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1.
Cell Rep ; 31(13): 107819, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32610122

RESUMO

The RNA N6-methyladenosine (m6A) methylation is installed by the METTL3-METTL14 methyltransferase complex. This modification has critical regulatory roles in various biological processes. Here, we report that deletion of Mettl14 dramatically reduces mRNA m6A methylation in developing B cells and severely blocks B cell development in mice. Deletion of Mettl14 impairs interleukin-7 (IL-7)-induced pro-B cell proliferation and the large-pre-B-to-small-pre-B transition and causes dramatic abnormalities in gene expression programs important for B cell development. Suppression of a group of transcripts by cytoplasmic m6A reader YTHDF2 is critical to the IL-7-induced pro-B cell proliferation. In contrast, the block in the large-pre-B-to-small-pre-B transition is independent of YTHDF1 or YTHDF2 but is associated with a failure to properly upregulate key transcription factors regulating this transition. Our data highlight the important regulatory roles of the RNA m6A methylation and its reader proteins in early B cell development.

2.
J Autoimmun ; : 102469, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32362501

RESUMO

Previous studies have reported robust inflammatory cell infiltration, synthesis of IgG, B-cell clonal expansion, deposition of immune complexes and complement within cerebral cavernous malformation (CCM) lesions. B-cell depletion has also been shown to reduce the maturation of CCM in murine models. We hypothesize that antigen(s) within the lesional milieu perpetuate the pathogenetic immune responses in CCMs. This study aims to identify those putative antigen(s) using monoclonal antibodies (mAbs) derived from plasma cells found in surgically removed human CCM lesions. We produced human mAbs from laser capture micro-dissected plasma cells from four CCM patients, and also germline-reverted versions. CCM mAbs were assayed using immunofluorescence on central nervous system (CNS) tissues and immunocytochemistry on human primary cell lines. Antigen characterization was performed using a combination of confocal microscopy, immunoprecipitation and mass spectrometry. Affinity was determined by enzyme-linked immunosorbent assay, and specificity by multi-color confocal microscopy and quantitative co-localization. CCM mAbs bound CNS tissue, especially endothelial cells and astrocytes. Non-muscle myosin heavy chain IIA (NMMHCIIA), vimentin and tubulin are three cytoskeleton proteins that were commonly targeted. Selection of cytoskeleton proteins by plasma cells was supported by a high frequency of immunoglobulin variable region somatic hypermutations, high affinity and selectivity of mAbs in their affinity matured forms, and profoundly reduced affinity and selectivity in the germline reverted forms. Antibodies produced by plasma cells in CCM lesions commonly target cytoplasmic and cytoskeletal autoantigens including NMMHCIIA, vimentin and tubulin that are abundant in endothelial cells and astrocytes. Binding to, and selection on autoantigen(s) in the lesional milieu likely perpetuates the pathogenetic immune response in CCMs. Blocking this in situ autoimmune response may yield a novel treatment for CCM.

3.
Nat Immunol ; 21(6): 660-670, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32341509

RESUMO

Within germinal centers (GCs), complex and highly orchestrated molecular programs must balance proliferation, somatic hypermutation and selection to both provide effective humoral immunity and to protect against genomic instability and neoplastic transformation. In contrast to this complexity, GC B cells are canonically divided into two principal populations, dark zone (DZ) and light zone (LZ) cells. We now demonstrate that, following selection in the LZ, B cells migrated to specialized sites within the canonical DZ that contained tingible body macrophages and were sites of ongoing cell division. Proliferating DZ (DZp) cells then transited into the larger DZ to become differentiating DZ (DZd) cells before re-entering the LZ. Multidimensional analysis revealed distinct molecular programs in each population commensurate with observed compartmentalization of noncompatible functions. These data provide a new three-cell population model that both orders critical GC functions and reveals essential molecular programs of humoral adaptive immunity.

4.
Sci Transl Med ; 12(538)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32269165

RESUMO

The kidney is a frequent target of autoimmune injury, including in systemic lupus erythematosus; however, how immune cells adapt to kidney's unique environment and contribute to tissue damage is unknown. We found that renal tissue, which normally has low oxygen tension, becomes more hypoxic in lupus nephritis. In the injured mouse tissue, renal-infiltrating CD4+ and CD8+ T cells express hypoxia-inducible factor-1 (HIF-1), which alters their cellular metabolism and prevents their apoptosis in hypoxia. HIF-1-dependent gene-regulated pathways were also up-regulated in renal-infiltrating T cells in human lupus nephritis. Perturbation of these environmental adaptations by selective HIF-1 blockade inhibited infiltrating T cells and reversed tissue hypoxia and injury in murine models of lupus. The results suggest that targeting HIF-1 might be effective for treating renal injury in autoimmune diseases.

