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1.
Proc Natl Acad Sci U S A ; 121(5): e2317762121, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38261616

RESUMO

Intravenous immunoglobulin (IVIg), a preparation of polyclonal serum IgG pooled from numerous blood donors, has been used for nearly three decades and is proving to be an efficient treatment for many autoimmune blistering diseases, including pemphigus vulgaris (PV). Despite its widespread use and therapeutic success, its mechanisms of action are not completely understood. Some of its anti-inflammatory and immunomodulatory actions have been studied. In this study, the authors present a twenty-year follow-up of 21 patients with clinical and immunopathological confirmed PV, treated with IVIg as monotherapy, according to an established published protocol. IVIg therapy produced long-term sustained, clinical, serological, and immunopathological remission. For 20 y, these patients received no drugs and experienced no disease. This observation suggests that there was the establishment of immune balance or restoration of immune regulation in these PV patients. Twelve (57%) patients experienced no relapse during follow-up. Six (29%) patients experienced a relapse due to acute stress or post-coronavirus infection and/or vaccination. Reinstitution of IVIg resulted in prompt sustained recovery. Three (14.2%) patients, in clinical and serological remission, died due to unrelated causes. No severe adverse effects from IVIg were documented in all 21 patients. The simultaneous or sequential anti-inflammatory and immunomodulatory effects of IVIg may have influenced the long-term clinical remission observed. This study provides a human prototype to examine the pathophysiology of autoimmunity and a model to study immune regulation and mechanisms that can facilitate restoring immune tolerance.


Assuntos
Doenças Autoimunes , Pênfigo , Humanos , Imunoglobulinas Intravenosas , Tolerância Imunológica , Anti-Inflamatórios
2.
Eur J Immunol ; 49(1): 195-198, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30267564

RESUMO

Intravenous immunoglobuin (IVIG) exerts protective effects in experimental allergic bronchopulmonary aspergillosis (ABPA) via a sialylation-dependent mechanism. The protection was associated with reduced recruitment of eosinophils, diminished goblet cell hyperplasia, suppressed Th2 and Th17 responses and reciprocally enhanced regulatory T cells and IL-10, and decreased IgE levels in the circulation.


Assuntos
Aspergilose Broncopulmonar Alérgica/terapia , Eosinófilos/imunologia , Células Caliciformes/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Células Cultivadas , Humanos , Imunoglobulina E/sangue , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ácido N-Acetilneuramínico/metabolismo
3.
Trends Immunol ; 38(11): 789-792, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28916232

RESUMO

Intravenous immunoglobulin (IVIG), a pooled normal IgG formulation prepared from thousands of healthy donors' plasma, is extensively used for the immunotherapy of autoimmune and inflammatory disorders. Recent reports demonstrate that IVIG exerts anti-inflammatory actions by stimulating the activation and expansion of regulatory T (Treg) cells by multiple mechanisms via antigen-presenting cells (APCs).


Assuntos
Células Dendríticas/metabolismo , Imunoglobulina G/imunologia , Imunoglobulinas Intravenosas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Circulação Sanguínea , Humanos , Imunização , Imunoglobulinas Intravenosas/uso terapêutico , Ativação Linfocitária , Camundongos
4.
J Immunol ; 200(6): 1957-1963, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29507120

RESUMO

The immunoregulatory and anti-infective properties of normal circulating polyclonal Abs have been exploited for the therapeutic purposes in the form of IVIG as well as several hyperimmune globulins. Current knowledge on the therapeutic use of normal Igs is based on the discoveries made by several pioneers of the field. In this paper, we review the evolution of IVIG over the years. More importantly, the process started as an s.c. replacement in γ globulin-deficient patients, underwent metamorphosis into i.m. Ig, was followed by IVIG, and is now back to s.c. forms. Following successful use of IVIG in immune thrombocytopenic purpura, there has been an explosion in the therapeutic applications of IVIG in diverse autoimmune and inflammatory conditions. In addition to clinically approved pathological conditions, IVIG has been used as an off-label drug in more than 100 different indications. The current worldwide consumption of IVIG is over 100 tons per year.


