNKT cell contact and could have important therapeutic implications for exploiting iNKT cell adjuvant/regulatory properties in autoimmune diseases, infections, and cancer.


Assuntos
Antígenos CD1d/imunologia , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Tolerância Imunológica , Células T Matadoras Naturais/imunologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Antígenos CD1d/genética , Antígenos CD40/genética , Antígenos CD40/imunologia , Ligante de CD40/genética , Ligante de CD40/imunologia , Comunicação Celular/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Interleucina-12/genética , Interleucina-12/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Células Mieloides/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Transdução de Sinais/genética , Receptor 4 Toll-Like/genética
7.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34180950

RESUMO

Intercellular communication among immune cells is vital for the coordination of proper immune responses. Extracellular vesicles and particles (EVPs) act as messengers in intercellular communication, with important consequences for target cell and organ physiology in both health and disease. Under normal physiological conditions, immune cell-derived EVPs participate in immune responses by regulating innate and adaptive immune responses. EVPs play a major role in antigen presentation and immune activation. On the other hand, immune cell-derived EVPs exert immunosuppressive and regulatory effects. Consequently, EVPs may contribute to pathological conditions, such as autoimmune and inflammatory diseases, graft rejection, and cancer progression and metastasis. Here, we provide an overview of the role of EVPs in immune homeostasis and pathophysiology, with a particular focus on their contribution to innate and adaptive immunity and their potential use for immunotherapies.


Assuntos
Imunidade Adaptativa , Comunicação Celular/imunologia , Micropartículas Derivadas de Células/imunologia , Vesículas Extracelulares/imunologia , Imunidade Inata , Animais , Humanos , Imunoterapia
8.
J Immunol ; 181(2): 869-77, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18606638

RESUMO

The regulatory function of invariant NKT (iNKT) cells for tolerance induction and prevention of autoimmunity is linked to a specific cytokine profile that comprises the secretion of type 2 cytokines like IL-4 and IL-10 (NKT2 cytokine profile). The mechanism responsible for iNKT cell differentiation toward a type 2 phenotype is unknown. Herein we show that costimulatory signals provided by the surface receptor signaling lymphocytic activation molecule (SLAM) on myeloid dendritic cells (mDC) to iNKT cells is crucial for NKT2 orientation. Additionally, we demonstrate that the impaired acquisition of an NKT2 cytokine phenotype in nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes is due to defective SLAM-induced signals generated by NOD mDC. Mature mDC of C57BL/6 mice express SLAM and induce C57BL/6 or NOD iNKT cells to acquire a predominant NKT2 cytokine phenotype in response to antigenic stimulation with the iNKT cell-specific Ag, the alpha-galactosylceramide. In contrast, mature NOD mDC express significantly lower levels of SLAM and are unable to promote GATA-3 (the SLAM-induced intracellular signal) up-regulation and IL-4/IL-10 production in iNKT cells from NOD or C57BL/6 mice. NOD mice carry a genetic defect of the Slamf1 gene that is associated with reduced SLAM expression on double-positive thymocytes and altered iNKT cell development in the thymus. Our data suggest that the genetic Slamf1 defect in NOD mice also affects SLAM expression on other immune cells such as the mDC, thus critically impairing the peripheral differentiation of iNKT cells toward a regulatory NKT2 type.


Assuntos
Antígenos CD/metabolismo , Células Dendríticas/imunologia , Fator de Transcrição GATA3/metabolismo , Células Matadoras Naturais/imunologia , Receptores de Superfície Celular/metabolismo , Subpopulações de Linfócitos T/imunologia , Animais , Antígenos CD/imunologia , Diferenciação Celular , Células Dendríticas/metabolismo , Fator de Transcrição GATA3/imunologia , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Receptores de Superfície Celular/imunologia , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Subpopulações de Linfócitos T/metabolismo
9.
Nat Med ; 25(1): 75-81, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30478422

RESUMO

Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5-CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Interleucina-10/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Ácido Succínico/metabolismo , Proliferação de Células , DNA Mitocondrial/genética , Células Dendríticas/metabolismo , Humanos , Memória Imunológica , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/imunologia , Oxirredução
10.
J Exp Med ; 213(5): 697-713, 2016 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-27091841

RESUMO

Autoantibodies against nucleic acids and excessive type I interferon (IFN) are hallmarks of human systemic lupus erythematosus (SLE). We previously reported that SLE neutrophils exposed to TLR7 agonist autoantibodies release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized (Ox) residues. When mtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor A mitochondria (TFAM), a dual high-mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFN-primed neutrophils, to antiribonucleotide protein autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, Ox nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of Ox nucleoids is a feature of SLE blood neutrophils, and autoantibodies against Ox mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE.


Assuntos
DNA Mitocondrial/imunologia , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Mitocôndrias/imunologia , Neutrófilos/imunologia , Adolescente , Autoanticorpos/imunologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino , Mitocôndrias/patologia , Proteínas Mitocondriais/imunologia , Neutrófilos/patologia , Oxirredução , Receptor 7 Toll-Like/imunologia , Fatores de Transcrição/imunologia
11.
FEBS Lett ; 579(22): 5095-9, 2005 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-16139273

RESUMO

Erythrocyte glyceraldehyde-3-phosphate dehydrogenase (G3PD) is a glycolytic enzyme containing critical thiol groups and whose activity is reversibly inhibited by binding to the cell membrane. Here, we demonstrate that the insertion of ferriprotoporphyrin IX (FP) into the red cell membranes exerts two opposite effects on membrane bound G3PD. First, the enzyme is partially inactivated through oxidation of critical thiols. Dithiothreitol restores part of the activity, but some critical thiols are irreversibly oxidized or crosslinked to products of FP-induced lipid peroxidation. Second, G3PD binding to the membrane is modified and the enzyme is activated through displacement into the cytosol and/or release from its binding site.