6.
Nat Commun ; 10(1): 4768, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628339

RESUMO

B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This 'alternate pathway' of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Receptores de Células Precursoras de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Medula Óssea/imunologia , Medula Óssea/metabolismo , Diferenciação Celular/genética , Cadeias Leves Substitutas da Imunoglobulina/genética , Cadeias Leves Substitutas da Imunoglobulina/imunologia , Cadeias Leves Substitutas da Imunoglobulina/metabolismo , Fígado/embriologia , Fígado/imunologia , Fígado/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Células Precursoras de Linfócitos B/genética , Receptores de Células Precursoras de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Receptores de Interleucina-7/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Fator de Transcrição STAT5/metabolismo
7.
Nat Immunol ; 20(10): 1393-1403, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477919

RESUMO

In B lymphopoiesis, activation of the pre-B cell antigen receptor (pre-BCR) is associated with both cell cycle exit and Igk recombination. Yet how the pre-BCR mediates these functions remains unclear. Here, we demonstrate that the pre-BCR initiates a feed-forward amplification loop mediated by the transcription factor interferon regulatory factor 4 and the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4). CXCR4 ligation by C-X-C motif chemokine ligand 12 activates the mitogen-activated protein kinase extracellular-signal-regulated kinase, which then directs the development of small pre- and immature B cells, including orchestrating cell cycle exit, pre-BCR repression, Igk recombination and BCR expression. In contrast, pre-BCR expression and escape from interleukin-7 have only modest effects on B cell developmental transcriptional and epigenetic programs. These data show a direct and central role for CXCR4 in orchestrating late B cell lymphopoiesis. Furthermore, in the context of previous findings, our data provide a three-receptor system sufficient to recapitulate the essential features of B lymphopoiesis in vitro.


Assuntos
Linfócitos B/imunologia , Cadeias kappa de Imunoglobulina/genética , Células Precursoras de Linfócitos B/fisiologia , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores CXCR4/metabolismo , Animais , Pontos de Checagem do Ciclo Celular , Células Cultivadas , Quimiocina CXCL12/metabolismo , Feminino , Fatores Reguladores de Interferon/genética , Linfopoese , Masculino , Camundongos , Receptores de Antígenos de Linfócitos B/genética , Receptores CXCR4/genética , Recombinação Genética
8.
Adv Immunol ; 141: 33-49, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30904132

RESUMO

The vertebrate immune system is tasked with the challenge of responding to any pathogen the organism might encounter, and retaining memory of that pathogen in case of future infection. Recognition and memory of pathogens are encoded within the adaptive immune system and production of T and B lymphocytes with diverse antigen receptor repertoires. In B lymphocytes, diversity is generated by sequential recombination between Variable (V), Diversity (D) and Joining (J) gene segments in the immunoglobulin heavy chain gene (Igh) and subsequent V-J recombination in immunoglobulin light chain genes (Igκ followed by Igλ). However, the process by which particular V, D and J segments are selected during recombination, and stochasticity is maintained to ensure antibody repertoire diversity, is still unclear. In this review, we focus on Igκ and recent findings regarding the relationships between gene structure, the generation of diversity and allelic choice. Surprisingly, the nuclear environment in which each Igκ allele resides, including transcription factories assembled on the nuclear matrix, plays critical roles in both gene regulation and in shaping the diversity of Vκ genes accessible to recombination. These findings provide a new paradigm for understanding Igκ recombination and Vκ diversity in the context of B lymphopoiesis.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Ciclina D3/metabolismo , Cadeias kappa de Imunoglobulina/genética , Células Precursoras de Linfócitos B/imunologia , RNA Polimerase II/metabolismo , Alelos , Animais , Linfócitos B/imunologia , Montagem e Desmontagem da Cromatina/imunologia , Ciclina D3/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/metabolismo , Camundongos , RNA Polimerase II/genética , Ativação Transcricional/genética , Ativação Transcricional/imunologia , Recombinação V(D)J/genética
9.
Nat Immunol ; 20(4): 503-513, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30778242