Assuntos
Anticorpos/imunologia , Imunoglobulinas Intravenosas/imunologia , Imunomodulação/imunologia , Animais , Diabetes Mellitus Tipo 1/imunologia , Humanos , Imunização Passiva/métodos , Inflamação/imunologia
5.
J Allergy Clin Immunol ; 144(2): 524-535.e8, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30529242

RESUMO

BACKGROUND: Therapeutic normal IgG or intravenous immunoglobulin (IVIG) exerts anti-inflammatory effects through several mutually nonexclusive mechanisms. Recent data in mouse models of autoimmune disease suggest that IVIG induces IL-4 in basophils by enhancing IL-33 in SIGN-related 1-positive innate cells. However, translational insight on these data is lacking. OBJECTIVE: We sought to investigate the effect of IVIG on human basophil functions. METHODS: Isolated circulating basophils from healthy donors were cultured in the presence of IL-3, IL-33, GM-CSF, thymic stromal lymphopoietin, or IL-25. The effect of IVIG and F(ab')2 and Fc IVIG fragments was examined based on expression of various surface molecules, phosphorylation of spleen tyrosine kinase, induction of cytokines, and histamine release. Basophil phenotypes were also analyzed from IVIG-treated patients with myopathy. Approaches, such as depletion of anti-IgE reactivity from IVIG, blocking antibodies, or inhibitors, were used to investigate the mechanisms. RESULTS: We report that IVIG directly induces activation of IL-3-primed human basophils, but IL-33 and other cytokines were dispensable for this effect. Activation of basophils by IVIG led to enhanced expression of CD69 and secretion of IL-4, IL-6, and IL-8. IVIG-treated patients with myopathy displayed enhanced expression of CD69 on basophils. The spleen tyrosine kinase pathway is implicated in these functions of IVIG and were mediated by F(ab')2 fragments. Mechanistically, IVIG induced IL-4 in human basophils by interacting with basophil surface-bound IgE but independent of FcγRII, type II Fc receptors, C-type lectin receptors, and sialic acid-binding immunoglobulin-like lectins. CONCLUSION: These results uncovered a pathway of promoting the TH2 response by IVIG through direct interaction of IgG with human basophils.


Assuntos
Anti-Inflamatórios/farmacologia , Basófilos/imunologia , Fragmentos Fc das Imunoglobulinas/farmacologia , Imunoglobulinas Intravenosas/farmacologia , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Basófilos/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Liberação de Histamina , Humanos , Imunoglobulina E/metabolismo , Interleucina-3/metabolismo , Lectinas Tipo C/metabolismo , Camundongos , Quinase Syk/metabolismo , Regulação para Cima
6.
Int J Mol Sci ; 21(2)2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31941161

RESUMO

Basophils are rare granulocytes and dysregulated functions of these cells are associated with several atopic and non-atopic allergic diseases of skin, respiratory system and gastrointestinal tract. Both cytokines and immunoglobulin E (IgE) are implicated in mediating the basophil activation and pathogenesis of these disorders. Several reports have shown that healthy individuals, and patients with allergic disorders display IgG autoantibodies to IgE and hence functional characterization of these anti-IgE IgG autoantibodies is critical. In general, anti-IgE IgG autoantibodies modulate basophil activation irrespective of allergen specificity by interacting with constant domains of IgE. Therefore, an ideal solution to prove the functions of such anti-IgE IgG autoantibodies would be to completely eliminate type I high affinity immunoglobulin E receptor (FcɛRI)-bound IgE from the surface of basophils and to demonstrate in an unequivocal manner the role of anti-IgE IgG autoantibodies. In line with previous reports, our data show that FcɛRI on peripheral blood basophils are almost saturated with IgE. Further, acetic acid buffer (pH 4) efficiently removes these FcɛRI-bound IgE. Although immediately following acetic acid-elution of IgE had no repercussion on the viability of basophils, following 24 hours culture with interleukin-3 (IL-3), the viability and yield of basophils were drastically reduced in acid-treated cells and had repercussion on the induction of activation markers. Lactic acid treatment on the other hand though had no adverse effects on the viability of basophils and IL-3-induced activation, it removed only a small fraction of the cell surface bound IgE. Thus, our results show that acid buffers could be used for the elution of FcɛRI-bound IgE on the basophil surface for the biochemical characterization of IgE antibodies or for the immediate use of basophils to determine their sensitivity to undergo degranulation by specific allergens. However, these methods are not utile for the functional assays of basophils that require longer duration of culture and entire removal of surface IgE to validate the role of anti-IgE IgG autoantibodies that interact with FcɛRI-bound IgE irrespective of allergen specificity.


