RESUMO
The consumption of processed foods and sugary sodas in Western diets correlates with an increased incidence of obesity, metabolic syndromes such as type 2 diabetes, cardiovascular diseases, and autoimmune diseases including inflammatory bowel disease and rheumatoid arthritis. All these diseases have an inflammatory component, of which T lymphocytes can play a critical role in driving. Much has been learned regarding the importance of sugar, particularly glucose, in fueling effector versus regulatory T cells that can promote or dampen inflammation, respectively. In particular, glucose and its metabolic breakdown products via glycolysis are essential for effector T cell differentiation and function, while fatty acid-fueled oxidative phosphorylation supports homeostasis and function of regulatory T cells. Nevertheless, a critical knowledge gap, given the prevalence of diabetes in Western societies, is the impact of elevated glucose concentrations on the balance between effector versus regulatory T cells. To begin addressing this, we cultured naïve CD4+ T cells with different concentrations of glucose, and examined their differentiation into effector versus regulatory lineages. Surprisingly, high glucose promoted regulatory T cell differentiation and inhibited Th1 effector differentiation. This skewing towards the regulatory lineage occurred via an indirect mechanism that depends on lactate produced by activated glycolytic T cells. Addition of lactate to the T cell differentiation process promotes the differentiation of Treg cells, and activates Akt/mTOR signaling cascade. Hence, our findings suggest the existence of a novel feedback mechanism in which lactate produced by activated, differentiating T cells skews their lineage commitment towards the regulatory fate.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Linfócitos T Reguladores , Diferenciação Celular , Glucose/metabolismo , Lactatos/metabolismoRESUMO
The past decade has seen the advent and widespread use of several immunotherapeutic modalities that have markedly improved treatment outcomes for patients with various cancers. Nevertheless, the study of cancer immunology traces its roots back to the inception of modern immunology, and played a critical role in the of discovery of central immunological concepts and development of key technologies and methodologies and that have propelled advances in all areas of immunology.
Assuntos
Neoplasias , Humanos , Neoplasias/terapia , Imunoterapia/métodosRESUMO
Deficiency of lymphocyte activation gene-3 (LAG3) is significantly associated with increased cardiovascular disease risk with in vitro results demonstrating increased TNF-α and decreased IL-10 secretion from LAG3-deficient human B lymphoblasts. The hypothesis tested in this study was that Lag3 deficiency in dendritic cells (DCs) would significantly affect cytokine expression, alter cellular metabolism, and prime naive T cells to greater effector differentiation. Experimental approaches used included differentiation of murine bone marrow-derived DCs (BMDCs) to measure secreted cytokines, cellular metabolism, RNA sequencing, whole cell proteomics, adoptive OT-II CD4+Lag3 +/+ donor cells into wild-type (WT) C57BL/6 and Lag3 -/- recipient mice, and ex vivo measurements of IFN-γ from cultured splenocytes. Results showed that Lag3 -/- BMDCs secreted more TNF-α, were more glycolytic, used fewer fatty acids for mitochondrial respiration, and glycolysis was significantly reduced by exogenous IL-10 treatment. Under basal conditions, RNA sequencing revealed increased expression of CD40 and CD86 and other cytokine-signaling targets as compared with WT. Whole cell proteomics identified a significant number of proteins up- and downregulated in Lag3 -/- BMDCs, with significant differences noted in exogenous IL-10 responsiveness compared with WT cells. Ex vivo, IFN-γ expression was significantly higher in Lag3 -/- mice as compared with WT. With in vivo adoptive T cell and in vitro BMDC:T coculture experiments, Lag3 -/- BMDCs showed greater T cell effector differentiation and proliferation, respectively, compared with WT BMDCs. In conclusion, Lag3 deficiency in DCs is associated with an inflammatory phenotype that provides a plausible mechanism for increased cardiovascular disease risk in humans with LAG3 deficiency.
