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1.
Scand J Immunol ; 93(2): e13017, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33351196

RESUMO

The neonatal Fc receptor (FcRn) was first recognized for its role in transfer of maternal IgG to the foetus or newborn, providing passive immunity early in life. However, it has become clear that the receptor is versatile, widely expressed and plays an indispensable role in both immunological and non-immunological processes throughout life. The receptor rescues immunoglobulin G (IgG) and albumin from intracellular degradation and shuttles the ligands across polarized cell barriers, in all cases via a pH-dependent binding-and-release mechanism. These processes secure distribution and high levels of both IgG and albumin throughout the body. At mucosal sites, FcRn transports IgG across polarized epithelial cells where it retrieves IgG in complex with luminal antigens that is delivered to tissue-localized immune cells. In dendritic cells (DCs), FcRn orchestrates processing of IgG-opsonized immune complexes (ICs) in concert with classical Fcγ receptors, which results in antigen presentation and cross-presentation of antigenic peptides on MHC class II and I to CD4+ and CD8+ T cells, respectively. Hence, FcRn regulates transport of the ligands within and across different types of cells, but also processing of IgG-ICs by immune cells. As such, the receptor is involved in immune surveillance and protection against infections. In this brief review, we highlight how FcRn expressed by hematopoietic and non-hematopoietic cells contributes to immune regulation at mucosal barriers-biology that can be utilized in development of biologics and subunit vaccines for non-invasive delivery.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Membrana Mucosa/imunologia , Receptores Fc/imunologia , Animais , Apresentação do Antígeno/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunoglobulina G/imunologia , Fatores Imunológicos/imunologia
2.
Mol Med Rep ; 22(6): 4485-4491, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33173966

RESUMO

In December 2019, an emergence of pneumonia was detected in patients infected with a novel coronavirus (CoV) in Wuhan (Hubei, China). The International Committee on Taxonomy of Viruses named the virus severe acute respiratory syndrome­CoV­2 and the disease CoV disease­19 (COVID­19). Patients with COVID­19 present with symptoms associated with respiratory system dysfunction and hematological changes, including lymphopenia, thrombocytopenia and coagulation disorders. However, to the best of our knowledge, the pathogenesis of COVID­19 remains unclear. Therefore, understanding the mechanisms underlying the hematological changes that manifest during COVID­19 may aid in the development of treatments and may improve patient prognosis.


Assuntos
Betacoronavirus , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Anticorpos Antivirais/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Microambiente Celular , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/sangue , Testes Diagnósticos de Rotina , Endotélio Vascular/patologia , Testes Hematológicos , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Humanos , Hipoalbuminemia/etiologia , Fígado/fisiopatologia , Pulmão/fisiopatologia , Linfopenia/etiologia , Linfopenia/fisiopatologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/terapia , Traumatismo por Reperfusão/etiologia , Trombocitopenia/etiologia , Trombocitopenia/fisiopatologia , Trombofilia/etiologia
3.
Sci Rep ; 10(1): 16219, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004978

RESUMO

COVID-19 pandemic has resulted in 16,114,449 cases with 646,641 deaths from the 217 countries, or territories as on July 27th 2020. Due to multifaceted issues and challenges in the implementation of the safety and preventive measures, inconsistent coordination between societies-governments and most importantly lack of specific vaccine to SARS-CoV-2, the spread of the virus that initially emerged at Wuhan is still uprising after taking a heavy toll on human life. In the present study, we mapped immunogenic epitopes present on the four structural proteins of SARS-CoV-2 and we designed a multi-epitope peptide based vaccine that, demonstrated a high immunogenic response with a vast application on world's human population. On codon optimization and in-silico cloning, we found that candidate vaccine showed high expression in E. coli and immune simulation resulted in inducing a high level of both B-cell and T-cell mediated immunity. The results predicted that exposure of vaccine by administrating three injections significantly subsidized the antigen growth in the system. The proposed candidate vaccine found promising by yielding desired results and hence, should be validated by practical experimentations for its functioning and efficacy to neutralize SARS-CoV-2.