Assuntos
Ácido Acético , Basófilos , Bioensaio , Imunoglobulina E , Receptores de IgE/imunologia , Ácido Acético/química , Ácido Acético/farmacologia , Basófilos/química , Basófilos/imunologia , Técnicas de Cultura de Células , Humanos , Imunoglobulina E/química , Imunoglobulina E/imunologia
7.
Int J Mol Sci ; 20(6)2019 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-30909599

RESUMO

Intravenous immunoglobulin (IVIg) therapy has diverse anti-inflammatory and immunomodulatory effects and has been employed successfully in autoimmune and inflammatory diseases. The role of IVIg therapy in the modulation of intestinal inflammation and fungal elimination has not been yet investigated. We studied IVIg therapy in a murine model of dextran sulfate sodium (DSS)-induced colitis. Mice received a single oral inoculum of Candida albicans and were exposed to DSS treatment for 2 weeks to induce colitis. All mice received daily IVIg therapy starting on day 1 for 7 days. IVIg therapy not only prevented a loss of body weight caused by the development of colitis but also reduced the severity of intestinal inflammation, as determined by clinical and histological scores. IVIg treatment significantly reduced the Escherichia coli, Enterococcus faecalis, and C. albicans populations in mice. The beneficial effects of IVIg were associated with the suppression of inflammatory cytokine interleukin (IL)-6 and enhancement of IL-10 in the gut. IVIg therapy also led to an increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), while toll-like receptor 4 (TLR-4) expression was reduced. IVIg treatment reduces intestinal inflammation in mice and eliminates C. albicans overgrowth from the gut in association with down-regulation of pro-inflammatory mediators combined with up-regulation of anti-inflammatory cytokines.


Assuntos
Candida albicans/imunologia , Colite/tratamento farmacológico , Colite/etiologia , Homeostase/efeitos dos fármacos , Homeostase/imunologia , Imunoglobulinas Intravenosas/administração & dosagem , Intestinos/imunologia , Intestinos/microbiologia , Animais , Carga Bacteriana , Colite/diagnóstico , Colite/mortalidade , Contagem de Colônia Microbiana , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Imuno-Histoquímica , Mediadores da Inflamação , Camundongos , Índice de Gravidade de Doença , Resultado do Tratamento
9.
Int Immunol ; 29(11): 491-498, 2017 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-28666326

RESUMO

Intravenous immunoglobulin (IVIG) is a pooled preparation of normal IgG obtained from several thousand healthy donors. It is widely used in the immunotherapy of a large number of autoimmune and inflammatory diseases. The mechanisms of action of IVIG are complex and, as discussed in this review, experimental and clinical data provide an indicator that the therapeutic benefit of IVIG therapy is due to several mutually non-exclusive mechanisms affecting soluble mediators as well as cellular components of the immune system. These mechanisms depend on Fc and/or F(ab')2 fragments. A better understanding of the effector functions of IVIG should help in identification of biomarkers of responses to IVIG in autoimmune patients.


Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Imunoglobulinas Intravenosas/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Inflamação/imunologia , Inflamação/terapia , Humanos
10.
J Immunol ; 196(10): 4075-81, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27067006

RESUMO

Renal transplant is the treatment of choice for patients with terminal end-stage renal disease. We have previously identified low levels of catalytic IgG as a potential prognosis marker for chronic allograft rejection. The origin and physiopathological relevance of catalytic Abs is not well understood, owing to the fact that catalytic Abs have been studied in relatively small cohorts of patients with rare diseases and/or without systematic follow-up. In the current study, we have followed the evolution of the levels of catalytic IgG in a large cohort of renal transplant patients over a 2-y period. Our results demonstrate that, prior to transplant, patients with renal failure present with heterogeneous levels of IgG hydrolyzing the generic proline-phenylalanine-arginine-methylcoumarinamide (PFR-MCA) substrate. PFR-MCA hydrolysis was greater for patients' IgG than for a therapeutic preparation of pooled IgG from healthy donors. Renal transplant was marked by a drastic decrease in levels of catalytic IgG over 3 mo followed by a steady increase during the next 21 mo. Patients who displayed high levels of catalytic IgG pretransplant recovered high levels of catalytic Abs 2 y posttransplant. Interestingly, IgG-mediated hydrolysis of a model protein substrate, procoagulant factor VIII, did not correlate with that of PFR-MCA prior transplantation, whereas it did 12 mo posttransplant. Taken together, our results suggest that the level of circulating catalytic IgG under pathological conditions is an intrinsic property of each individual's immune system and that recovery of pretransplant levels of catalytic IgG is accompanied by changes in the repertoire of target Ags.


Assuntos
Biomarcadores/metabolismo , Rejeição de Enxerto/imunologia , Sistema Imunitário , Imunoglobulina G/metabolismo , Transplante de Rim , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Catalíticos , Autoanticorpos/metabolismo , Coagulação Sanguínea , Doença Crônica , Fator VIII/metabolismo , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Transplantados , Adulto Jovem
11.
J Infect Dis ; 216(10): 1281-1294, 2017 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-28968869

RESUMO

Background: Human dendritic cell (DC) response to α-(1,3)-glucan polysaccharide of Aspergillus fumigatus and ensuing CD4+ T-cell polarization are poorly characterized. Methods: α-(1,3)-Glucan was isolated from A. fumigatus conidia and mycelia cell wall. For the analysis of polarization, DCs and autologous naive CD4+ T cells were cocultured. Phenotype of immune cells was analyzed by flow cytometry, and cytokines by enzyme-linked immunosorbent assay (ELISA). Blocking antibodies were used to dissect the role of Toll-like receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) in regulating α-(1,3)-glucan-mediated DC activation and T-cell responses. DCs from TLR2-deficient mice were additionally used to consolidate the findings. Results: α-(1,3)-Glucan induced the maturation of DCs and was dependent in part on TLR2. "α-(1,3)-Glucan-educated" DCs stimulated the activation of naive T cells and polarized a subset of these cells into CD4+CD25+FoxP3+ regulatory T cells (Tregs). Mechanistically, Treg stimulation by α-(1,3)-glucan was dependent on the PD-L1 pathway that negatively regulated interferon-gamma (IFN-γ) secretion. Short α-(1,3)-oligosaccharides lacked the capacity to induce maturation of DCs but significantly blocked α-(1,3)-glucan-induced Treg polarization. Conclusions: PD-L1 dictates the balance between Treg and IFN-γ responses induced by α-(1,3)-glucan. Our data provide a rationale for the exploitation of immunotherapeutic approaches that target PD-1-PD-L1 to enhance protective immune responses to A. fumigatus infections.


Assuntos
Aspergillus fumigatus/imunologia , Antígeno B7-H1/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Expressão Gênica , Glucanos/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/imunologia , Animais , Biomarcadores , Citocinas/metabolismo , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Knockout , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo
12.
J Neuroinflammation ; 14(1): 58, 2017 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-28320438

RESUMO

BACKGROUND: Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (Treg) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking. METHODS: Ten newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4-5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA. RESULTS: The fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with Treg cell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and Treg cell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. Treg cell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α. CONCLUSION: Treg cell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. Treg cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.


