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1.
Nat Commun ; 12(1): 1032, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589587

RESUMO

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPß1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (ß = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.


Assuntos
Autoanticorpos/genética , Doenças Autoimunes/genética , Predisposição Genética para Doença , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Cadeias HLA-DRB1/genética , Proteinose Alveolar Pulmonar/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático , Autoanticorpos/biossíntese , Doenças Autoimunes/etnologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Estudos de Casos e Controles , Cromossomos Humanos Par 6 , Feminino , Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Cadeias HLA-DRB1/imunologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Razão de Chances , Isoformas de Proteínas/genética , Proteinose Alveolar Pulmonar/etnologia , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/patologia , Surfactantes Pulmonares/imunologia , Surfactantes Pulmonares/metabolismo , Risco
2.
Clin Appl Thromb Hemost ; 27: 1076029620977702, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33539214

RESUMO

The SARS-CoV-2 pandemic has focused attention on prevention, restriction and treatment methods that are acceptable worldwide. This means that they should be simple and inexpensive. This review examines the possible role of glycosaminoglycan (GAG) antithrombotics in the treatment of COVID-19. The pathophysiology of this disease reveals a complex interplay between the hemostatic and immune systems that can be readily disrupted by SARS-CoV-2. Some of the GAG antithrombotics also possess immune-modulatory actions and since they are relatively inexpensive they could play an important role in the management of COVID-19 and its complications.


Assuntos
/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Autoanticorpos/biossíntese , /fisiopatologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Endotélio Vascular/virologia , Feminino , Glicosaminoglicanos/uso terapêutico , Hemorragia/etiologia , Transtornos Hemostáticos/tratamento farmacológico , Transtornos Hemostáticos/etiologia , Transtornos Hemostáticos/fisiopatologia , Humanos , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/fisiopatologia , Masculino , Pandemias , Fatores de Risco , Trombina/biossíntese , Trombose/etiologia
3.
Eur J Immunol ; 50(1): 73-85, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31621069

RESUMO

Antibody production by the B cell compartment is a crucial part of the adaptive immune response. Dysregulated antibody production in the form of autoantibodies can cause autoimmune disease. To date, B-cell depletion with anti-CD20 antibodies is commonly applied in autoimmunity, but pre-existing plasma cells are not eliminated in this way. Alternative ways of more selective inhibition of antibody production would add to the treatment of these autoimmune diseases. To explore novel therapeutic targets in signaling pathways essential for plasmablast formation and/or immunoglobulin production, we performed a compound screen of almost 200 protein kinase inhibitors in a robust B-cell differentiation culture system. This study yielded 35 small cell-permeable compounds with a reproducible inhibitory effect on B-cell activation and plasmablast formation, among which was the clinically applied mammalian target of rapamycin (mTOR) inhibitor rapamycin. Two additional compounds targeting the phosphoinositide 3-kinase-AKT-mTOR pathway (BKM120 and WYE-354) did not affect proliferation and plasmablast formation, but specifically reduced the immunoglobulin production. With this compound screen we successfully applied a method to investigate therapeutic targets for B-cell differentiation and identified compounds in the phosphoinositide 3-kinase-AKT-mTOR pathway that could specifically inhibit immunoglobulin production only. These drugs may well be explored to be of value in current B-cell-depleting treatment regimens in autoimmune disorders.


Assuntos
Autoanticorpos/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Plasmócitos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Aminopiridinas/farmacologia , Formação de Anticorpos/efeitos dos fármacos , Autoanticorpos/biossíntese , Doenças Autoimunes/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Diferenciação Celular/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Morfolinas/farmacologia , Plasmócitos/imunologia , Purinas/farmacologia , Sirolimo/farmacologia
4.
Ann N Y Acad Sci ; 1461(1): 73-103, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31025378