Assuntos
Epitopos/imunologia , Simulação de Acoplamento Molecular , Vacinas de Subunidades/imunologia , Vacinas Virais/imunologia , Complexo Antígeno-Anticorpo/química , Complexo Antígeno-Anticorpo/imunologia , Antígenos Virais/imunologia , Linfócitos B/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Epitopos/química , Antígenos HLA/química , Antígenos HLA/imunologia , Humanos , Imunogenicidade da Vacina , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/imunologia , Fosfoproteínas , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Receptores Toll-Like/imunologia , Vacinas de Subunidades/química , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/imunologia , Vacinas Virais/química
4.
Paediatr Respir Rev ; 35: 81-87, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32792288

RESUMO

The rapid spread of SARS-CoV-2 infection globally coupled with the relatively high case-fatality rate has led to immediate need for therapeutic intervention to prevent and treat COVID-19 disease. There is accumulating evidence that morbidity and mortality in COVID-19 may be exacerbated by a dysregulated host immune response resulting in significant hyperinflammation and cytokine release. The aim of this review is to describe the basis for the immune dysregulation caused by SARS-CoV-2 infection and to examine current investigations into immunomodulatory therapies aimed at targeting the excessive host immune response.


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo Antígeno-Anticorpo/imunologia , Betacoronavirus , Criança , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/fisiopatologia , Síndrome da Liberação de Citocina/terapia , Humanos , Imunização Passiva/métodos , Imunoglobulinas Intravenosas/uso terapêutico , Inflamação/imunologia , Inflamação/fisiopatologia , Inflamação/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Receptores de Interleucina-6/antagonistas & inibidores , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Síndrome de Resposta Inflamatória Sistêmica/terapia
5.
Science ; 369(6505): 793-799, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32792392

RESUMO

Monoclonal antibodies (mAbs) targeting human antigen CD20 (cluster of differentiation 20) constitute important immunotherapies for the treatment of B cell malignancies and autoimmune diseases. Type I and II therapeutic mAbs differ in B cell binding properties and cytotoxic effects, reflecting differential interaction mechanisms with CD20. Here we present 3.7- to 4.7-angstrom cryo-electron microscopy structures of full-length CD20 in complexes with prototypical type I rituximab and ofatumumab and type II obinutuzumab. The structures and binding thermodynamics demonstrate that upon binding to CD20, type II mAbs form terminal complexes that preclude recruitment of additional mAbs and complement components, whereas type I complexes act as molecular seeds to increase mAb local concentration for efficient complement activation. Among type I mAbs, ofatumumab complexes display optimal geometry for complement recruitment. The uncovered mechanisms should aid rational design of next-generation immunotherapies targeting CD20.


Assuntos
Anticorpos Monoclonais Humanizados/química , Complexo Antígeno-Anticorpo/química , Antígenos CD20/química , Antineoplásicos/química , Imunoterapia , Linfoma de Células B/terapia , Rituximab/química , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo Antígeno-Anticorpo/imunologia , Antígenos CD20/imunologia , Antineoplásicos/imunologia , Linfócitos B/imunologia , Ativação do Complemento , Microscopia Crioeletrônica , Humanos , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/imunologia , Ligação Proteica , Conformação Proteica , Rituximab/imunologia , Rituximab/uso terapêutico
7.
Subcell Biochem ; 94: 123-161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189298