Assuntos
Síndrome de Guillain-Barré , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interleucina-33/sangue , Linfócitos T Reguladores/patologia , Idoso , Idoso de 80 Anos ou mais , Dinoprostona/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Seguimentos , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Estatísticas não Paramétricas
13.
Molecules ; 21(7)2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27428940

RESUMO

Extracts of Viscum album (VA); a semi-parasitic plant, are frequently used in the complementary therapy of cancer and other immunological disorders. Various reports show that VA modulates immune system and exerts immune-adjuvant activities that might influence tumor regression. Currently, several therapeutic preparations of VA are available and hence an insight into the mechanisms of action of different VA preparations is necessary. In the present study, we performed a comparative study of five different preparations of VA on maturation and activation of human dendritic cells (DCs) and ensuing CD4⁺ T cell responses. Monocyte-derived human DCs were treated with VA Qu Spez, VA Qu Frf, VA M Spez, VA P and VA A. Among the five VA preparations tested VA Qu Spez, a fermented extract with a high level of lectins, significantly induced DC maturation markers CD83, CD40, HLA-DR and CD86, and secretion of pro-inflammatory cytokines such as IL-6, IL-8, IL-12 and TNF-α. Furthermore, analysis of T cell cytokines in DC-T cell co-culture revealed that VA Qu Spez significantly stimulated IFN-γ secretion without modulating regulatory T cells and other CD4⁺ T cytokines IL-4, IL-13 and IL-17A. Our study thus delineates differential effects of VA preparations on DC maturation; function and T cell responses.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Ativação Linfocitária/efeitos dos fármacos , Extratos Vegetais/farmacologia , Viscum album/química , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Citocinas/biossíntese , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Humanos , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo
15.
Eur J Immunol ; 44(7): 2059-63, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24700174

RESUMO

Several mechanisms account for the beneficial effect of intravenous immunoglobulin (IVIg) in autoimmune and inflammatory diseases. These mechanisms include effects on the cellular compartment and on the humoral compartment. Thus, IVIg impacts on dendritic cells, macrophages, neutrophils, basophils, NK cells, and B and T lymphocytes. Several studies have emphasized that the antiinflammatory effect of IVIg is dependent on α2,6-sialylation of the N-linked glycan on asparagine-297 of the Fc portion of IgG. However, recent reports have questioned the necessity of sialylated Fc and the role of FcγRIIB in IVIg-mediated antiinflammatory effects. In view of the critical role played by Th17 cells in several autoimmune pathologies and the increasing use of IVIg in several of these conditions, by using neuraminidase-treated, desialylated IVIg, we addressed whether the α2,6-sialylation of IgG is essential for the beneficial effect of IVIg in experimental autoimmune encephalomyelitis (EAE), a Th17-driven condition, and for the reciprocal modulation of helper T-cell subsets. We observed no difference in the ability of IVIg to ameliorate EAE irrespective of its sialylation. Our findings thus show that sialylation of IVIg is not necessary for IVIg-mediated amelioration of EAE or for downregulation of Th17 cells and upregulation of regulatory T cells.


Assuntos
Imunoglobulinas Intravenosas/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/etiologia , Feminino , Fragmentos Fc das Imunoglobulinas/metabolismo , Imunoglobulinas Intravenosas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Ácido N-Acetilneuramínico/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/fisiologia
16.
Eur J Immunol ; 44(5): 1363-74, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24643627

RESUMO

The mechanisms underlying Japanese encephalitis virus (JEV) pathogenesis need to be thoroughly explored to delineate therapeutic approaches. It is believed that JEV manipulates the innate and adaptive compartments of the host's immune system to evade immune response and cross the blood-brain barrier. The present study was thus designed to investigate the functional modulation of DCs after exposure to JEV and to assess the consequences on CD4(+) T-lymphocyte functions. Human monocyte-derived DCs were either infected with 1 MOI of live virus, UV-inactivated virus, or were mock-infected. Replication-competent JEV induced a significant increase in the expression of maturation markers 48 h postinfection, along with that of programmed cell death 1 ligand 1 (PD-L1; also called B7-H1 and CD274). JEV-infected DCs expanded the Treg cells in allogenic mixed lymphocyte reactions. The expansion of Treg cells by JEV-infected DCs was significantly reduced upon blocking PD-L1 using an antagonist. In addition, JEV-infected DCs significantly altered the proliferation and reduced the polarization of Th cells toward the Th1-cell phenotype. The results, for the first time, suggest that JEV evades the host's immune system by modulating the crosstalk between DCs and T lymphocytes via the PD-L1 axis.