Assuntos
Antígenos CD/metabolismo , Doenças Cardiovasculares/genética , Células Dendríticas/imunologia , Inflamação/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD/genética , Doenças Cardiovasculares/epidemiologia , Células Cultivadas , Reprogramação Celular , Humanos , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Risco , Proteína do Gene 3 de Ativação de LinfócitosAssuntos
COVID-19/imunologia , Doenças Transmissíveis/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , SARS-CoV-2/fisiologia , Antivirais/uso terapêutico , Produtos Biológicos/uso terapêutico , COVID-19/terapia , Interações Medicamentosas , Infecções por HIV/terapia , Humanos , Fator de Impacto de RevistasRESUMO
Metastatic tumors that have become resistant to androgen deprivation therapy represent the major challenge in treating prostate cancer. Although these recurrent tumors typically remain dependent on the androgen receptor (AR), non-AR-driven tumors that also emerge are particularly deadly and becoming more prevalent. Here, we present a new genetically engineered mouse model for non-AR-driven prostate cancer that centers on a negative regulator of G protein-coupled receptors that is downregulated in aggressive human prostate tumors. Thus, prostate-specific expression of a dominant-negative G protein-coupled receptor kinase 2 (GRK2-DN) transgene diminishes AR and AR target gene expression in the prostate, and confers resistance to castration-induced involution. Further, the GRK2-DN transgene dramatically accelerates oncogene-initiated prostate tumorigenesis by increasing primary tumor size, potentiating visceral organ metastasis, suppressing AR, and inducing neuroendocrine marker mRNAs. In summary, GRK2 enforces AR-dependence in the prostate, and the loss of GRK2 function in prostate tumors accelerates disease progression toward the deadliest stage.
Assuntos
Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Masculino , Camundongos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
BACKGROUND: The IL-17 family cytokines are potent drivers of colorectal cancer (CRC) development. We and others have shown that IL-17 mainly signals to tumor cells to promote CRC, but the underlying mechanism remains unclear. IL-17 also dampens Th1-armed anti-tumor immunity, in part by attracting myeloid cells to tumor. Whether IL-17 controls the activity of adaptive immune cells in a more direct manner, however, is unknown. METHODS: Using mouse models of sporadic or inducible colorectal cancers, we ablated IL-17RA in the whole body or specifically in colorectal tumor cells. We also performed adoptive bone marrow reconstitution to knockout CXCR3 in hematopoietic cells. Histological and immunological experimental methods were used to reveal the link among IL-17, chemokine production, and CRC development. RESULTS: Loss of IL-17 signaling in mouse CRC resulted in marked increase in the recruitment of CD8+ cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs), starting from early stage CRC lesions. This is accompanied by the increased expression of anti-inflammatory cytokines IL-10 and TGF-ß. IL-17 signaling also inhibits the production of T cell attracting chemokines CXCL9 and CXCL10 by tumor cells. Conversely, the inability of hematopoietic cells to respond to CXCL9/10 resulted in decreased tumor infiltration by CTLs and Tregs, decreased levels of IL-10 and TGF-ß, and increased numbers of tumor lesions. Blockade of IL-17 signaling resulted in increased expression of immune checkpoint markers. On the other hand, treatment of mouse CRC with anti-CTLA-4 antibody led to increased expression of pro-tumor IL-17. CONCLUSION: IL-17 signals to colorectal tumor cells and inhibits their production of CXCL9/10 chemokines. By doing so, IL-17 inhibits the infiltration of CD8+ CTLs and Tregs to CRC, thus promoting CRC development. Cancer immunotherapy may be benefited by the use of anti-IL-17 agents as adjuvant therapies, which serve to block both IL-17-mediated tumor promotion and T cell exclusion.