RESUMO

Two-photon excitation microscopy (TPEM) has revolutionized the understanding of adaptive immunity. However, TPEM usually requires animal models and is not amenable to the study of human disease. The recognition of antigen by T cells requires cell contact and is associated with changes in T cell shape. We postulated that by capturing these features in fixed tissue samples, we could quantify in situ adaptive immunity. Therefore, we used a deep convolutional neural network to identify fundamental distance and cell-shape features associated with cognate help (cell-distance mapping (CDM)). In mice, CDM was comparable to TPEM in discriminating cognate T cell-dendritic cell (DC) interactions from non-cognate T cell-DC interactions. In human lupus nephritis, CDM confirmed that myeloid DCs present antigen to CD4+ T cells and identified plasmacytoid DCs as an important antigen-presenting cell. These data reveal a new approach with which to study human in situ adaptive immunity broadly applicable to autoimmunity, infection, and cancer.


Assuntos
Imunidade Adaptativa , Células Dendríticas/imunologia , Microscopia de Fluorescência por Excitação Multifotônica , Linfócitos T/imunologia , Animais , Núcleo Celular/ultraestrutura , Células Dendríticas/citologia , Humanos , Nefrite Lúpica/imunologia , Camundongos , Camundongos Transgênicos , Redes Neurais de Computação , Linfócitos T/citologia , Linfócitos T/ultraestrutura
10.
Nat Commun ; 9(1): 3888, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250168

RESUMO

Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 regulates over 7000 genes to repress proliferative and induce differentiation programs. However, BRWD1 does not regulate the expression of TFs required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations have B-cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1-/- mice. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B-cell development.


Assuntos
Agamaglobulinemia/genética , Proteínas de Transporte/metabolismo , Epigênese Genética/fisiologia , Linfopoese/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Agamaglobulinemia/sangue , Animais , Proteínas de Transporte/genética , Diferenciação Celular/genética , Criança , Elementos Facilitadores Genéticos/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/fisiologia , Humanos , Leucócitos Mononucleares , Masculino , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Células Precursoras de Linfócitos B , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Interferente Pequeno/metabolismo , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
11.
Cell Rep ; 24(9): 2443-2456, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30157436

RESUMO

Expression of vast repertoires of antigen receptors by lymphocytes, with each cell expressing a single receptor, requires stochastic activation of individual variable (V) genes for transcription and recombination. How this occurs remains unknown. Using single-cell RNA sequencing (scRNA-seq) and allelic variation, we show that individual pre-B cells monoallelically transcribe divergent arrays of Vκ genes, thereby opening stochastic repertoires for subsequent Vκ-Jκ recombination. Transcription occurs upon translocation of Vκ genes to RNA polymerase II arrayed on the nuclear matrix in transcription factories. Transcription is anchored by CTCF-bound sites or E2A-loaded Vκ promotors and continues over large genomic distances delimited only by topological associating domains (TADs). Prior to their monoallelic activation, Vκ loci are transcriptionally repressed by cyclin D3, which prevents capture of Vκ gene containing TADs by transcription factories. Cyclin D3 also represses protocadherin, olfactory, and other monoallelically expressed genes, suggesting a widely deployed mechanism for coupling monoallelic gene activation with cell cycle exit.


Assuntos
Região Variável de Imunoglobulina/genética , Transcrição Genética/genética , Animais , Humanos
12.
Nat Immunol ; 19(9): 910-911, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30127436
13.
Front Immunol ; 9: 1516, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30038611

