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1.
Annu Rev Immunol ; 29: 163-83, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21219184

RESUMO

Plasmacytoid dendritic cells (pDCs) are specialized in rapid and massive secretion of type I interferon (IFN-α/ß) in response to foreign nucleic acids. Combined with their antigen presentation capacity, this powerful functionality enables pDCs to orchestrate innate and adaptive immune responses. pDCs combine features of both lymphocytes and classical dendritic cells and display unique molecular adaptations to nucleic acid sensing and IFN production. In the decade since the identification of the pDC as a distinct immune cell type, our understanding of its molecular underpinnings and role in immunity has progressed rapidly. Here we review select aspects of pDC biology including cell fate establishment and plasticity, specific molecular mechanisms of pDC function, and the role of pDCs in T cell responses, antiviral immunity, and autoimmune diseases. Important unresolved questions remain in these areas, promising exciting times in pDC research for years to come.


Assuntos
Células Dendríticas/citologia , Células Dendríticas/imunologia , Animais , Doenças Autoimunes/imunologia , Linhagem da Célula , Células Dendríticas/metabolismo , Humanos , Infecções/imunologia , Transdução de Sinais
2.
Cell ; 166(1): 88-101, 2016 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-27293190

RESUMO

Antibodies to DNA and chromatin drive autoimmunity in systemic lupus erythematosus (SLE). Null mutations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 are linked to familial and sporadic SLE, respectively. We report that DNASE1L3-deficient mice rapidly develop autoantibodies to DNA and chromatin, followed by an SLE-like disease. Circulating DNASE1L3 is produced by dendritic cells and macrophages, and its levels inversely correlate with anti-DNA antibody response. DNASE1L3 is uniquely capable of digesting chromatin in microparticles released from apoptotic cells. Accordingly, DNASE1L3-deficient mice and human patients have elevated DNA levels in plasma, particularly in circulating microparticles. Murine and human autoantibody clones and serum antibodies from human SLE patients bind to DNASE1L3-sensitive chromatin on the surface of microparticles. Thus, extracellular microparticle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism can contribute to SLE, and its restoration may represent a therapeutic opportunity in the disease.


Assuntos
Autoanticorpos/imunologia , Micropartículas Derivadas de Células/química , Cromatina/imunologia , DNA/imunologia , Endodesoxirribonucleases/genética , Lúpus Eritematoso Sistêmico/imunologia , Animais , Micropartículas Derivadas de Células/metabolismo , Modelos Animais de Doenças , Endodesoxirribonucleases/deficiência , Endodesoxirribonucleases/metabolismo , Humanos , Células Jurkat , Lúpus Eritematoso Sistêmico/enzimologia , Lúpus Eritematoso Sistêmico/genética , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
Immunity ; 52(6): 1022-1038.e7, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32454024

RESUMO

Class-switched antibodies to double-stranded DNA (dsDNA) are prevalent and pathogenic in systemic lupus erythematosus (SLE), yet mechanisms of their development remain poorly understood. Humans and mice lacking secreted DNase DNASE1L3 develop rapid anti-dsDNA antibody responses and SLE-like disease. We report that anti-DNA responses in Dnase1l3-/- mice require CD40L-mediated T cell help, but proceed independently of germinal center formation via short-lived antibody-forming cells (AFCs) localized to extrafollicular regions. Type I interferon (IFN-I) signaling and IFN-I-producing plasmacytoid dendritic cells (pDCs) facilitate the differentiation of DNA-reactive AFCs in vivo and in vitro and are required for downstream manifestations of autoimmunity. Moreover, the endosomal DNA sensor TLR9 promotes anti-dsDNA responses and SLE-like disease in Dnase1l3-/- mice redundantly with another nucleic acid-sensing receptor, TLR7. These results establish extrafollicular B cell differentiation into short-lived AFCs as a key mechanism of anti-DNA autoreactivity and reveal a major contribution of pDCs, endosomal Toll-like receptors (TLRs), and IFN-I to this pathway.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular , DNA/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interferon Tipo I/metabolismo , Animais , Anticorpos Antinucleares/imunologia , Autoantígenos/imunologia , Autoimunidade , Biomarcadores , Ligante de CD40/deficiência , Comunicação Celular/genética , Comunicação Celular/imunologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Endodesoxirribonucleases/deficiência , Imunofluorescência , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Knockout , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo
4.
Eur J Immunol ; 54(6): e2350903, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38576111