Assuntos
Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Interleucina-17/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Quimiocina CXCL10/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Citocinas/biossíntese , Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Estadiamento de Neoplasias , Transdução de Sinais/efeitos dos fármacosRESUMO
Combined agonist stimulation of the TNFR costimulatory receptors 4-1BB (CD137) and OX40(CD134) has been shown to generate supereffector CD8 T cells that clonally expand to greater levels, survive longer, and produce a greater quantity of cytokines compared to T cells stimulated with an agonist of either costimulatory receptor individually. In order to understand the mechanisms for this effect, we have created a mathematical model for the activation of the CD8 T cell intracellular signaling network by mono- or dual-costimulation. We show that supereffector status is generated via downstream interacting pathways that are activated upon engagement of both receptors, and in silico simulations of the model are supported by published experimental results. The model can thus be used to identify critical molecular targets of T cell dual-costimulation in the context of cancer immunotherapy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária , Modelos Teóricos , Receptores OX40/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Humanos , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores OX40/agonistas , Transdução de Sinais , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistasRESUMO
Chronic exposure to tumor-associated antigens inactivates cognate T cells, restricting the repertoire of tumor-specific effector T cells. This problem was studied here by transferring TCR transgenic CD4 T cells into recipient mice that constitutively express a cognate self-antigen linked to MHC II on CD11c-bearing cells. Immunotherapeutic agonists to CD134 plus CD137, "dual costimulation," induces specific CD4 T cell expansion and expression of the receptor for the Th2-associated IL-1 family cytokine IL-33. Rather than producing IL-4, however, they express the tumoricidal Th1 cytokine IFNγ when stimulated with IL-33 or IL-36 (a related IL-1 family member) plus IL-12 or IL-2. IL-36, which is induced within B16-F10 melanomas by dual costimulation, reduces tumor growth when injected intratumorally as a monotherapy and boosts the efficacy of tumor-nonspecific dual costimulated CD4 T cells. Dual costimulation thus enables chronic antigen-exposed CD4 T cells, regardless of tumor specificity, to elaborate tumoricidal function in response to tumor-associated cytokines.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunidade Inata , Imunoterapia Adotiva/métodos , Melanoma/terapia , Animais , Células Dendríticas/imunologia , Feminino , Interferon gama/genética , Interferon gama/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Combination immunotherapies utilizing complementary modalities that target distinct tumor attributes or immunosuppressive mechanisms, or engage different arms of the antitumor immune response, can elicit greater therapeutic efficacy than the component monotherapies. Increasing the number of agents included in a therapeutic cocktail can further increase efficacy, however, this approach poses numerous challenges for clinical translation. Here, a novel platform to simplify combination immunotherapy by covalently linking immunotherapeutic agonists to the costimulatory receptors CD134 and CD137 into a single heterodimeric drug, "OrthomAb", is shown. This reagent not only retains costimulatory T cell activity, but also elicits unique T cell functions that are not programmed by either individual agonist, and preferentially expands effector T cells over Tregs. Finally, in an aggressive melanoma model OrthomAb elicits better therapeutic efficacy compared to the unlinked agonists. This demonstration that two drugs can be combined into one provides a framework for distilling complex combination drug cocktails into simpler delivery platforms.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia , Melanoma Experimental/tratamento farmacológico , Receptores OX40/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Diferenciação Celular , Feminino , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores OX40/antagonistas & inibidores , Células Tumorais Cultivadas , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/antagonistas & inibidoresRESUMO
Agonists to the TNF/TNFR costimulatory receptors CD134 (OX40) and CD137 (4-1BB) elicit antitumor immunity. Dual costimulation with anti-CD134 plus anti-CD137 is particularly potent because it programs cytotoxic potential in CD8+ and CD4+ T cells. Cytotoxicity in dual-costimulated CD4 T cells depends on the T-box transcription factor eomesodermin (Eomes), which we report is induced via a mechanism that does not rely on IL-2, in contrast to CD8+ CTL, but rather depends on the CD8 T cell lineage commitment transcription factor Runx3, which supports Eomes expression in mature CD8+ CTLs. Further, Eomes and Runx3 were indispensable for dual-costimulated CD4 T cells to mediate antitumor activity in an aggressive melanoma model. Runx3 is also known to be expressed in standard CD4 Th1 cells where it fosters