RESUMO

Insects possess powerful immune systems that have evolved to defend against wounding and environmental pathogens such as bacteria, fungi, protozoans, and parasitoids. This surprising sophistication is accomplished through the activation of multiple immune pathways comprised of a large array of components, many of which have been identified and studied in detail using both genetic manipulations and traditional biochemical techniques. Recent advances indicate that certain pathways activate arrays of proteins that interact to form large functional complexes. Here we discuss three examples from multiple insects that exemplify such processes, including pathogen recognition, melanization, and coagulation. The functionality of each depends on integrating recognition with the recruitment of immune effectors capable of healing wounds and destroying pathogens. In both melanization and coagulation, protein interactions also appear to be essential for enzymatic activities tied to the formation of melanin and for the recruitment of hemocytes. The importance of these immune complexes is highlighted by the evolution of mechanisms in pathogens to disrupt their formation, an example of which is provided. While technically difficult to study, and not always readily amenable to dissection through genetics, modern mass spectrometry has become an indispensable tool in the study of these higher-order protein interactions. The formation of immune complexes should be viewed as an essential and emerging frontier in the study of insect immunity.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Hemolinfa/imunologia , Insetos/imunologia , Animais , Hemócitos/imunologia , Hemócitos/metabolismo , Hemolinfa/citologia , Proteínas de Insetos/imunologia , Proteínas de Insetos/metabolismo , Melaninas/biossíntese
8.
Subcell Biochem ; 94: 465-497, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189312

RESUMO

In vertebrates, immunoglobulins (Igs), commonly known as antibodies, play an integral role in the armamentarium of immune defense against various pathogens. After an antigenic challenge, antibodies are secreted by differentiated B cells called plasma cells. Antibodies have two predominant roles that involve specific binding to antigens to launch an immune response, along with activation of other components of the immune system to fight pathogens. The ability of immunoglobulins to fight against innumerable and diverse pathogens lies in their intrinsic ability to discriminate between different antigens. Due to this specificity and high affinity for their antigens, antibodies have been a valuable and indispensable tool in research, diagnostics and therapy. Although seemingly a simple maneuver, the association between an antibody and its antigen, to make an antigen-antibody complex, is comprised of myriads of non-covalent interactions. Amino acid residues on the antigen binding site, the epitope, and on the antibody binding site, the paratope, intimately contribute to the energetics needed for the antigen-antibody complex stability. Structural biology methods to study antigen-antibody complexes are extremely valuable tools to visualize antigen-antibody interactions in detail; this helps to elucidate the basis of molecular recognition between an antibody and its specific antigen. The main scope of this chapter is to discuss the structure and function of different classes of antibodies and the various aspects of antigen-antibody interactions including antigen-antibody interfaces-with a special focus on paratopes, complementarity determining regions (CDRs) and other non-CDR residues important for antigen binding and recognition. Herein, we also discuss methods used to study antigen-antibody complexes, antigen recognition by antibodies, types of antigens in complexes, and how antigen-antibody complexes play a role in modern day medicine and human health. Understanding the molecular basis of antigen binding and recognition by antibodies helps to facilitate the production of better and more potent antibodies for immunotherapy, vaccines and various other applications.


Assuntos
Complexo Antígeno-Anticorpo/química , Complexo Antígeno-Anticorpo/imunologia , Animais , Sítios de Ligação de Anticorpos , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/imunologia , Epitopos/química , Epitopos/imunologia , Humanos , Modelos Moleculares
9.
J Immunother Cancer ; 8(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32217759

RESUMO

BACKGROUND: Tumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy. METHODS: A mouse IgG1 (kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14+ monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models. RESULTS: Through coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues. CONCLUSIONS: LTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Citocinas/imunologia , Lactoferrina/imunologia , Macrófagos/imunologia , Melanoma Experimental/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais/imunologia , Complexo Antígeno-Anticorpo/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo
10.
Clin Immunol ; 212: 108360, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32035179