RESUMO

We induced systemic sclerosis (SSc)-like disease in both wild-type and Dnase1l3-deficient mice using two distinct approaches involving bleomycin and hypochlorous acid injections. Our observations revealed that the deficiency in DNASE1L3 did not affect tissue fibrosis or inflammation caused by these treatments. Despite the association of single nucleotide polymorphisms in humans with SSc pathogenesis, our study demonstrates that DNASE1L3 is dispensable in two inducible murine models of SSc-like pathogenesis.


Assuntos
Bleomicina , Modelos Animais de Doenças , Endodesoxirribonucleases , Camundongos Knockout , Escleroderma Sistêmico , Animais , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/imunologia , Camundongos , Endodesoxirribonucleases/deficiência , Endodesoxirribonucleases/genética , Humanos , Ácido Hipocloroso , Fibrose , Camundongos Endogâmicos C57BL
5.
J Immunol ; 211(10): 1475-1480, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37800687

RESUMO

Autoantibodies to chromatin and dsDNA are a hallmark of systemic lupus erythematosus (SLE). In a mouse model of monogenic human SLE caused by DNASE1L3 deficiency, the anti-DNA response is dependent on endosomal nucleic acid-sensing TLRs TLR7 and TLR9. In this study, we report that this response also required TLR2, a surface receptor for microbial products that is primarily expressed on myeloid cells. Cell transfers into lymphopenic DNASE1L3-deficient mice showed that TLR2 was required for anti-DNA Ab production by lymphocytes. TLR2 was detectably expressed on B cells and facilitated the production of IL-6 by B cells activated in the presence of microbial products. Accordingly, treatment with broad-spectrum antibiotics or Ab-mediated blockade of IL-6 delayed the anti-DNA response in DNASE1L3-deficient mice. These studies reveal an unexpected B cell-intrinsic role of TLR2 in systemic autoreactivity to DNA, and they suggest that microbial products may synergize with self-DNA in the activation of autoreactive B cells in SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Receptor 2 Toll-Like , Camundongos , Animais , Humanos , Interleucina-6 , Linfócitos B , Autoanticorpos , Anticorpos Antinucleares , DNA
6.
Immunity ; 43(2): 277-88, 2015 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-26231120

RESUMO

Plasmacytoid dendritic cells (pDCs) are primary producers of type I interferon (IFN) in response to viruses. The IFN-producing capacity of pDCs is regulated by specific inhibitory receptors, yet none of the known receptors are conserved in evolution. We report that within the human immune system, receptor protein tyrosine phosphatase sigma (PTPRS) is expressed specifically on pDCs. Surface PTPRS was rapidly downregulated after pDC activation, and only PTPRS(-) pDCs produced IFN-α. Antibody-mediated PTPRS crosslinking inhibited pDC activation, whereas PTPRS knockdown enhanced IFN response in a pDC cell line. Similarly, murine Ptprs and the homologous receptor phosphatase Ptprf were specifically co-expressed in murine pDCs. Haplodeficiency or DC-specific deletion of Ptprs on Ptprf-deficient background were associated with enhanced IFN response of pDCs, leukocyte infiltration in the intestine and mild colitis. Thus, PTPRS represents an evolutionarily conserved pDC-specific inhibitory receptor, and is required to prevent spontaneous IFN production and immune-mediated intestinal inflammation.


Assuntos
Colite/imunologia , Células Dendríticas/imunologia , Intestinos/imunologia , Leucócitos/fisiologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Animais , Diferenciação Celular , Movimento Celular/genética , Células Cultivadas , Colite/genética , Modelos Animais de Doenças , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética
7.
Am J Hum Genet ; 107(5): 882-894, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022220

RESUMO

Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.