RESUMO

Type 1 diabetes (T1D) affects over a million Americans, and disease incidence is on the rise. Despite decades of research, there is still no cure for this disease. Exciting beta cell replacement strategies are being developed, but in order for such approaches to work, targeted immunotherapies must be designed. To selectively halt the autoimmune response, researchers must first understand how this response is regulated and which tolerance checkpoints fail during T1D development. Herein, we discuss the current understanding of T1D pathogenesis in humans, genetic and environmental risk factors, presumed roles of CD4+ and CD8+ T cells as well as B cells, and implicated autoantigens. We also highlight studies in non-obese diabetic mice that have demonstrated the requirement for CD4+ and CD8+ T cells and B cells in driving T1D pathology. We present an overview of central and peripheral tolerance mechanisms and comment on existing controversies in the field regarding central tolerance. Finally, we discuss T cell- and B cell-intrinsic tolerance mechanisms, with an emphasis on the roles of inhibitory receptors in maintaining islet tolerance in humans and in diabetes-prone mice, and strategies employed to date to harness inhibitory receptor signaling to prevent or reverse T1D.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Tolerância Imunológica , Receptores de Superfície Celular/metabolismo , Animais , Autoanticorpos/biossíntese , Diabetes Mellitus Tipo 1/genética , Modelos Animais de Doenças , Humanos , Fatores de Risco
5.
Front Immunol ; 10: 2619, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787984

RESUMO

Previous infection with Epstein-Barr virus (EBV) is believed to trigger autoimmunity and to drive autoantibody generation as occurring in patients with systemic lupus erythematosus (SLE). Complement C1q and autoantibodies targeting it (anti-C1q) are also considered to be involved in the pathogenesis of SLE, independently of the impact of environmental insults. Still, the circumstances under which these autoantibodies arise remain elusive. By studying a major antigenic site of C1q targeted by anti-C1q (A08), we aimed to determine environmental factors and possible mechanisms leading to the development of anti-C1q. First, we determined antigenic residues of A08 that were critical for the binding of anti-C1q; importantly, we found the binding to depend on amino-acid-identity. Anti-C1q of SLE patients targeting these critical antigenic residues specifically cross-reacted with the EBV-related EBNA-1 (Epstein-Barr virus nuclear antigen 1)-derived peptide EBNA348. In a cohort of 180 SLE patients we confirmed that patients that were seropositive for EBV and recognized the EBNA348 peptide had increased levels of anti-A08 and anti-C1q, respectively. The correlation of anti-EBNA348 with anti-A08 levels was stronger in SLE patients than in matched healthy controls. Finally, EBNA348 peptide-immunization of C1q-/- mice induced the generation of cross-reactive antibodies which recognized both the A08 epitope of C1q and intact C1q. These findings suggest that anti-C1q in SLE patients could be induced by an EBV-derived epitope through molecular mimicry, thereby further supporting the pathogenic role of EBV in the development of SLE. Considering the role of C1q and anti-C1q, modifying the anti-EBV response might be a promising strategy to improve the course of the disease.


Assuntos
Autoanticorpos/biossíntese , Complemento C1q/imunologia , Herpesvirus Humano 4/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Complemento C1q/fisiologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Adulto Jovem
6.
Immunohorizons ; 3(7): 306-316, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31356160

RESUMO

Autoantibodies can result from excessive T follicular helper (Tfh) cell activity, whereas T follicular regulatory (Tfr) cells negatively regulate autoantibody production. IL-2 knockout (KO) mice on the BALB/c background have elevated Tfh responses, produce autoantibodies, and develop lethal autoimmunity. We analyzed Tfh and Tfr cells in IL-2 KO mice on the C57BL/6 (B6) genetic background. In B6 IL-2 KO mice, the spontaneous formation of Tfh cells and germinal center B cells was greatly enhanced, along with production of anti-DNA autoantibodies. IL-2 has been reported to repress Tfr cell differentiation; however, Tfr cells were not increased over wild-type levels in the B6 IL-2 KO mice. To assess Tfh and Tfr cell regulation of autoantibody production in IL-2 KO mice, we generated IL-2 KO mice with a T cell-specific deletion of the master Tfh cell transcription factor Bcl6. In IL-2 KO Bcl6 conditional KO (2KO-Bcl6TC) mice, Tfh cells, Tfr cells, and germinal center B cells were ablated. In contrast to expectations, autoantibody IgG titers in 2KO-Bcl6TC mice were significantly elevated over autoantibody IgG titers in IL-2 KO mice. Specific deletion of Tfr cells with Foxp3-cre Bcl6-flox alleles in IL-2 KO mice led to early lethality, before high levels of autoantibodies could develop. We found IL-2+/+ Tfr cell-deficient mice produce significant levels of autoantibodies. Our overall findings provide evidence that Tfh cells are dispensable for high-level production of autoantibodies and also reveal a complex interplay between Tfh and Tfr cells in autoantibody production and autoimmune disease.