RESUMO

Rheumatoid arthritis (RA) is characterized by the production of anti-citrullinated protein antibodies (ACPAs). To gain insights into the relationship between ACPA-expressing B cells in peripheral blood (PB) and synovial tissue (ST), we sequenced the B cell repertoire in paired PB and ST samples from five individuals with established, ACPA+ RA. Bioinformatics analysis of paired heavy- and light-chain sequences revealed clonally-related family members shared between PB and ST. ST-derived antibody repertoires exhibited reduced diversity and increased normalized clonal family size compared to PB-derived repertoires. Functional characterization showed that seven recombinant antibodies (rAbs) expressed from subject-derived sequences from both compartments bound citrullinated antigens and immune complexes (ICs) formed using one ST-derived rAb stimulated macrophage TNF-α production. Our findings demonstrate B cell trafficking between PB and ST in subjects with RA and ST repertoires include B cells that encode ACPA capable of forming ICs that stimulate cellular responses implicated in RA pathogenesis.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Complexo Antígeno-Anticorpo/imunologia , Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Macrófagos/imunologia , Membrana Sinovial/imunologia , Fator de Necrose Tumoral alfa/imunologia , Diversidade de Anticorpos/imunologia , Biologia Computacional , Humanos , Ativação de Macrófagos/imunologia , Membrana Sinovial/citologia
11.
Expert Rev Gastroenterol Hepatol ; 14(2): 113-125, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31951758

RESUMO

Introduction: Multiple studies have revealed a strong relationship between the development of nephropathy and hepatitis B virus (HBV) infection. The underlying pathogenesis of hepatitis B-related glomerulonephritis (HBV-GN) involves immune complexes, which can be isolated from kidney tissues. Clearance of HBV antigenemia improves renal impairment and proteinuria in HBV-GN patients.Areas covered: In this review, we present our current understanding of the epidemiology, pathogenesis, pathology, diagnosis, and treatment of HBV-GN. We discuss the advantages and disadvantages of oral nucleoside/nucleotide analogs (NAs), and the main pharmaceutical treatment for hepatis B.Expert opinion: Currently, antiviral agents are the main HBV-GN therapeutic agents. Although no randomized controlled clinical trials have compared the efficacy of interferon (IFN) and NA, we suggest IFN treatment for pediatric patients (IFN-α in patients ≥1 year; pegIFN-α in patients ≥3 years) considering treatment duration and absence of resistance. Novel NAs have brought about promising treatment options involving high efficacy viral suppression and low resistance rates. NAs with a high barrier to resistance (e.g. entecavir) are recommended as first-line therapy of HBV-GN. Immunosuppression monotherapy, such as corticosteroids, is of little benefit and potentially harmful to HBV-GN patients due to the possibility of viral reactivation.


Assuntos
Glomerulonefrite/diagnóstico , Glomerulonefrite/tratamento farmacológico , Hepatite B Crônica/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antivirais/uso terapêutico , Glomerulonefrite/epidemiologia , Glomerulonefrite/etiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Humanos , Doenças do Complexo Imune/imunologia , Doenças do Complexo Imune/patologia , Doenças do Complexo Imune/virologia , Imunossupressores/uso terapêutico , Interferon-alfa/uso terapêutico , Rim/imunologia , Rim/patologia , Nucleosídeos/efeitos adversos , Nucleosídeos/uso terapêutico , Nucleotídeos/uso terapêutico
12.
Semin Immunol ; 47: 101388, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31924500

RESUMO

A humoral immune response in the form of autoantibodies to tumor antigens occurs early during tumor development. Identification of antigens that induce an autoantibody response restricted to a cancer type has the potential to yield markers useful for early detection. A multitude of strategies are currently available for the discovery of tumor antigens directed autoantibodies in circulation. Each approach has advantages and limitations for comprehensive discovery of antigenic epitopes. Herein, we review established and novel strategies and methodologies and highlight potential cancer applications.


Assuntos
Antígenos de Neoplasias/imunologia , Autoanticorpos/imunologia , Biomarcadores Tumorais , Neoplasias/imunologia , Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/genética , Autoantígenos/imunologia , Técnicas de Visualização da Superfície Celular , Biologia Computacional/métodos , Detecção Precoce de Câncer , Mapeamento de Epitopos/métodos , Epitopos/imunologia , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Peptídeos/genética , Peptídeos/imunologia , Prognóstico , Proteômica/métodos
13.
J Allergy Clin Immunol ; 145(1): 301-311.e4, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31437490