Assuntos
DNA/genética , Endodesoxirribonucleases/genética , Lúpus Eritematoso Sistêmico/genética , Mutação , Animais , Estudos de Casos e Controles , DNA/sangue , Fragmentação do DNA , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Endodesoxirribonucleases/deficiência , Endodesoxirribonucleases/metabolismo , Terapia Genética , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/enzimologia , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Transgênicos , Especificidade por Substrato , Transdução Genética
8.
Proc Natl Acad Sci U S A ; 116(2): 641-649, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30593563

RESUMO

Circulating DNA in plasma consists of short DNA fragments. The biological processes generating such fragments are not well understood. DNASE1L3 is a secreted DNASE1-like nuclease capable of digesting DNA in chromatin, and its absence causes anti-DNA responses and autoimmunity in humans and mice. We found that the deletion of Dnase1l3 in mice resulted in aberrations in the fragmentation of plasma DNA. Such aberrations included an increase in short DNA molecules below 120 bp, which was positively correlated with anti-DNA antibody levels. We also observed an increase in long, multinucleosomal DNA molecules and decreased frequencies of the most common end motifs found in plasma DNA. These aberrations were independent of anti-DNA response, suggesting that they represented a primary effect of DNASE1L3 loss. Pregnant Dnase1l3-/- mice carrying Dnase1l3+/- fetuses showed a partial restoration of normal frequencies of plasma DNA end motifs, suggesting that DNASE1L3 from Dnase1l3-proficient fetuses could enter maternal systemic circulation and affect both fetal and maternal DNA fragmentation in a systemic as well as local manner. However, the observed shortening of circulating fetal DNA relative to maternal DNA was not affected by the deletion of Dnase1l3 Collectively, our findings demonstrate that DNASE1L3 plays a role in circulating plasma DNA homeostasis by enhancing fragmentation and influencing end-motif frequencies. These results support a distinct role of DNASE1L3 as a regulator of the physical form and availability of cell-free DNA and may have important implications for the mechanism whereby this enzyme prevents autoimmunity.


Assuntos
Ácidos Nucleicos Livres/sangue , Fragmentação do DNA , DNA/sangue , Endodesoxirribonucleases/metabolismo , Motivos de Nucleotídeos , Animais , Ácidos Nucleicos Livres/genética , DNA/genética , Endodesoxirribonucleases/genética , Feminino , Feto/metabolismo , Deleção de Genes , Camundongos , Camundongos Knockout , Gravidez
9.
Eur J Immunol ; 46(2): 354-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26518732

RESUMO

Intestinal DCs orchestrate gut immune homeostasis by dampening proinflammatory T-cell responses and inducing anti-inflammatory IgA responses. Although no specific DC subset has been strictly assigned so far to govern IgA response, some candidate subsets emerge. In particular, plasmacytoid DCs (pDCs), which notoriously promote anti-viral immunity and T-cell tolerance to innocuous antigens (Ags), contribute to IgA induction in response to intestinal viral infection and promote T-cell-independent IgA responses in vitro. Here, using two transgenic mouse models, we show that neither short-term nor long-term pDC depletion alters IgA class switch recombination in Peyer's patches and frequency of IgA plasma cells in intestinal mucosa at steady state, even in the absence of T-cell help. In addition, pDCs are dispensable for induction of intestinal IgA plasma cells in response to oral immunization with T-cell-dependent or T-cell-independent Ags, and are not required for proliferation and IgA switch of Ag-specific B cells in GALT. These results show that pDCs are dispensable for noninfectious IgA responses, and suggest that various DC subsets may play redundant roles in the control of intestinal IgA responses.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Imunoglobulina A/metabolismo , Mucosa Intestinal/imunologia , Plasmócitos/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Imunização , Switching de Imunoglobulina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T/imunologia , Fator de Transcrição 4
10.
Curr Rheumatol Rep ; 19(8): 48, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28718063