Assuntos
Antígeno B7-H1/imunologia , Células Dendríticas/imunologia , Vírus da Encefalite Japonesa (Espécie)/imunologia , Encefalite Japonesa/imunologia , Regulação da Expressão Gênica/imunologia , Evasão da Resposta Imune/imunologia , Linfócitos T Reguladores/imunologia , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Antígeno B7-H1/biossíntese , Antígeno B7-H1/genética , Proliferação de Células , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Células Dendríticas/virologia , Vírus da Encefalite Japonesa (Espécie)/genética , Vírus da Encefalite Japonesa (Espécie)/metabolismo , Encefalite Japonesa/genética , Encefalite Japonesa/metabolismo , Encefalite Japonesa/patologia , Feminino , Regulação da Expressão Gênica/genética , Humanos , Evasão da Resposta Imune/genética , Masculino , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Monócitos/virologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
17.
Blood ; 122(8): 1419-27, 2013 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-23847198

RESUMO

CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) play a critical role in the maintenance of immune tolerance. Intravenous immunoglobulin (IVIg), a therapeutic preparation of normal pooled human IgG, expands Tregs in various experimental models and in patients. However, the cellular and molecular mechanisms by which IVIg expands Tregs are relatively unknown. As Treg expansion in the periphery requires signaling by antigen-presenting cells such as dendritic cells (DCs) and IVIg has been demonstrated to modulate DC functions, we hypothesized that IVIg induces distinct signaling events in DCs that subsequently mediate Treg expansion. We demonstrate that IVIg expands Tregs via induction of cyclooxygenase (COX)-2-dependent prostaglandin E2 (PGE2) in human DCs. However, costimulatory molecules of DCs such as programmed death ligands, OX40 ligand, and inducible T-cell costimulator ligands were not implicated. Inhibition of PGE2 synthesis by COX-2 inhibitors prevented IVIg-mediated Treg expansion in vitro and significantly diminished IVIg-mediated Treg expansion in vivo and protection from disease in experimental autoimmune encephalomyelitis model. IVIg-mediated COX-2 expression, PGE2 production, and Treg expansion were mediated in part via interaction of IVIg and F(ab')2 fragments of IVIg with DC-specific intercellular adhesion molecule-3-grabbing nonintegrin. Our results thus uncover novel cellular and molecular mechanism by which IVIg expands Tregs.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Células Dendríticas/citologia , Dinoprostona/metabolismo , Imunoglobulinas Intravenosas/uso terapêutico , Linfócitos T Reguladores/citologia , Animais , Moléculas de Adesão Celular/metabolismo , Técnicas de Cocultura , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Lectinas Tipo C/metabolismo , Leucócitos Mononucleares/citologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Superfície Celular/metabolismo
18.
J Immunol ; 190(9): 4535-41, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23526819

RESUMO

Despite an increasing use of high-dose therapy of i.v. gammaglobulin (IVIg) in the treatment of various T cell- and Ab-mediated inflammatory and autoimmune diseases, comprehension of the mechanisms underlying its therapeutic benefit has remained a major challenge. Particularly, the effect of IVIg in T cell-mediated autoimmune conditions remains unexplored. Using an actively induced experimental autoimmune encephalomyelitis model, a T cell-mediated autoimmune condition, we demonstrate that IVIg inhibits the differentiation of naive CD4 T cells into encephalitogenic subsets (Th1 and Th17 cells) and concomitantly induces an expansion of Foxp3(+) regulatory T cells. Further, IVIg renders effector T cells less pathogenic by decreasing the expression of encephalitogenic molecular players like GM-CSF and podoplanin. Intriguingly and contrary to the current arguments, the inhibitory FcγRIIB is dispensable for IVIg-mediated reciprocal modulation of effector and regulatory CD4 subsets. Additionally, F(ab')2 fragments also retained this function of IVIg. IVIg or F(ab')2 fragments decrease the sphingosine-1 phosphate receptor on CD4 cells, thus sequestering these cells in the draining lymph nodes and decreasing their infiltration into the CNS. Our study reveals a novel role of Igs in the modulation of polarization and trafficking of T lymphocytes, accounting for the observed beneficial effect in IVIg therapy.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Encefalite/imunologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Imunoglobulinas Intravenosas/farmacologia , Receptores de Lisoesfingolipídeo/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Administração Intravenosa/métodos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Encefalite/tratamento farmacológico , Encefalite/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Imunoglobulinas Intravenosas/imunologia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Receptores de Lisoesfingolipídeo/imunologia , Receptores de Esfingosina-1-Fosfato , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Serina-Treonina Quinases TOR/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
19.
J Immunol ; 191(2): 623-31, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23776176