RESUMO

BACKGROUND: Type I hypersensitivity is mediated by allergen-specific IgE, which sensitizes the high-affinity IgE receptor FcεRI on mast cells and basophils and drives allergic inflammation upon secondary allergen contact. CD23/FcεRII, the low-affinity receptor for IgE, is constitutively expressed on B cells and has been shown to regulate immune responses. Simultaneous binding of IgE to FcεRI and CD23 is blocked by reciprocal allosteric inhibition, suggesting that the 2 receptors exert distinct roles in IgE handling. OBJECTIVE: We aimed to study how free IgE versus precomplexed IgE-allergen immune complexes (IgE-ICs) target the 2 IgE receptors FcεRI and CD23, and we investigated the functional implications of the 2 pathways. METHODS: We performed binding and activation assays with human cells in vitro and IgE pharmacokinetics and anaphylaxis experiments in vivo. RESULTS: We demonstrate that FcεRI preferentially binds free IgE and CD23 preferentially binds IgE-ICs. We further show that those different binding properties directly translate to distinct biological functions: free IgE initiated allergic inflammation through FcεRI on allergic effector cells, while IgE-ICs were noninflammatory because of reduced FcεRI binding and enhanced CD23-dependent serum clearance. CONCLUSION: We propose that IgE-ICs are noninflammatory through reduced engagement by FcεRI but increased targeting of the CD23 pathway.


Assuntos
Alérgenos/imunologia , Anafilaxia/imunologia , Complexo Antígeno-Anticorpo/imunologia , Imunoglobulina E/imunologia , Lectinas Tipo C/imunologia , Receptores de IgE/imunologia , Transdução de Sinais/imunologia , Alérgenos/genética , Anafilaxia/genética , Anafilaxia/patologia , Animais , Complexo Antígeno-Anticorpo/genética , Humanos , Lectinas Tipo C/genética , Camundongos , Camundongos Knockout , Receptores de IgE/genética , Transdução de Sinais/genética
14.
Int Immunol ; 32(2): 89-104, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31713625

RESUMO

Staphylococcus aureus is a main pathogen of osteomyelitis and protein A is a virulence factor with high affinity for IgG. In this study, we investigated whether S. aureus affects the differentiation and bone resorption of osteoclasts through the IgG-binding capacity of protein A. Staphylococcus aureus pre-treated with serum or IgG showed marked enhancement in osteoclastogenesis and bone resorption compared to non-treated S. aureus or a protein A-deficient mutant. Blocking of the Fc receptor and deletion of the Fcγ receptor gene in osteoclast precursor cells showed that enhanced osteoclastogenesis stimulated by S. aureus IgG immune complexes (ICs) was mediated by the Fc receptor on osteoclast precursor cells. In addition, osteoclastogenesis stimulated by S. aureus ICs but not the protein A-deficient mutant was markedly reduced in osteoclast precursor cells of Myd88-knockout mice. Moreover, NFATc1, Syk and NF-κB signals were necessary for osteoclastogenesis stimulated by S. aureus ICs. The results suggest the contribution of a of Toll-like receptor 2 (TLR2)-Myd88 signal to the activity of S. aureus ICs. We further examined the expression of pro-inflammatory cytokines that is known to be enhanced by FcγR-TLR cross-talk. Osteoclasts induced by S. aureus ICs showed higher expression of TNF-α and IL-1ß, and marked stimulation of proton secretion of osteoclasts activated by pro-inflammatory cytokines. Finally, injection of S. aureus, but not the protein A-deficient mutant, exacerbated bone loss in implantation and intra-peritoneal administration mouse models. Our results provide a novel mechanistic aspect of bone loss induced by S. aureus in which ICs and both Fc receptors and TLR pathways are involved.