RESUMO

PURPOSE OF REVIEW: Current knowledge on the role of platelets and platelet-derived microparticles (PMPs) on the immune system has been fast-growing. Systemic lupus erythematosus (SLE) is a systemic auto-immune disorder characterized by a loss of tolerance toward nuclear auto-antigens. Although recent studies allowed a better understanding of SLE pathogenesis, there is an urgent need for the development of new treatments and the identification of new biomarkers to assess the disease activity. We describe here the state-of-the-art knowledge linking platelets and PMPs to SLE. RECENT FINDINGS: Platelet system activation is a key event in the pathogenesis of SLE. Circulating immune complexes, anti-phospholipid antibodies, and infectious agents such as virus are the main activators of platelets in SLE. Platelet activation can be monitored through different ways such as P-selectin expression, mean platelet volume, or circulating PMP levels, suggesting their potential use as biomarkers. Upon activation, platelets promote type I interferon production, NETosis, dendritic cell activation, and T and B lymphocyte activation, all essential events contributing to the development of SLE. Of interest, platelets also play a fundamental role in SLE organ disease such as the development of cardiovascular, thrombotic, and renal diseases. Finally, we review current knowledge on drugs targeting platelet activation and their potential impact on SLE pathogenesis. Platelets play a major role in SLE pathogenesis and organ disease and represent a great potential for novel biomarkers and drug development.


Assuntos
Autoimunidade/fisiologia , Plaquetas/imunologia , Micropartículas Derivadas de Células/imunologia , Lúpus Eritematoso Sistêmico/sangue , Humanos , Lúpus Eritematoso Sistêmico/imunologia
11.
Int J Cancer ; 133(3): 771-8, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23389942

RESUMO

We previously reported that plasmacytoid dendritic cells (pDCs) infiltrating breast tumors are impaired for their interferon-α (IFN-α) production, resulting in local regulatory T cells amplification. We designed our study to decipher molecular mechanisms of such functional defect of tumor-associated pDC (TApDC) in breast cancer. We demonstrate that besides IFN-α, the production by Toll-like receptor (TLR)-activated healthy pDC of IFN-ß and TNF-α but not IP-10/CXCL10 nor MIP1-α/CCL3 is impaired by the breast tumor environment. Importantly, we identified TGF-ß and TNF-α as major soluble factors involved in TApDC functional alteration. Indeed, recombinant TGF-ß1 and TNF-α synergistically blocked IFN-α production of TLR-activated pDC, and neutralization of TGF-ß and TNF-α in tumor-derived supernatants restored pDCs' IFN-α production. The involvment of tumor-derived TGF-ß was further confirmed in situ by the detection of phosphorylated Smad2 in the nuclei of TApDC in breast tumor tissues. Mechanisms of type I IFN inhibition did not involve TLR downregulation but the inhibition of IRF-7 expression and nuclear translocation in pDC after their exposure to tumor-derived supernatants or recombinant TGF-ß1 and TNF-α. Our findings indicate that targeting TApDC to restore their IFN-α production might be an achievable strategy to induce antitumor immunity in breast cancer by combining TLR7/9-based immunotherapy with TGF-ß and TNF-α antagonists.


Assuntos
Neoplasias da Mama/metabolismo , Células Dendríticas/metabolismo , Interferon-alfa/biossíntese , Fator de Crescimento Transformador beta/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Quimiocina CCL3/biossíntese , Quimiocina CXCL10/biossíntese , Feminino , Humanos , Fator Regulador 7 de Interferon/biossíntese , Interferon beta/biossíntese , Fosforilação , Transporte Proteico , Proteínas Recombinantes/farmacologia , Proteína Smad2/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/metabolismo
12.
Blood ; 118(19): 5130-40, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21937703