RESUMO

Most vaccines, including those against influenza, were developed by focusing solely on humoral response for protection. However, vaccination activates different adaptive compartments that might play a role in protection. We took advantage of the pandemic 2009 A(H1N1) influenza vaccination to conduct a longitudinal integrative multiparametric analysis of seven immune parameters in vaccinated subjects. A global analysis underlined the predominance of induction of humoral and CD4 T cell responses, whereas pandemic 2009 A(H1N1)-specific CD8 responses did not improve after vaccination. A principal component analysis and hierarchical clustering of individuals showed a differential upregulation of influenza vaccine-specific immunity including hemagglutination inhibition titers, IgA(+) and IgG(+) Ab-secreting cells, effector CD4 or CD8 T cell frequencies at day 21 among individuals, suggesting a fine-tuning of the immune parameters after vaccination. This is related to individual factors including the magnitude and quality of influenza-specific immune responses before vaccination. We propose a graphical delineation of immune determinants that would be essential for a better understanding of vaccine-induced immunity in vaccination strategies.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Anticorpos Antivirais/imunologia , Testes de Inibição da Hemaglutinação , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Análise de Componente Principal , Vacinação , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia
20.
Nature ; 460(7259): 1117-21, 2009 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-19713928

RESUMO

The air we breathe is filled with thousands of fungal spores (conidia) per cubic metre, which in certain composting environments can easily exceed 10(9) per cubic metre. They originate from more than a hundred fungal species belonging mainly to the genera Cladosporium, Penicillium, Alternaria and Aspergillus. Although these conidia contain many antigens and allergens, it is not known why airborne fungal microflora do not activate the host innate immune cells continuously and do not induce detrimental inflammatory responses following their inhalation. Here we show that the surface layer on the dormant conidia masks their recognition by the immune system and hence prevents immune response. To explore this, we used several fungal members of the airborne microflora, including the human opportunistic fungal pathogen Aspergillus fumigatus, in in vitro assays with dendritic cells and alveolar macrophages and in in vivo murine experiments. In A. fumigatus, this surface 'rodlet layer' is composed of hydrophobic RodA protein covalently bound to the conidial cell wall through glycosylphosphatidylinositol-remnants. RodA extracted from conidia of A. fumigatus was immunologically inert and did not induce dendritic cell or alveolar macrophage maturation and activation, and failed to activate helper T-cell immune responses in vivo. The removal of this surface 'rodlet/hydrophobin layer' either chemically (using hydrofluoric acid), genetically (DeltarodA mutant) or biologically (germination) resulted in conidial morphotypes inducing immune activation. All these observations show that the hydrophobic rodlet layer on the conidial cell surface immunologically silences airborne moulds.


Assuntos
Antígenos de Fungos/imunologia , Esporos Fúngicos/imunologia , Transferência Adotiva , Microbiologia do Ar , Alérgenos , Animais , Antígenos de Fungos/química , Antígenos de Fungos/genética , Antígenos de Plantas , Aspergillus fumigatus/química , Aspergillus fumigatus/imunologia , Aspergillus fumigatus/fisiologia , Linfócitos T CD4-Positivos/imunologia , Catepsinas , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Proteínas Fúngicas , Humanos , Ácido Fluorídrico/química , Sistema Imunitário/imunologia , Ativação Linfocitária , Macrófagos Alveolares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Esporos Fúngicos/química , Esporos Fúngicos/genética
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