RESUMO

Vimentin has been implicated in pulmonary sarcoidosis as a T-cell autoantigen, particularly in the context of HLA-DRB1*03, the Vα2.3/Vß22 T-cell receptor (TCR), and Löfgren's syndrome. As vimentin is a known antigenic target in B-cell-mediated autoimmunity, we investigated in situ humoral anti-vimentin responses in pulmonary sarcoidosis and their relationship with HLA-DRB1*03. Sarcoid and healthy control (HC) lung biopsies were analyzed by multi-color confocal microscopy for B-cells, T-cells, proliferation, and vimentin, and compared to tonsillectomy tissue. Bronchoalveolar lavage fluid (BALF) and serum from 48 sarcoidosis patients and 15 healthy volunteers were typed for HLA-DRB1*03 and titrated for antibodies to full-length vimentin, vimentin truncations, and total IgG and IgA by ELISA. Presence of extracellular vimentin in BALF was determined by mass spectrometry and T-cell populations measured by flow cytometry. Sarcoid lung samples, especially from HLA-DRB1*03+ patients, contained vimentin-rich tertiary lymphoid structures and corresponding BALF was highly enriched for both IgG and IgA anti-vimentin antibody (AVA) titers. Furthermore, sarcoidosis patient BALF AVA concentrations (expressed as arbitrary units per milligram of total immunoglobulin isotype) correlated with the percentage of CD4+ T-cells expressing the Vα2.3/Vß22 TCR. BALF antibody reactivity to the vimentin N-terminus was most prominent in HCs, whereas reactivity to the C-terminus (VimC-term) was enriched in the sarcoid lung. Specifically, HLA-DRB1*03+ patient BALF contained higher concentrations of anti-VimC-term antibodies than BALF from both HCs and HLA-DRB1*03- patients. Consistent with the lung as a site of AVA production, the concentration of AVAs in BALF was dramatically higher than in matched serum samples. Overall, there was a poor correlation between BALF and serum AVA concentrations. Together, these studies reveal the presence of linked in situ recognition of vimentin by both T- and B-cells in HLA-DRB1*03+ sarcoidosis patients, associated with a selective humoral immune response to the vimentin C-terminus.

14.
J Exp Med ; 214(12): 3775-3790, 2017 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-29141870

RESUMO

A wealth of in vitro data has demonstrated a central role for receptor ubiquitination in endocytic sorting. However, how receptor ubiquitination functions in vivo is poorly understood. Herein, we report that ablation of B cell antigen receptor ubiquitination in vivo uncouples the receptor from CD19 phosphorylation and phosphatidylinositol 3-kinase (PI3K) signals. These signals are necessary and sufficient for accumulating phosphatidylinositol (3,4,5)-trisphosphate (PIP3) on B cell receptor-containing early endosomes and proper sorting into the MHC class II antigen-presenting compartment (MIIC). Surprisingly, MIIC targeting is dispensable for T cell-dependent immunity. Rather, it is critical for activating endosomal toll-like receptors and antiviral humoral immunity. These findings demonstrate a novel mechanism of receptor endosomal signaling required for specific peripheral immune responses.


Assuntos
Antígenos CD79/metabolismo , Endossomos/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais , Ubiquitinação , Animais , Linfócitos B/metabolismo , Endocitose , Antígenos de Histocompatibilidade Classe II/metabolismo , Imunidade Humoral , Masculino , Camundongos Endogâmicos C57BL , Fosfatos de Fosfatidilinositol/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores Toll-Like/metabolismo , Ubiquitina/metabolismo
15.
J Immunol ; 198(12): 4682-4691, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28490575

RESUMO

The histone methyltransferase EZH2 is required for B and T cell development; however, the molecular mechanisms underlying this requirement remain elusive. In a murine model of lymphoid-specific EZH2 deficiency we found that EZH2 was required for proper development of adaptive, but not innate, lymphoid cells. In adaptive lymphoid cells EZH2 prevented the premature expression of Cdkn2a and the consequent stabilization of p53, an effector of the pre-Ag receptor checkpoints. Deletion of Cdkn2a in EZH2-deficient lymphocytes prevented p53 stabilization, extended lymphocyte survival, and restored differentiation resulting in the generation of mature B and T lymphocytes. Our results uncover a crucial role for EZH2 in adaptive lymphocytes to control the developmental timing of effectors of the pre-Ag receptor checkpoints.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Receptores de Antígenos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Imunidade Adaptativa , Animais , Linfócitos B/imunologia , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/deficiência , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação da Expressão Gênica , Genes p53 , Células Matadoras Naturais/imunologia , Linfopoese , Camundongos , Receptores de Antígenos/genética , Receptores de Antígenos/imunologia
16.
Curr Opin Rheumatol ; 28(5): 460-7, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27341623