RESUMO

Absent in peripheral tissues during homeostasis, human plasmacytoid dendritic cells (pDCs) are described in inflamed skin or mucosa. Here, we report that, unlike blood pDCs, a subset of tonsil pDCs express functional CCR6 and CCR10, and their respective ligands CCL20 and CCL27are detected in inflamed epithelia contacting blood dendritic cell antigen 2(+) pDCs. Moreover, pDCs are recruited to imiquimod-treated skin tumors in WT but not CCR6-deficient mice, and competitive adoptive transfers reveal that CCR6-deficient pDCs are impaired in homing to inflamed skin tumors after intravenous transfer. On IL-3 culture, CCR6 and CCR10 expression is induced on human blood pDCs that become responsive to CCL20 and CCL27/CCL28, respectively. Interestingly, unlike myeloid DC, blood pDCs initially up-regulate CCR7 expression and CCL19 responsiveness on IL-3 ± CpG-B and then acquire functional CCR6 and CCR10. Finally, IL-3-differentiated CCR6(+) CCR10(+) pDCs secrete high levels of IFN-α in response to virus. Overall, we propose an unexpected pDCs migratory model that may best apply for mucosal-associated lymphoid tissues. After CCR7-mediated extravasation into lymphoid tissues draining inflamed epithelia, blood pDCs may be instructed to up-regulate CCR6 and/or CCR10 allowing their homing into inflamed epithelia (in mucosae or skin). At this site, pDCs can then produce IFN-α contributing to pathogen clearance and/or local inflammation.


Assuntos
Células Dendríticas/imunologia , Inflamação/imunologia , Receptores CCR10/metabolismo , Receptores CCR6/metabolismo , Transferência Adotiva , Animais , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Quimiocina CCL19/farmacologia , Quimiocina CCL20/farmacologia , Células Dendríticas/patologia , Epitélio/imunologia , Epitélio/patologia , Feminino , Humanos , Inflamação/patologia , Interferon-alfa/biossíntese , Interleucina-3/farmacologia , Ligantes , Tecido Linfoide/imunologia , Tecido Linfoide/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Imunológicos , Tonsila Palatina/citologia , Tonsila Palatina/imunologia , Receptores CCR6/deficiência , Receptores CCR6/genética , Receptor 7 Toll-Like/metabolismo
13.
Methods Mol Biol ; 2618: 3-16, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36905505

RESUMO

Dendritic cells are cells of hematopoietic origin that are specialized in antigen presentation and instruction of innate and adaptive immune responses. They are a heterogenous group of cells populating lymphoid organs and most tissues. Dendritic cells are commonly separated in three main subsets that differ in their developmental paths, phenotype, and functions. Most studies on dendritic cells were done primarily in mice; therefore, in this chapter, we propose to summarize the current knowledge and recent progress on mouse dendritic cell subsets' development, phenotype, and functions.


Assuntos
Apresentação de Antígeno , Células Dendríticas , Animais , Camundongos , Fenótipo
14.
Methods Mol Biol ; 2618: 173-186, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36905517

RESUMO

Dendritic cells (DCs) are antigen-presenting cells (APCs) that shape innate and adaptive immunity. There are multiple subsets of DCs distinguished according to their phenotype and functional specialization. DCs are present in lymphoid organs and across multiple tissues. However, their frequency and numbers at these sites are very low making their functional study difficult. Multiple protocols have been developed to generate DCs in vitro from bone marrow progenitors, but they do not fully recapitulate DC complexity found in vivo. Therefore, directly amplifying endogenous DCs in vivo appears as an option to overcome this specific caveat. In this chapter, we describe a protocol to amplify murine DCs in vivo by the injection of a B16 melanoma cell line expressing the trophic factor FMS-like tyrosine kinase 3 ligand (Flt3L). We have also compared two methods of magnetic sorting of amplified DCs, both giving high yields of total murine DCs, but different representation of the main DC subsets found in vivo.


Assuntos
Células Dendríticas , Proteínas de Membrana , Camundongos , Animais , Proteínas de Membrana/metabolismo , Baço/metabolismo
15.
J Leukoc Biol ; 113(3): 305-314, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36807447

RESUMO

Chronic lymphocytic leukemia (CLL) is characterized by an expansion of mature B cells in the bone marrow, peripheral lymphoid organs, and blood. CD4 T helper (Th) lymphocytes significantly contribute to the physiopathology of CLL, but the subset(s) of Th cell involved in CLL pathogenesis is (are) still under debate. In this study, we performed flow cytometry analysis of the circulatory T cells of untreated CLL patients and observed an increase in follicular helper T cells (Tfh), which is a subset of T cells specialized in B cell help. Elevated numbers of Tfh cells correlated with disease severity as measured by the Binet staging system. Tfh from CLL patients were activated and skewed toward a Th1 profile as evidenced by their PD-1+IL-21+IFNγ+ phenotype and their CXCR3+CCR6- chemokine receptor profile. Tfh efficiently enhanced B-CLL survival and proliferation through IL-21 but independently of IFNγ. Finally, we observed an inverse correlation between the Tfh1 and IgA and IgG serum levels in patients, suggesting a role for this Tfh subset in the immune dysfunction associated with CLL. Altogether, our data highlight an impairment in circulatory Tfh subsets in CLL patients and their critical role in CLL physiopathology.


Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Linfócitos T Auxiliares-Indutores , Linfócitos B , Linfócitos T CD4-Positivos/patologia , Proliferação de Células
16.
Biol Rev Camb Philos Soc ; 98(5): 1668-1686, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37157910

RESUMO

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.


Assuntos
Neoplasias , Filosofia , Pesquisa , Estudos Interdisciplinares
17.
Front Immunol ; 12: 629922, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717156

RESUMO

Detection of microbial nucleic acids by the innate immune system is mediated by numerous intracellular nucleic acids sensors. Upon the detection of nucleic acids these sensors induce the production of inflammatory cytokines, and thus play a crucial role in the activation of anti-microbial immunity. In addition to microbial genetic material, nucleic acid sensors can also recognize self-nucleic acids exposed extracellularly during turn-over of cells, inefficient efferocytosis, or intracellularly upon mislocalization. Safeguard mechanisms have evolved to dispose of such self-nucleic acids to impede the development of autoinflammatory and autoimmune responses. These safeguard mechanisms involve nucleases that are either specific to DNA (DNases) or RNA (RNases) as well as nucleic acid editing enzymes, whose biochemical properties, expression profiles, functions and mechanisms of action will be detailed in this review. Fully elucidating the role of these enzymes in degrading and/or processing of self-nucleic acids to thwart their immunostimulatory potential is of utmost importance to develop novel therapeutic strategies for patients affected by inflammatory and autoimmune diseases.


Assuntos
Autoimunidade/imunologia , Autoimunidade/fisiologia , Imunidade Inata/imunologia , Imunidade Inata/fisiologia , Ácidos Nucleicos/imunologia , Animais , Doenças Autoimunes , Desoxirribonucleases/imunologia , Humanos , Ribonucleases/imunologia
19.
J Exp Med ; 218(5)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33783474

RESUMO

Antibodies to double-stranded DNA (dsDNA) are prevalent in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis, yet the nature and regulation of antigenic cell-free DNA (cfDNA) are poorly understood. Null mutations in the secreted DNase DNASE1L3 cause human monogenic SLE with anti-dsDNA autoreactivity. We report that >50% of sporadic SLE patients with nephritis manifested reduced DNASE1L3 activity in circulation, which was associated with neutralizing autoantibodies to DNASE1L3. These patients had normal total plasma cfDNA levels but showed accumulation of cfDNA in circulating microparticles. Microparticle-associated cfDNA contained a higher fraction of longer polynucleosomal cfDNA fragments, which bound autoantibodies with higher affinity than mononucleosomal fragments. Autoantibodies to DNASE1L3-sensitive antigens on microparticles were prevalent in SLE nephritis patients and correlated with the accumulation of cfDNA in microparticles and with disease severity. DNASE1L3-sensitive antigens included DNA-associated proteins such as HMGB1. Our results reveal autoantibody-mediated impairment of DNASE1L3 activity as a common nongenetic mechanism facilitating anti-dsDNA autoreactivity in patients with severe sporadic SLE.


Assuntos
Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , DNA/imunologia , Endodesoxirribonucleases/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Adulto , Animais , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/imunologia , Criança , Endodesoxirribonucleases/sangue , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Feminino , Células HEK293 , Proteína HMGB1/imunologia , Proteína HMGB1/metabolismo , Humanos , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Índice de Gravidade de Doença
20.
Sci Transl Med ; 13(600)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193612

RESUMO

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor-ß axis, altering the phenotype of Treg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin-dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue.


Assuntos
Lúpus Eritematoso Sistêmico , Linfócitos T Reguladores , Animais , Humanos , Camundongos , Selectinas , Fator de Crescimento Transformador beta
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