Assuntos
Autoanticorpos/biossíntese , Autoimunidade/imunologia , Técnicas de Inativação de Genes , Interleucina-2/genética , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo
7.
Immunohorizons ; 3(7): 331-340, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31356162

RESUMO

Ets1 is emerging as a key transcription factor that is required to prevent autoimmunity in mice and humans. Ets1 is expressed in both B and T cells, and mice lacking Ets1 are characterized by excess B and T cell activation, leading to enhanced formation of Ab-secreting cells and high titers of autoantibodies. In humans, genome-wide association studies have detected associations of single nucleotide polymorphisms in the human ETS1 gene with autoimmune diseases, including lupus. An increased fraction of CD4+ T cells from Ets1-/- mice have an activated effector-memory phenotype, and there are aberrations in differentiation that contribute to the autoimmune phenotype. In vitro studies of B cells suggest that Ets1 may have B cell-intrinsic effects as well. To confirm B cell-intrinsic roles for Ets1, we crossed CD19-Cre mice to mice with a floxed allele of Ets1. Mice with a B cell-specific deletion of Ets1 show increases in B cell activation, numbers of Ab-secreting cells, and levels of autoantibodies, despite the fact that T cells are normal. However, when compared with conventional Ets1 knockout mice, mice with B cell-specific loss of Ets1 have a significantly milder phenotype. These results demonstrate that Ets1 is required in B cells to prevent autoimmune responses but that loss of Ets1 activity in other cell types is required for maximal autoimmune phenotypes.


Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Ativação Linfocitária , Proteína Proto-Oncogênica c-ets-1/metabolismo , Alelos , Animais , Complexo Antígeno-Anticorpo/metabolismo , Autoanticorpos/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/genética , Técnicas de Inativação de Genes , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Rim/imunologia , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Proteína Proto-Oncogênica c-ets-1/genética
8.
Proc Natl Acad Sci U S A ; 116(30): 15134-15139, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31285344

RESUMO

B cells play important roles in autoimmune diseases through autoantibody production, cytokine secretion, or antigen presentation to T cells. In most cases, the contribution of B cells as antigen-presenting cells is not well understood. We have studied the autoantibody response against the enzyme transglutaminase 2 (TG2) in celiac disease patients by generating recombinant antibodies from single gut plasma cells reactive with discrete antigen domains and by undertaking proteomic analysis of anti-TG2 serum antibodies. The majority of the cells recognized epitopes in the N-terminal domain of TG2. Antibodies recognizing C-terminal epitopes interfered with TG2 cross-linking activity, and B cells specific for C-terminal epitopes were inefficient at taking up TG2-gluten complexes for presentation to gluten-specific T cells. The bias toward N-terminal epitopes hence reflects efficient T-B collaboration. Production of antibodies against N-terminal epitopes coincided with clinical onset of disease, suggesting that TG2-reactive B cells with certain epitope specificities could be the main antigen-presenting cells for pathogenic, gluten-specific T cells. The link between B cell epitopes, antigen presentation, and disease onset provides insight into the pathogenic mechanisms of a T cell-mediated autoimmune condition.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Doença Celíaca/imunologia , Epitopos de Linfócito B/imunologia , Proteínas de Ligação ao GTP/imunologia , Linfócitos T/imunologia , Transglutaminases/imunologia , Idade de Início , Células Apresentadoras de Antígenos/patologia , Autoanticorpos/biossíntese , Autoanticorpos/genética , Autoantígenos/genética , Autoantígenos/imunologia , Linfócitos B/patologia , Doença Celíaca/genética , Doença Celíaca/patologia , Duodeno/imunologia , Duodeno/patologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/genética , Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/genética , Glutens/química , Glutens/imunologia , Humanos , Soros Imunes/química , Cadeias Leves de Imunoglobulina/biossíntese , Cadeias Leves de Imunoglobulina/genética , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Linfócitos T/patologia , Transglutaminases/química , Transglutaminases/genética
9.
Thyroid ; 29(9): 1286-1301, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31237525