RESUMO

PURPOSE OF REVIEW: Despite recent developments and treatment successes, the outcome, and prognosis of patients with lupus nephritis (LuN) have not greatly changed since the 1980s. This review covers the application of new concepts to the understanding of renal inflammation and the study of new pharmacologic agents to improve patient outcomes. RECENT FINDINGS: Studies have shown that the presence of anti-vimentin antibodies and T follicular helper cells in patient biopsies is associated with more severe interstitial inflammation, which has been tied to faster disease progression and onset of end-stage renal disease. Additionally, data regarding the role of serum IgE antidouble-stranded DNA antibodies in LuN by means of mediating IFN1 production by plasmacytoid dendritic cells are highlighted. Finally, a thorough review of completed and currently open clinical trials of therapeutic agents is provided. SUMMARY: Current management of LuN is guided almost exclusively by glomerular involvement. Based on the data provided in this review, we argue that renal tubulointerstitial inflammation is no less important and represents an overlooked feature in the current clinical approach to patients. Tubulointerstitial inflammation is driven by both adaptive and innate immune mechanisms that are still poorly understood. Studying these pathogenic processes promises to reveal new therapeutic opportunities for those LuN patients with the worst prognosis. VIDEO ABSTRACT: Alternate video abstract introduction (see Video, Supplemental Digital Content 1, with introduction by two of the authors - VL and KT). Abstract Video: http://links.lww.com/COR/A35.


Assuntos
Autoanticorpos/imunologia , Células Dendríticas/imunologia , Interferon Tipo I/imunologia , Nefrite Lúpica/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Abatacepte/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biópsia , Ciclofosfamida/uso terapêutico , Progressão da Doença , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Inflamação , Falência Renal Crônica/etiologia , Nefrite Lúpica/complicações , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Quimioterapia de Manutenção , Ácido Micofenólico/uso terapêutico , Prognóstico , Quinolonas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Indução de Remissão , Ribonucleosídeos/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento , Vimentina/imunologia
17.
Arthritis Rheumatol ; 68(11): 2740-2751, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27159593

RESUMO

OBJECTIVE: In lupus nephritis, tubulointerstitial inflammation (TII) is associated with in situ adaptive immune cell networks that amplify local tissue damage. Since conventional therapy appears ineffective for severe TII, and these patients often progress to renal failure, understanding in situ mechanisms might reveal new therapeutic targets. This study was undertaken to assess whether dysregulated apoptotic regulators maintain local adaptive immunity and drive inflammation in TII. METHODS: This study utilized novel computational approaches that, when applied to multicolor confocal images, quantified apoptotic regulator protein expression in selected lymphocyte subsets. This approach was validated using laser-capture microdissection (LCM) coupled to quantitative polymerase chain reaction (qPCR). Furthermore, the consequences of dysregulated apoptotic mediator expression were explored in a murine model of lupus nephritis. RESULTS: Analyses of renal biopsy tissue from patients with lupus nephritis and those with mixed cellular renal allograft rejection revealed that the B cell lymphoma 2 protein (Bcl-2) was frequently expressed in infiltrating lymphocytes, whereas expression of myeloid cell leukemia 1 was low. In contrast, the reciprocal pattern of expression was observed in tonsil germinal centers. These results were consistent with RNA expression data obtained using LCM and qPCR. Bcl-2 was also highly expressed in tubulointerstitial infiltrates in (NZB × NZW)F1 (NZB/NZW) mice. Furthermore, treatment of NZB/NZW mice with ABT-199, a selective oral inhibitor of Bcl-2, prolonged survival and prevented proteinuria and development of TII in a lupus prevention model. Interestingly, glomerular immune complexes were partially ameliorated by ABT-199 treatment, and serum anti-double-stranded DNA antibody titers were unaffected. CONCLUSION: These data demonstrate that Bcl-2 is an attractive therapeutic target in patients with lupus nephritis who manifest TII.


