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1.
Nat Immunol ; 21(6): 660-670, 2020 06.
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.


Assuntos
Microambiente Celular/genética , Microambiente Celular/imunologia , Centro Germinativo/citologia , Centro Germinativo/fisiologia , Animais , Biomarcadores , Biologia Computacional/métodos , Imunofluorescência , Perfilação da Expressão Gênica , Genômica/métodos , Camundongos , Fosforilação , Proteoma , Proteômica/métodos , Transcriptoma
2.
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
3.
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
4.
Arterioscler Thromb Vasc Biol ; 38(11): 2706-2717, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354229

RESUMO

Objective- Continuous T-cell production from thymus is essential in replenishing naïve T-cell pool and maintaining optimal T-cell functions. However, the underlying mechanisms regulating the T-cell development in thymus remains largely unknown. Approach and Results- We identified SR-BI (scavenger receptor class B type 1), an HDL (high-density lipoprotein) receptor, as a novel modulator in T-cell development. We found that SR-BI deficiency in mice led to reduced thymus size and decreased T-cell production, which was accompanied by narrowed peripheral naïve T-cell pool. Further investigation revealed that SR-BI deficiency impaired progenitor thymic homing, causing a dramatic reduction in the percentage of earliest thymic progenitors, but did not affect other downstream T-cell developmental steps inside the thymus. As a result of the impaired progenitor thymic homing, SR-BI-deficient mice displayed delayed thymic regeneration postirradiation. Using a variety of experimental approaches, we revealed that the impaired T-cell development in SR-BI-deficient mice was not caused by hematopoietic SR-BI deficiency or SR-BI deficiency-induced hypercholesterolemia, but mainly attributed to the SR-BI deficiency in adrenal glands, as adrenal-specific SR-BI-deficient mice exhibited similar defects in T-cell development and thymic regeneration with SR-BI-deficient mice. Conclusions- This study demonstrates that SR-BI deficiency impaired T-cell development and delayed thymic regeneration by affecting progenitor thymic homing in mice, elucidating a previously unrecognized link between SR-BI and adaptive immunity.


Assuntos
Glândulas Suprarrenais/metabolismo , Proliferação de Células , Ativação Linfocitária , Regeneração , Receptores Depuradores Classe B/metabolismo , Linfócitos T/metabolismo , Timócitos/metabolismo , Timo/metabolismo , Imunidade Adaptativa , Glândulas Suprarrenais/imunologia , Animais , Células Cultivadas , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Antígenos Comuns de Leucócito/deficiência , Antígenos Comuns de Leucócito/genética , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tamanho do Órgão , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores Depuradores Classe B/deficiência , Receptores Depuradores Classe B/genética , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Linfócitos T/imunologia , Timócitos/imunologia , Timo/imunologia
5.
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.

6.
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
7.
Crit Care Med ; 43(11): e490-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26308430

RESUMO

OBJECTIVES: Corticosteroid therapy is frequently used in septic patients given the rationale that there is an increased demand for corticosteroid in sepsis, and up to 60% of severe septic patients experience adrenal insufficiency. However, the efficacy of corticosteroid therapy and whether the therapy should be based on the results of adrenal function testing are highly controversial. The lack of an adrenal insufficiency animal model and our poor understanding of the pathogenesis caused by adrenal insufficiency present significant barriers to address this long-standing clinical issue. DESIGN: Prospective experimental study. SETTING: University laboratory. SUBJECTS: Scavenger receptor BI null and adrenal-specific scavenger receptor BI null mice. INTERVENTIONS: Sepsis was induced by cecal ligation and puncture. MEASUREMENTS AND MAIN RESULTS: Using scavenger receptor BI mice as the first relative adrenal insufficiency animal model, we found that corticosteroid therapy significantly improved the survival in cecal ligation and puncture-treated scavenger receptor BI mice but causes more septic death in wild-type mice. We identified a corticosteroid cocktail that provides effective protection 18 hours post cecal ligation and puncture; using adrenal-specific scavenger receptor BI mice as an inducible corticosteroid-deficient animal model, we found that inducible corticosteroid specifically suppresses interleukin-6 production without affecting tumor necrosis factor-α, nitric oxide, and interleukin-10 production. We further found that inducible corticosteroid does not induce peripheral lymphocyte apoptosis but promotes phagocytic activity of macrophages and neutrophils. CONCLUSIONS: This study demonstrates that corticosteroid treatment benefits mice with adrenal insufficiency but harms mice without adrenal insufficiency. This study also reveals that inducible corticosteroid has both immunosuppressive and immunopermissive properties, suppressing interleukin-6 production, promoting phagocytosis of immune effector cells, but not inducing peripheral lymphocyte apoptosis. These findings support our hypothesis that corticosteroid is an effective therapy for a subgroup of septic patients with adrenal insufficiency but harms septic patients without adrenal insufficiency and encourage further efforts to test this hypothesis in clinic.