RESUMO

Graves' disease (GD) and Graves' orbitopathy are associated with stimulating thyrotropin receptor (TSHR) autoantibodies and autoreactive T cells. Recent in vitro studies suggested that sphingosine-1-phosphate (S1P) signaling is involved in the pathogenesis of orbitopathy. In this study, we explored the immune modulatory potential of S1P receptor antagonist fingolimod in a murine model for GD. Fingolimod was orally administered preventively during disease onset or therapeutically after disease onset. Administration of fingolimod during disease onset completely prevented the formation of TSHR-stimulating autoantibodies. Intervention after disease onset rarely reduced TSHR-stimulating autoantibodies and blocking autoantibodies were induced in some animals. Consequently, autoimmune hyperthyroidism characterized by elevated serum thyroxin levels, hyperplastic thyroid morphology accompanied by T cell infiltration, weight gain, enhanced body temperature, and tachycardia did not manifest preventively and showed milder manifestation in therapeutically treated animals. Importantly, examination of orbital tissue showed significant amelioration of orbitopathy manifestations through reduction of T cell infiltration, adipogenesis, and hyaluronan deposition. Autoimmune hyperthyroidism and orbitopathy were accompanied by changes in peripheral and splenic T cell proportions with high CD3+, CD4+, and CD8+ T cells. Activated T cells CD4+CD25+ were elevated whereas regulatory T cells CD4+Foxp3+ cells remained unchanged in spleens. Fingolimod decreased elevated T cell levels and increased CD4+CD25+Foxp3+ regulatory T cell populations. Analysis of total disease outcome revealed that treatment during disease onset protected animals against autoimmune hyperthyroidism and orbitopathy. Of note, therapeutic intervention after disease onset suppressed disease in half of the animals and in the other half disease remained at mild stages. The results of this study support a clinical trial to investigate the immunologic and clinical benefits of early treatment with S1P-based drugs in GD.


Assuntos
Autoanticorpos/biossíntese , Cloridrato de Fingolimode/uso terapêutico , Doença de Graves/tratamento farmacológico , Oftalmopatia de Graves/tratamento farmacológico , Receptores da Tireotropina/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Doença de Graves/imunologia , Oftalmopatia de Graves/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/efeitos dos fármacos
10.
Front Immunol ; 10: 1317, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244856

RESUMO

Bacillus Calmette Guérin (BCG) is the only currently available vaccine against tuberculosis (TB), but it confers incomplete and variable protection against pulmonary TB in humans and bovine TB (bTB) in cattle. Insights into the immune response induced by BCG offer an underexploited opportunity to gain knowledge that may inform the design of a more efficacious vaccine, which is urgently needed to control these major global epidemics. Humoral immunity in TB and bTB has been neglected, but recent studies supporting a role for antibodies in protection against TB has driven a growing interest in determining their relevance to vaccine development. In this manuscript we review what is known about the humoral immune response to BCG vaccination and re-vaccination across species, including evidence for the induction of specific B cells and antibodies; and how these may relate to protection from TB or bTB. We discuss potential explanations for often conflicting findings and consider how factors such as BCG strain, manufacturing methodology and route of administration influence the humoral response. As novel vaccination strategies include BCG prime-boost regimens, the literature regarding off-target immunomodulatory effects of BCG vaccination on non-specific humoral immunity is also reviewed. Overall, reported outcomes to date are inconsistent, but indicate that humoral responses are heterogeneous and may play different roles in different species, populations, or individual hosts. Further study is warranted to determine whether a new TB vaccine could benefit from the targeting of humoral as well as cell-mediated immunity.