IFN-γ expression; however, the CD4 T cell lineage commitment factor ThPOK represses transcription of Eomes and other CD8 lineage genes, such as Cd8a Hence, CD4 T cells can differentiate into Eomes+ cytotoxic CD4+CD8+ double-positive T cells by terminating ThPOK expression. In contrast, dual-costimulated CD4 T cells express Eomes, despite the continued expression of ThPOK and the absence of CD8α, indicating that Eomes is selectively released from ThPOK repression. Finally, although Eomes was induced by CD137 agonist, but not CD134 agonist, administered individually, CD137 agonist failed to induce CD134-/- CD4 T cells to express Eomes or Runx3, indicating that both costimulatory pathways are required for cytotoxic Th1 programming, even when only CD137 is intentionally engaged with a therapeutic agonist.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Melanoma Experimental/imunologia , Proteínas com Domínio T/biossíntese , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistas , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Diferenciação Celular/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/imunologia , Imunoterapia , Ativação Linfocitária/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Transgênicos , Receptores OX40/agonistas , Receptores OX40/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismoRESUMO
Chronic overnutrition and obesity induces low-grade inflammation throughout the body. Termed "meta-inflammation," this chronic state of inflammation is mediated by macrophages located within the colon, liver, muscle, and adipose tissue. A sentinel orchestrator of immune activity and homeostasis, macrophages adopt variable states of activation as a function of time and environmental cues. Meta-inflammation phenotypically skews these polarization states and has been linked to numerous metabolic disorders. The past decade has revealed several key regulators of macrophage polarization, including the signal transducer and activator of transcription family, the peroxisome proliferator-activated receptor gamma, the CCAAT-enhancer-binding proteins (C/EBP) family, and the interferon regulatory factors. Recent studies have also suggested that microRNAs and long noncoding RNA influence macrophage polarization. The pathogenic alteration of macrophage polarization in meta-inflammation is regulated by both extracellular and intracellular cues, resulting in distinct secretome profiles. Meta-inflammation-altered macrophage polarization has been linked to insulin insensitivity, atherosclerosis, inflammatory bowel disease, cancer, and autoimmunity. Thus, further mechanistic exploration into the skewing of macrophage polarization promises to have profound impacts on improving global health.
Assuntos
Inflamação/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Obesidade/complicações , Tecido Adiposo/citologia , Tecido Adiposo/patologia , Animais , Colo/patologia , Humanos , Inflamação/etiologia , Fígado/patologia , MicroRNAs , RNA Longo não Codificante , Transdução de SinaisRESUMO
The goal of cancer immunotherapy is to boost a patient's immune response to a tumour. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumour microenvironment, immune-modulating effects of conventional treatments and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modelling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumour classification, optimal treatment scheduling and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modellers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumour-immune biology. We conclude the review with recommendations for modellers both with respect to methodology and biological direction that might help keep modellers at the forefront of cancer immunotherapy development.
Assuntos
Simulação por Computador , Imunoterapia/métodos , Modelos Biológicos , Neoplasias/terapia , Humanos , Neoplasias/genéticaRESUMO
Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
Assuntos
2',5'-Oligoadenilato Sintetase/genética , Interferon Tipo I/genética , Locos de Características Quantitativas/genética , Síndrome de Sjogren/genética , 2',5'-Oligoadenilato Sintetase/biossíntese , Alelos , Processamento Alternativo/genética , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interferon Tipo I/metabolismo , Masculino , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Viroses/genética , Viroses/virologiaRESUMO
Recent advances in cancer biology and genetics have fostered precision therapies targeting tumor-specific attributes. Immune-based therapies that elicit cytolytic T cells (CTL) specific for tumor antigens can provide therapeutic benefit to cancer patients, however, cure rates are typically low. This largely results from immunosuppressive mechanisms operating within the tumor microenvironment, many of which inflict metabolic stresses upon CTL. Conversely, immunotherapies can mitigate specific metabolic stressors. For instance, dual costimulation immunotherapy with CD134 (OX40) plus CD137 (4-1BB) agonists appears to mediate tumor control in part by engaging cytokine networks that enable infiltrating CTL to compete for limiting supplies of glucose. Future efforts combining modalities that endow CTL with complimentary metabolic advantages should improve therapeutic efficacies.
Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Animais , Movimento Celular , Terapia Combinada , Citocinas/metabolismo , Citotoxicidade Imunológica , Glucose/metabolismo , Humanos , Neoplasias/imunologia , Receptores OX40/agonistas , Linfócitos T Citotóxicos/transplante , Evasão Tumoral , Microambiente Tumoral , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistasRESUMO
INTRODUCTION: Monoclonal antibodies (mAbs) targeting checkpoint inhibitors have demonstrated clinical benefit in treating patients with cancer and have paved the way for additional immune-modulating mAbs such as those targeting costimulatory receptors. The full clinical utility of these agents, however, is hampered by immune-related adverse events (irAEs) that can occur during therapy. AREAS COVERED: We first provide a general overview of tumor immunity, followed by a review of the two major classes of immunomodulatory mAbs being developed as cancer therapeutics: checkpoint inhibitors and costimulatory receptor agonists. We then discuss therapy-associated adverse events. Finally, we describe in detail the mechanisms driving their therapeutic activity, with an emphasis on interactions between antibody fragment crystallizable (Fc) domains and Fc receptors (FcR). EXPERT OPINION: Given that Fc-FcR interactions appear critical in facilitating the ability of immunomodulatory mAbs to elicit both therapeutically useful as well as adverse effects, the engineering of mAbs that can effectively engage their targets while limiting interaction with FcRs might represent a promising future avenue for developing the next generation of immune-enhancing tumoricidal agents with increased safety and retention of efficacy.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Imunomodulação , Neoplasias/terapia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Neoplasias/imunologiaRESUMO
OBJECTIVES: Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. METHODS: Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. RESULTS: The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10(-4), OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10(-7), OR 0.71; case-only pmeta=1.9×10(-4), OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. CONCLUSIONS: These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.
Assuntos
Anticorpos Antinucleares/sangue , Lúpus Eritematoso Sistêmico/genética , Receptores de Complemento 3d/genética , Adolescente , Adulto , Subpopulações de Linfócitos B/imunologia , Estudos de Casos e Controles , DNA/imunologia , Predisposição Genética para Doença , Variação Genética , Genótipo , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de Complemento 3b/biossíntese , Medição de Risco/métodos , Fatores de Transcrição/metabolismo , Adulto JovemRESUMO
OBJECTIVE: More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in â¼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. METHODS: All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. RESULTS: We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was â¼2.5 and â¼2.9 times higher, respectively, than that in women with 46,XX and â¼25 and â¼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.
Assuntos
Artrite Reumatoide/epidemiologia , Cirrose Hepática Biliar/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/epidemiologia , Síndrome de Sjogren/epidemiologia , Doenças Autoimunes/epidemiologia , Estudos de Casos e Controles , Cromossomos Humanos X , Feminino , Dosagem de Genes , Humanos , Hibridização in Situ Fluorescente , Prevalência , Sarcoidose/epidemiologia , Aberrações dos Cromossomos Sexuais , Distribuição por Sexo , TrissomiaRESUMO
CD134- and CD137-primed CD8 T cells mount powerful effector responses upon recall, but even without recall these dual-costimulated T cells respond to signal 3 cytokines such as IL-12. We searched for alternative signal 3 receptor pathways and found the IL-1 family member IL-36R. Although IL-36 alone did not stimulate effector CD8 T cells, in combination with IL-12, or more surprisingly IL-2, it induced striking and rapid TCR-independent IFN-γ synthesis. To understand how signal 3 responses functioned in dual-costimulated T cells we showed that IL-2 induced IL-36R gene expression in a JAK/STAT-dependent manner. These data help delineate a sequential stimulation process where IL-2 conditioning must precede IL-36 for IFN-γ synthesis. Importantly, this responsive state was transient and functioned only in effector T cells capable of aerobic glycolysis. Specifically, as the effector T cells metabolized glucose and consumed O2, they also retained potential to respond through IL-36R. This suggests that T cells use innate receptor pathways such as the IL-36R/axis when programmed for aerobic glycolysis. To explore a function for IL-36R in vivo, we showed that dual costimulation therapy reduced B16 melanoma tumor growth while increasing IL-36R gene expression. In summary, cytokine therapy to eliminate tumors may target effector T cells, even outside of TCR specificity, as long as the effectors are in the correct metabolic state.