Assuntos
Corticosteroides/uso terapêutico , Insuficiência Adrenal/tratamento farmacológico , Sepse/tratamento farmacológico , Insuficiência Adrenal/fisiopatologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout , Distribuição Aleatória , Medição de Risco , Sepse/mortalidade , Sepse/fisiopatologia , Taxa de Sobrevida , Resultado do Tratamento
8.
J Biol Chem ; 289(21): 14666-73, 2014 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-24719333

RESUMO

Recent studies revealed that scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. However, the mechanisms underlying this protection remain largely unknown. In this study, using Scarb1(I179N) mice, a mouse model specifically deficient in hepatic SR-BI, we report that hepatic SR-BI protects against cecal ligation and puncture (CLP)-induced sepsis as shown by 75% fatality in Scarb1(I179N) mice, but only 21% fatality in C57BL/6J control mice. The increase in fatality in Scarb1(I179N) mice was associated with an exacerbated inflammatory cytokine production. Further study demonstrated that hepatic SR-BI exerts its protection against sepsis through its role in promoting LPS clearance without affecting the inflammatory response in macrophages, the glucocorticoid production in adrenal glands, the leukocyte recruitment to peritoneum or the bacterial clearance in liver. Our findings reveal hepatic SR-BI as a critical protective factor in sepsis and point out that promoting hepatic SR-BI-mediated LPS clearance may provide a therapeutic approach for sepsis.


Assuntos
Lipopolissacarídeos/imunologia , Fígado/imunologia , Receptores Depuradores Classe B/imunologia , Sepse/imunologia , Glândulas Suprarrenais/imunologia , Glândulas Suprarrenais/metabolismo , Animais , Western Blotting , Ceco/cirurgia , Linhagem Celular , Citocinas/imunologia , Citocinas/metabolismo , Glucocorticoides/biossíntese , Glucocorticoides/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Leucócitos/imunologia , Leucócitos/metabolismo , Ligadura/efeitos adversos , Fígado/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Peritônio/imunologia , Peritônio/metabolismo , Mutação Puntual , Punções/efeitos adversos , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Sepse/etiologia , Sepse/microbiologia
9.
Arterioscler Thromb Vasc Biol ; 34(5): 966-75, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24603680