Assuntos
Vacina BCG/imunologia , Animais , Anticorpos Antibacterianos/biossíntese , Especificidade de Anticorpos , Autoanticorpos/biossíntese , Linfócitos B/imunologia , Vacina BCG/administração & dosagem , Vacinas Anticâncer/imunologia , Bovinos , Humanos , Hipersensibilidade Imediata/prevenção & controle , Imunidade Humoral , Imunoglobulina E/biossíntese , Imunomodulação , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Bovina/imunologia , Tuberculose Bovina/prevenção & controle , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/prevenção & controle
11.
J Neuroimmunol ; 332: 112-125, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31005712

RESUMO

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults in the developed world. The accuracy of early outcome-prediction remains poor even when all known prognostic factors are considered, suggesting important currently unidentified variables. In addition, whilst survival and neurological outcomes have improved markedly with the utilisation of therapies that optimise physiology, no treatments specifically modulate the underlying pathophysiology. The immunological response to TBI represents both a potential contributor to outcome heterogeneity and a therapeutically tractable component of the acute disease process. Furthermore, chronic inflammation has been linked with neurodegeneration, and may mark a bridge between acute brain injury and the subsequent neurodegenerative process seen in a proportion of patients following TBI. Given the complexity of the immune response and its varying functions ranging from repair of injury to bystander damage of healthy tissue, attempts at immunomodulatory intervention must necessarily be highly targeted towards the maladaptive facets of the inflammatory process. In this review we aim to provide an integrated description of the immunological processes triggered by TBI in both humans and animal models, in particular considering the interplay between the innate immune system, danger-associated molecular patterns and loss of self-tolerance leading to adaptive autoimmunity.


Assuntos
Lesões Encefálicas Traumáticas/imunologia , Imunidade Adaptativa , Alarminas/imunologia , Animais , Astrócitos/imunologia , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/etiologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/prevenção & controle , Dano Encefálico Crônico/etiologia , Dano Encefálico Crônico/prevenção & controle , Lesões Encefálicas Traumáticas/complicações , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Citocinas/imunologia , Humanos , Imunidade Inata , Imunomodulação , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Knockout , Microglia/imunologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/prevenção & controle , Neutrófilos/imunologia , Reconhecimento Automatizado de Padrão , Ratos , Fatores de Tempo
12.
Transfus Clin Biol ; 26(2): 99-101, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30926306

RESUMO

Post-transfusion hemolysis is the most frequent immune reaction to transfusion in sickle cell disease. Its frequency is underestimated due to its biological and clinical characteristics. It results principally from the high incidence of alloimmunization in these patients, but no antibodies are detectable in 30% of cases. Prevention is based on the prevention of alloimmunization through the use of matched RBCs for highly immunogenic blood groups, taking into account the patient's transfusion history, particularly in patients undergoing occasional transfusion, which is associated with a higher risk of DHTR development than chronic transfusion. In addition to the use of matched RBCs, the prevention of alloimmunization through immunotherapy should be considered.