Assuntos
Apoptose , Nefrite Lúpica/metabolismo , Linfócitos/metabolismo , Nefrite Intersticial/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Imunidade Adaptativa/imunologia , Animais , Complexo Antígeno-Anticorpo/efeitos dos fármacos , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Proteína 11 Semelhante a Bcl-2/genética , Proteína 11 Semelhante a Bcl-2/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Feminino , Centro Germinativo/metabolismo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Inflamação , Rim/efeitos dos fármacos , Rim/imunologia , Rim/metabolismo , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Transplante de Rim , Microdissecção e Captura a Laser , Nefrite Lúpica/imunologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos NZB , Microscopia Confocal , Microscopia de Fluorescência , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Nefrite Intersticial/imunologia , Tonsila Palatina , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/farmacologia
18.
Nat Immunol ; 17(2): 196-203, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26692173

RESUMO

Canonically, immunoglobulin E (IgE) mediates allergic immune responses by triggering mast cells and basophils to release histamine and type 2 helper cytokines. Here we found that in human systemic lupus erythematosus (SLE), IgE antibodies specific for double-stranded DNA (dsDNA) activated plasmacytoid dendritic cells (pDCs), a type of cell of the immune system linked to viral defense, which led to the secretion of substantial amounts of interferon-α (IFN-α). The concentration of dsDNA-specific IgE found in patient serum correlated with disease severity and greatly potentiated pDC function by triggering phagocytosis via the high-affinity FcɛRI receptor for IgE, followed by Toll-like receptor 9 (TLR9)-mediated sensing of DNA in phagosomes. Our findings expand the known pathogenic mechanisms of IgE-mediated inflammation beyond those found in allergy and demonstrate that IgE can trigger interferon responses capable of exacerbating self-destructive autoimmune responses.


Assuntos
Autoanticorpos/imunologia , Autoimunidade , Imunoglobulina E/imunologia , Interferons/metabolismo , Anticorpos Antinucleares/imunologia , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Citocinas/sangue , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Masculino , Fagocitose/imunologia , Fagossomos/metabolismo , Plasmócitos/imunologia , Plasmócitos/metabolismo , Receptor Toll-Like 9/metabolismo
19.
Semin Nephrol ; 35(5): 455-64, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26573548

RESUMO

Nephritis is a common complication of systemic lupus erythematosus for which current therapies often prove inadequate. Current lupus nephritis classification systems emphasize glomerular acuity and scarring. However, tubulointerstitial inflammation (TII) and scarring are much better predictors of progression to renal failure. It now is becoming clear that the immunologic features, and probable underlying mechanisms, are very different in lupus glomerulonephritis and TII at the time of biopsy. Although glomerulonephritis is a manifestation of systemic autoimmunity, TII is associated with local in situ adaptive immune cell networks predicted to amplify local inflammation and tissue damage. In addition, poorly defined networks of innate immune cells and effectors likely contribute to the severity of local inflammation. Defining these in situ immune mechanisms should lead to a better understanding of prognostically meaningful lupus nephritis subsets and show novel therapeutic opportunities.


Assuntos
Autoimunidade/imunologia , Rim/imunologia , Nefrite Lúpica/imunologia , Nefrite Intersticial/imunologia , Imunidade Adaptativa/imunologia , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Humanos , Imunidade Inata/imunologia , Imunossupressores/uso terapêutico , Inflamação , Rim/patologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Nefrite Intersticial/tratamento farmacológico , Nefrite Intersticial/patologia
20.
Nat Immunol ; 16(10): 1094-103, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26301565

RESUMO

B lymphopoiesis requires that immunoglobulin genes be accessible to RAG1-RAG2 recombinase. However, the RAG proteins bind widely to open chromatin, which suggests that additional mechanisms must restrict RAG-mediated DNA cleavage. Here we show that developmental downregulation of interleukin 7 (IL-7)-receptor signaling in small pre-B cells induced expression of the bromodomain-family member BRWD1, which was recruited to a specific epigenetic landscape at Igk dictated by pre-B cell receptor (pre-BCR)-dependent Erk activation. BRWD1 enhanced RAG recruitment, increased gene accessibility and positioned nucleosomes 5' to each Jκ recombination signal sequence. BRWD1 thus targets recombination to Igk and places recombination within the context of signaling cascades that control B cell development. Our findings represent a paradigm in which, at any particular antigen-receptor locus, specialized mechanisms enforce lineage- and stage-specific recombination.


Assuntos
Histona Acetiltransferases/metabolismo , Imunoglobulinas/genética , Recombinação Genética/imunologia , Animais , Apoptose , Regulação para Baixo/imunologia , Histona Acetiltransferases/genética , Histona Acetiltransferases/imunologia , Interleucina-7/genética , Interleucina-7/imunologia , Camundongos , Transdução de Sinais/imunologia , Regulação para Cima/imunologia
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