RESUMO

OBJECTIVE: Thymocyte apoptosis is a major event in sepsis; however, how this process is regulated remains poorly understood. APPROACH AND RESULTS: Septic stress induces glucocorticoids production which triggers thymocyte apoptosis. Here, we used scavenger receptor BI (SR-BI)-null mice, which are completely deficient in inducible glucocorticoids in sepsis, to investigate the regulation of thymocyte apoptosis in sepsis. Cecal ligation and puncture induced profound thymocyte apoptosis in SR-BI(+/+) mice, but no thymocyte apoptosis in SR-BI(-/-) mice because of lack of inducible glucocorticoids. Unexpectedly, supplementation of glucocorticoids only partly restored thymocyte apoptosis in SR-BI(-/-) mice. We demonstrated that high-density lipoprotein (HDL) is a critical modulator for thymocyte apoptosis. SR-BI(+/+) HDL significantly enhanced glucocorticoid-induced thymocyte apoptosis, but SR-BI(-/-) HDL had no such activity. Further study revealed that SR-BI(+/+) HDL modulates glucocorticoid-induced thymocyte apoptosis via promoting glucocorticoid receptor translocation, but SR-BI(-/-) HDL loses such regulatory activity. To understand why SR-BI(-/-) HDL loses its regulatory activity, we analyzed HDL cholesterol contents. There was 3-fold enrichment of unesterified cholesterol in SR-BI(-/-) HDL compared with SR-BI(+/+) HDL. Normalization of unesterified cholesterol in SR-BI(-/-) HDL by probucol administration or lecithin cholesteryl acyltransferase expression restored glucocorticoid-induced thymocyte apoptosis, and incorporating unesterified cholesterol into SR-BI(+/+) HDL rendered SR-BI(+/+) HDL dysfunctional. Using lckCre-GR(fl/fl) mice in which thymocytes lack cecal ligation and puncture-induced thymocyte apoptosis, we showed that lckCre-GR(fl/fl) mice were significantly more susceptible to cecal ligation and puncture-induced septic death than GR(fl/fl) control mice, suggesting that glucocorticoid-induced thymocyte apoptosis is required for protection against sepsis. CONCLUSIONS: The findings in this study reveal a novel regulatory mechanism of thymocyte apoptosis in sepsis by SR-BI and HDL.


Assuntos
Apoptose , HDL-Colesterol/sangue , Receptores Depuradores Classe B/metabolismo , Sepse/metabolismo , Timócitos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ceco/microbiologia , Ceco/cirurgia , Células Cultivadas , Corticosterona/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Ligadura , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Probucol/farmacologia , Transporte Proteico , Punções , Receptores de Glucocorticoides/metabolismo , Receptores Depuradores Classe B/deficiência , Receptores Depuradores Classe B/genética , Sepse/sangue , Sepse/microbiologia , Sepse/patologia , Transdução de Sinais , Timócitos/efeitos dos fármacos , Timócitos/patologia
10.
Curr Opin Endocrinol Diabetes Obes ; 21(2): 121-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24569553

RESUMO

PURPOSE OF REVIEW: To summarize the recent findings about the roles of scavenger receptor class B type I (SR-BI) in immunity and discuss the underlying mechanisms by which SR-BI prevents immune dysfunctions. RECENT FINDINGS: SR-BI is well known as a high-density lipoprotein (HDL) receptor playing key roles in HDL metabolism and in protection against atherosclerosis. Recent studies have indicated that SR-BI is also an essential modulator in immunity. SR-BI deficiency in mice causes immune dysfunctions, including increased atherosclerosis, elevated susceptibility to sepsis, impaired lymphocyte homeostasis, and autoimmune disorders. SR-BI exerts its protective roles through a variety of HDL-dependent and HDL-independent mechanisms. SR-BI is also involved in hepatitis C virus cell entry. A deficiency of SR-BI in humanized mice has been shown to decrease hepatitis C virus infectivity. SUMMARY: SR-BI regulates immunity via multiple mechanisms and its deficiency causes numerous diseases. A comprehensive understanding of the roles of SR-BI in protection against immune dysfunctions may provide a therapeutic target for intervention against its associated diseases.


Assuntos
Imunidade Adaptativa , Aterosclerose/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/prevenção & controle , Estresse Oxidativo/imunologia , Receptores Depuradores Classe B/imunologia , Sepse/imunologia , Animais , Aterosclerose/metabolismo , Doenças Autoimunes/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Humanos , Lipoproteínas HDL/imunologia , Camundongos , Camundongos Knockout , Receptores de Lipoproteínas/imunologia , Receptores Depuradores Classe B/deficiência , Sepse/metabolismo
11.
J Biol Chem ; 288(25): 17947-53, 2013 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-23658016