Assuntos
Anemia Hemolítica/prevenção & controle , Anemia Falciforme/complicações , Reação Transfusional/prevenção & controle , Anemia Hemolítica/etiologia , Anemia Hemolítica/imunologia , Anemia Falciforme/sangue , Anemia Falciforme/terapia , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Incompatibilidade de Grupos Sanguíneos/complicações , Hemólise , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/biossíntese , Isoanticorpos/imunologia , Pré-Medicação , Medição de Risco , Rituximab/uso terapêutico , Fatores de Tempo , Reação Transfusional/imunologia
13.
Toxicol Appl Pharmacol ; 370: 1-13, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30862457

RESUMO

To date, the connection between inorganic mercury (Hg) and social behavior remains incompletely understood. The aim of this study was to investigate the influence of maternal autoimmunity by inorganic Hg (Hg2+) exposure on social behavior of offspring. Wild-type (WT) and immunoglobulin deficient (Ig-/-) B10.S dams fertilized by male WT B10.S or SJL mice were treated with 50 µM Hg chloride (HgCl2). Non-pregnant female WT B10.S mice were used to investigate factors regulating HgCl2-induced autoimmunity to brain. HgCl2 selectively impaired social behavior in male offspring, but not female offspring from WT B10.S dams × male SJL, in that only male offspring displayed reduced time distribution with the stranger mouse, decreased sniffing to the stranger mouse and increased self-grooming. HgCl2 did not disrupt social behavior of male or female offspring from WT B10.S dams × male WT B10.S or Ig-/- B10.S dams × male SJL. The offspring from WT and Ig-/- B10.S dams × male SJL had equivalent autoimmunity to brain antigens during HgCl2 exposure, indicating that maternal, but not offspring-derived anti-brain antibodies (Ab) impaired social behavior of the offspring. Non-pregnant WT B10.S mice treated with HgCl2 had increased anti-brain Ab dependent on increase in CD4 T cell activation and IFNγ signaling to macrophages. IFNγ interaction with macrophages drove B cells and plasma cells to produce IgG. Therefore, HgCl2 selectively impaired social behavior in males with certain genetic background via maternally derived anti-brain Ab production, thus providing a novel insight into our current understanding of Hg toxicity.


Assuntos
Autoimunidade/efeitos dos fármacos , Autoimunidade/genética , Imunoglobulinas/deficiência , Cloreto de Mercúrio/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Comportamento Social , Animais , Autoanticorpos/biossíntese , Encéfalo/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Predisposição Genética para Doença/psicologia , Imunoglobulinas/genética , Interferon gama/fisiologia , Ativação Linfocitária , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout , Gravidez , Fatores Sexuais
14.
Inflammopharmacology ; 27(6): 1113-1122, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30721371

RESUMO

BACKGROUND AND AIMS: Behçet disease (BD) is a chronic multisystem disease. It stands at the crossroads between the auto-immunity and auto-inflammatory disorders. Our study aims to evaluate corticosteroids therapy effects on serum immunoglobulin isotypes and anti-phospholipid auto-anti-body production in Algerian BD patients with different clinical manifestations. METHODS: We evaluated serum immunoglobulin isotypes and anti-phospholipid (anti-cardiolipin, anti-ß2glycoprotein I, anti-prothrombin) auto-anti-body production using Turbidimetric or Luminex platform assays. Our study was conducted in naïve active BD patients and in corticosteroid-treated patients with different clinical manifestations. RESULTS AND DISCUSSION: Our results indicate that IgM, IgG, and IgA levels were higher in naïve active patients. The increase in sera isotypes did not differ according to the clinical manifestation, except for IgA production, which was associated with an increased risk of mucocutaneous and ocular involvement. Interestingly, in corticosteroid-treated active patients, no difference was reported between each clinical subgroup. Furthermore,anti-cardiolipin, anti-ß2glycoprotein I and anti-prothrombin auto-anti-body levels were elevated in naïve active patients. Contrary to anti-prothrombin, high anti-cardiolipin and anti-ß2glycoprotein I, production differed according to the clinical manifestations and was associated with an increased risk of mucocutaneous and ocular involvement. Importantly, corticosteroid therapy significantly reduced these immune markers regardless of the clinical manifestations. CONCLUSION: Our results suggest that high IgA production could be a risk marker of uveitis in naïve active patients. Moreover, concomitant high anti-cardiolipin, anti-ß2glycoprotein I and anti-prothrombin production is related to an increased risk of mucocutaneous lesions, ocular and vascular involvement. Collectively, our data indicate the importance of evaluating the corticosteroid effect on immune responses associated with BD to ensure an adequate investigation of each related clinical manifestation.