Assuntos
Eritrócitos/enzimologia , Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/metabolismo , Hemina/metabolismo , Membrana Celular/metabolismo , Membrana Eritrocítica/enzimologia , Eritrócitos/citologia , Humanos , Oxirredução , Ligação Proteica , Compostos de Sulfidrila/química
12.
Curr Opin Immunol ; 24(6): 671-7, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23127555

RESUMO

Neutrophils have long been known to participate in acute inflammation, but a role in chronic inflammatory and autoimmune diseases is now emerging. These cells are key players in the recognition and elimination of pathogens, but they also sense self components, including nucleic acids and products of sterile tissue damage. While this normally contributes to tissue repair, it can also lead to the release of highly immunogenic products that can trigger and/or amplify autoimmune pathogenic loops. Understanding the mechanisms that underlie neutrophil activation, migration, survival and their various forms of death in health and disease might provide us with new approaches to treat chronic inflammatory conditions.


Assuntos
Doenças Autoimunes/imunologia , Inflamação/imunologia , Neutrófilos/fisiologia , Doença Crônica , Humanos , Doenças do Sistema Imunitário , Transtornos Leucocíticos , Ativação de Neutrófilo/fisiologia
13.
Autoimmunity ; 44(1): 11-22, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20672910

RESUMO

Invariant natural killer T (iNKT) cells represent an important regulatory T-cell subset that perceives signals of danger and/or cellular distress and modulate the adaptive immune response accordingly. In the presence of pathogens, iNKT cells acquire an adjuvant function that is fundamental to boost anti-microbial and anti-tumor immunity. At the same time, iNKT cells can play a negative regulatory function to maintain peripheral T-cell tolerance toward self-antigens and to prevent autoimmune disease. Both these effects of iNKT cells involve the modulation of the activity of dendritic cells (DCs) through cell-cell interaction. Indeed, iNKT cells can either boost Th1 immunity by enhancing maturation of pro-inflammatory DCs or promote immune tolerance through the maturation of tolerogenic DCs. This dual action of iNKT cells opens questions on the modalities by which a single-cell subset can exert opposite effects on DCs and may even put in question the overall immunosuppressive properties of iNKT cells. This review presents the large body of evidence that shows the ability of iNKT cells to negatively regulate autoimmunity and to prevent autoimmune diseases including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. In addition, an update is provided on the mechanisms of iNKT-DCs interactions and how this can result in inflammatory or tolerogenic responses.


Assuntos
Doenças Autoimunes/imunologia , Células Dendríticas/imunologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Tolerância a Antígenos Próprios , Imunidade Adaptativa , Doenças Autoimunes/prevenção & controle , Humanos , Células Th1/imunologia , Tolerância ao Transplante
14.
Sci Transl Med ; 3(73): 73ra20, 2011 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-21389264

RESUMO

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)-induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α and associated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis. Although neutrophils have long been shown to be associated with lupus, their potential role in disease pathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1, neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs (pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-like receptor 9)-dependent manner. Our results reveal an unsuspected role for neutrophils in SLE pathogenesis and identify a novel link between nucleic acid-recognizing antibodies and type I IFN production in this disease.


Assuntos
Interferon Tipo I/biossíntese , Lúpus Eritematoso Sistêmico/imunologia , Neutrófilos/imunologia , Adolescente , Anticorpos Antinucleares/sangue , Apoptose/imunologia , Autoanticorpos/sangue , Estudos de Casos e Controles , Criança , Células Dendríticas/imunologia , Perfilação da Expressão Gênica , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , NADP/sangue , Neutrófilos/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de IgG/sangue , Ribonucleoproteínas/imunologia , Receptor 7 Toll-Like/sangue
15.
Immunology ; 122(3): 409-17, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17617156

RESUMO

Type 1 interferon-beta (T1IFN-beta) is an innate cytokine and the first-choice therapy for multiple sclerosis (MS). It is still unclear how T1IFN-beta, whose main function is to promote innate immunity during infections, plays a beneficial role in autoimmune disease. Here we show that T1IFN-beta promoted the expansion and function of invariant natural killer (iNKT) cells, an innate T-cell subset with strong immune regulatory properties that is able to prevent autoimmune disease in pre-clinical models of MS and type 1 diabetes. Specifically, we observed that T1IFN-beta treatment significantly increased the percentages of Valpha24(+) NKT cells in peripheral blood mononuclear cells of MS patients. Furthermore, iNKT cells of T1IFN-beta-treated individuals showed a dramatically improved secretion of cytokines (interleukins 4 and 5 and interferon-gamma) in response to antigenic stimulation compared to iNKT cells isolated from the same patients before T1IFN-beta treatment. The effect of T1IFN-beta on iNKT cells was mediated through the modulation of myeloid dendritic cells (DCs). In fact, DCs modulated in vivo or in vitro by T1IFN-beta were more efficient antigen-presenting cells for iNKT cells. Such a modulatory effect of T1IFN-beta was associated with up-regulation on DCs of key costimulatory molecules for iNKT (i.e. CD80, CD40 and CD1d). Our data identified the iNKT cell/DC pathway as a new target for the immune regulatory effect of T1IFNs in autoimmune diseases and provide a possible mechanism to explain the clinical efficacy of T1IFN-beta in MS.


Assuntos
Células Dendríticas/imunologia , Interferon beta/uso terapêutico , Células Matadoras Naturais/imunologia , Esclerose Múltipla/tratamento farmacológico , Adulto , Apresentação de Antígeno/imunologia , Antígenos de Diferenciação de Linfócitos B/análise , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe II/análise , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Subpopulações de Linfócitos T/imunologia
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