RESUMO

HDL has been considered to be a protective factor in sepsis; however, most contributing studies were conducted using the endotoxic animal model, and evidence from clinically relevant septic animal models remains limited and controversial. Furthermore, little is known about the roles of HDL in sepsis other than LPS neutralization. In this study, we employed cecal ligation and puncture (CLP), a clinically relevant septic animal model, and utilized apoA-I knock-out (KO) and transgenic mice to elucidate the roles of HDL in sepsis. ApoA-I-KO mice were more susceptible to CLP-induced septic death as shown by the 47.1% survival of apoA-I-KO mice versus the 76.7% survival of C57BL/6J (B6) mice (p = 0.038). ApoA-I-KO mice had exacerbated inflammatory cytokine production during sepsis compared with B6 mice. Further study indicated that serum from apoA-I-KO mice displayed less capacity for LPS neutralization compared with serum from B6 mice. In addition, apoA-I-KO mice had less LPS clearance, reduced corticosterone generation, and impaired leukocyte recruitment in sepsis. In contrast to apoA-I-KO mice, apoA-I transgenic mice were moderately resistant to CLP-induced septic death compared with B6 mice. In conclusion, our findings reveal multiple protective roles of HDL in CLP-induced sepsis. In addition to its well established role in neutralization of LPS, HDL exerts its protection against sepsis through promoting LPS clearance and modulating corticosterone production and leukocyte recruitment. Our study supports efforts to raise HDL levels as a therapeutic approach for sepsis.


Assuntos
Apolipoproteína A-I/imunologia , Infecções Bacterianas/imunologia , Lipoproteínas HDL/imunologia , Sepse/imunologia , Animais , Apolipoproteína A-I/genética , Infecções Bacterianas/complicações , Ceco/cirurgia , Corticosterona/sangue , Corticosterona/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Ligadura , Lipopolissacarídeos/sangue , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Lipoproteínas/imunologia , Lipoproteínas/metabolismo , Lipoproteínas HDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infiltração de Neutrófilos/imunologia , Peritônio/imunologia , Peritônio/metabolismo , Punções , Sepse/etiologia , Sepse/mortalidade , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
13.
Arterioscler Thromb Vasc Biol ; 31(11): 2543-51, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21836069

RESUMO

OBJECTIVE: Scavenger receptor BI (SR-BI) is a high-density lipoprotein (HDL) receptor. Recent studies revealed that SR-BI protects against sepsis via modulating innate immunity. However, its role in adaptive immunity is unclear. METHODS AND RESULTS: SR-BI-null mice exhibited impaired lymphocyte homeostasis as shown by splenomegaly and imbalanced expansion of T and B lymphocytes in the spleens. Importantly, the activated T and B lymphocytes were increased 3- to 4-fold, indicating a heightened active status of T and B lymphocytes. More importantly, in line with the accumulation of the activated T and B lymphocytes, SR-BI-null mice developed systemic autoimmune disorders characterized by the presence of autoantibodies in circulation, the deposition of immune complexes in glomeruli, and the leukocyte infiltration in kidney. Further analyses revealed that SR-BI deficiency enhanced lymphocyte proliferation, caused imbalanced interferon-γ and interleukin-4 production in lymphocytes, and caused elevated inflammatory cytokine production in macrophages. Furthermore, HDL from SR-BI-null mice exhibited less capability of suppressing lymphocyte proliferation. CONCLUSION: SR-BI regulates lymphocyte homeostasis, likely through its roles in modulating the proliferation of lymphocytes, the cytokine production by lymphocytes and macrophages, and the function of HDL. Its deficiency leads to impaired lymphocyte homeostasis and autoimmune disorders. Our findings reveal a previously unrecognized role of SR-BI in adaptive immunity.


Assuntos
Doenças Autoimunes/fisiopatologia , Linfócitos B/patologia , Homeostase/fisiologia , Receptores Depuradores Classe B/deficiência , Linfócitos T/patologia , Imunidade Adaptativa/fisiologia , Animais , Doenças Autoimunes/metabolismo , Linfócitos B/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Interferon gama/metabolismo , Interleucina-4/metabolismo , Camundongos , Camundongos Knockout , Receptores Depuradores Classe B/genética , Esplenomegalia/fisiopatologia , Linfócitos T/metabolismo
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