Assuntos
Corticosteroides/uso terapêutico , Autoimunidade , Síndrome de Behçet/imunologia , Adulto , Anticorpos Antifosfolipídeos/sangue , Autoanticorpos/biossíntese , Síndrome de Behçet/complicações , Síndrome de Behçet/tratamento farmacológico , Feminino , Humanos , Isotipos de Imunoglobulinas/sangue , Masculino , Pessoa de Meia-Idade , Uveíte/etiologia
15.
J Bone Miner Res ; 34(7): 1352-1365, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30779858

RESUMO

Next to proinflammatory cytokines, autoimmunity has been identified as a key trigger for osteoclast activation and bone loss. IgG-rheumatoid factor (IgG-RF) immune complexes, which are present in patients with rheumatoid arthritis, were shown to boost osteoclast differentiation. To date, the regulation of IgG-RF production in the absence of inflammatory triggers is unknown. Herein, we describe Fra1 as a key checkpoint that controls IgG-RF production by plasma cells and regulates autoimmune-mediated bone loss. Fra1 deficiency in B cells (Fra1ΔBcell ) led to increased IgG1-producing bone marrow plasma cells, enhanced IgG-RF production, and increased bone loss associated with elevated osteoclast numbers after immunization. The effect of IgG-RF on osteoclasts in vitro and on osteoclasts associated with bone loss in vivo was dependent on FcγR, especially FcγR3. Furthermore, immunization of WT mice with T-cell-dependent antigens induced a significant and robust decrease in Fra1 expression in bone marrow B cells, which was followed by increased IgG1 production and the induction of osteoclast-mediated bone loss. Overall, these data identify Fra1 as a key mediator of IgG-RF production and autoimmune-mediated bone loss. © 2019 American Society for Bone and Mineral Research.


Assuntos
Autoanticorpos/biossíntese , Células da Medula Óssea/metabolismo , Reabsorção Óssea/imunologia , Reabsorção Óssea/patologia , Plasmócitos/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fator Reumatoide/metabolismo , Animais , Osso e Ossos/patologia , Contagem de Células , Diferenciação Celular , Deleção de Genes , Imunidade Humoral , Imunização , Imunoglobulina G/metabolismo , Camundongos Endogâmicos C57BL , Osteoclastos/patologia , Osteogênese , Osteoporose/imunologia , Fenótipo , Proteínas Proto-Oncogênicas c-fos/deficiência , Receptores de IgG/deficiência , Receptores de IgG/metabolismo , Linfócitos T/imunologia
16.
Ann Rheum Dis ; 78(4): 509-518, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30679154

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by autoantibody production and widespread inflammation damaging many organs. Previous genome-wide association studies (GWASs) have revealed over 80 genetic determinants of SLE, but they collectively explain a fraction of the heritability, and only a few were proven in vivo for the involvement in SLE. We conducted a meta-analysis of SLE GWAS in the Japanese population, followed by functional analyses of a susceptibility gene with use of mutant mice. METHODS: We conducted a meta-analysis of two GWASs comprising a total of 1363 cases and 5536 controls using the 1000 Genome Project data as an imputation reference. Enrichment analyses for functional annotations were conducted. We examined Phospholipase D4 (Pld4) mutant mice to assess functional involvement of a genetic determinant. RESULTS: We found a total of 14 significant loci, which included rs2582511 in AHNAK2/PLD4 recently reported in a Chinese study and a novel locus of rs143181706 in MAMLD1 (p=7.9×10-11 and 3.7×10-8, respectively). PLD4 risk allele was associated with anti-dsDNA antibody production. Enrichment analysis of genetic signals revealed involvement of a wide range of immune-related cells and pathways. Pld4 mutant mice revealed remarkably low body weight. The mice demonstrated autoimmune phenotypes compatible with SLE, including splenomegaly and lymphadenopathy, expansion of B cells and hypersecretion of BAFF and production of autoantibodies especially anti-nuclear antibody and anti-dsDNA antibody. CONCLUSIONS: We found a novel susceptibility gene to SLE. Pld4 mutant mice revealed autoimmune phenotypes suggesting functional involvement of PLD4 with the basics of SLE.


Assuntos
Doenças Autoimunes/genética , Exonucleases/genética , Lúpus Eritematoso Sistêmico/genética , Animais , Anticorpos Antinucleares/biossíntese , Autoanticorpos/biossíntese , Doenças Autoimunes/imunologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Imunofenotipagem , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Camundongos Mutantes , Polimorfismo de Nucleotídeo Único
17.
Ann Rheum Dis ; 78(2): 249-260, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30472652

RESUMO

BACKGROUND: The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies. Primary Sjögren's syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function. Given the central role of B cells in pSS pathogenesis, we investigated PI3Kδ pathway activation in pSS and the functional consequences of blocking PI3Kδ in a murine model of focal sialoadenitis that mimics some features of pSS. METHODS AND RESULTS: Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands. In vivo blockade of PI3Kδ activity with seletalisib, a PI3Kδ-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes. Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib. CONCLUSION: These data demonstrate activation of PI3Kδ pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kδ pathway inhibition in this condition.


Assuntos
Fosfatidilinositol 3-Quinase/metabolismo , Piridinas/farmacologia , Quinolinas/farmacologia , Sialadenite/enzimologia , Transdução de Sinais/efeitos dos fármacos , Síndrome de Sjogren/enzimologia , Animais , Autoanticorpos/biossíntese , Linfócitos B/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Camundongos , Fosfatidilinositol 3-Quinase/efeitos dos fármacos , Plasmócitos/metabolismo , Proteína S6 Ribossômica/metabolismo , Glândulas Salivares/metabolismo , Sialadenite/tratamento farmacológico , Síndrome de Sjogren/tratamento farmacológico
19.
Clin Exp Nephrol ; 23(3): 291-303, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30406499

RESUMO

BACKGROUND: Immunoglobulin A nephropathy (IgAN), the most frequent cause of primary glomerulonephritis worldwide, is an autoimmune disease with complex pathogenesis. In this review, we focus on T cells and summarize knowledge about their involvement in pathophysiology and treatment of IgAN METHODS: We reviewed the literature for (1) alterations of T cell subpopulations in IgAN, (2) experimental and clinical proofs for T cells' participation in IgAN pathogenesis, (3) clinical correlations with T cell-associated alterations, and (4) influence of drugs used in IgAN therapy on T cell subpopulations. RESULTS: We found that IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and γδ T cells, but lower Th1 and Treg cells. We discuss genetic and epigenetic makeup that may contribute to this immunological phenotype. We found that Th2, Th17 and Tfh-type interleukins contribute to elevated synthesis of galactose-deficient IgA1 (Gd-IgA1) and that the production of anti-Gd-IgA1 autoantibodies may be stimulated by Tfh cells. We described the roles of Th2, Th17, Th22 and Treg cells in the renal injury and summarized correlations between T cell-associated alterations and clinical features of IgAN (proteinuria, reduced GFR, hematuria). We detailed the impact of immunosuppressive drugs on T cell subpopulations and found that the majority of drugs have nonoptimal influence on T cells in IgAN patients. CONCLUSIONS: T cells play an important role in IgAN pathogenesis and are correlated with its clinical severity. Clinical trials with the drugs targeting the reported alterations of the T-cell compartment are highly desirable.


Assuntos
Glomerulonefrite por IGA/imunologia , Linfócitos T/fisiologia , Corticosteroides/uso terapêutico , Autoanticorpos/biossíntese , Receptor 1 de Quimiocina CX3C/análise , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/etiologia , Humanos , Imunoglobulina A/imunologia , Imunossupressores/uso terapêutico , Subpopulações de Linfócitos T/fisiologia
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