Assuntos
Complexo Antígeno-Anticorpo/imunologia , Diferenciação Celular , Imunoglobulina G/imunologia , Receptores Fc/imunologia , Proteína Estafilocócica A/imunologia , Staphylococcus aureus/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteogênese/efeitos dos fármacos , Ligante RANK/antagonistas & inibidores , Ligante RANK/farmacologia , Receptores Fc/deficiência , Receptores Fc/genética , Proteína Estafilocócica A/genética , Staphylococcus aureus/citologia , Ácidos Teicoicos/farmacologia
15.
J Immunol Res ; 2019: 6047085, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886305

RESUMO

A new method for the detection by flow cytometry of anti-double-stranded DNA antibodies and of circulating immune complexes (IC) containing endogenous DNA (IC-eDNA) is described. From each serum sample, two samples were taken, one was used to detect IC-eDNA. The other to detect anti-DNA antibodies was incubated with calf thymus DNA. ICs were isolated by polyethylene glycol precipitation or by cryoprecipitation, after which immunoglobulins were labeled with FITC-conjugated anti-human globulin. Serum samples from 63 systemic lupus erythematosus (SLE) patients, 32 incomplete lupus, and 87 control patients were tested. Detection of anti-dsDNA antibodies by flow cytometry had a diagnostic sensitivity and specificity almost comparable to routine tests, the fluorescent enzyme immunoassay EliA™-dsDNA test, and the ultrasensitive Crithidia luciliae indirect immunofluorescence test. In 21 (33%) out of 63 SLE serum samples, IC-eDNA was detected. In these samples, free anti-dsDNA antibodies were hardly detectable or undetectable by flow cytometry or by routine tests. When anti-DNA antibodies are neutralized by endogenous DNA and can no longer be detected by routine tests, the serologic diagnosis and the follow-up of relapses in patients with SLE is compromised. To overcome this obstacle, we propose an accessible solution: the detection of circulating IC-eDNA by flow cytometry.


Assuntos
Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Complexo Antígeno-Anticorpo/sangue , Complexo Antígeno-Anticorpo/imunologia , DNA/imunologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Biomarcadores , Citometria de Fluxo , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Sensibilidade e Especificidade
16.
Cell Rep ; 29(12): 3946-3957.e5, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31851925

RESUMO

Passive immunization (PI) with external antibodies has been used classically for rapid but temporary alleviation of disease. Transcending this role, recent studies have shown PI to induce lasting improvements in natural antibody production, suggesting that PI could become a powerful tool to engineer humoral responses. We propose a mechanism with which PI can alter the humoral response. Antigen-specific B cells evolve and get selected in germinal centers (GCs) on the basis of their ability to acquire antigen from antibody-antigen complexes presented in GCs. When external antibodies of high affinity for antigen are used, they form the majority of the complexes in GCs, letting only B cells with even higher affinities be selected. Using an in silico GC reaction model, we show that this mechanism explains the improved humoral responses following PI. The model also synthesizes several independent experimental observations, indicating the robustness of the mechanism, and proposes tunable handles to optimize PI.


Assuntos
Afinidade de Anticorpos/imunologia , Complexo Antígeno-Anticorpo/imunologia , Antígenos/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunidade Humoral/imunologia , Imunização Passiva/métodos , Animais , Formação de Anticorpos , Simulação por Computador , Camundongos
17.
Front Immunol ; 10: 2824, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849989

RESUMO

Neutrophil extracellular traps (NETs) have been initially described as main actors in host defense owing to their ability to immobilize and sometimes kill microorganisms. Subsequent studies have demonstrated their implication in the pathophysiology of various diseases, due to the toxic effects of their main components on surrounding tissues. Several distinct NETosis pathways have been described in response to various triggers. Among these triggers, IgG immune complexes (IC) play an important role since they induce robust NET release upon binding to activating FcγRs on neutrophils. Few in vitro studies have documented the mechanisms of IC-induced NET release and evidence about the partners involved is controversial. In vivo, animal models and clinical studies have strongly suggested the importance of IgG IC-induced NET release for autoimmunity and anaphylaxis. In this review, we will focus on two autoimmune diseases in which NETs are undoubtedly major players, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). We will also discuss anaphylaxis as another example of disease recently associated with IC-induced NET release. Understanding the role of IC-induced NETs in these settings will pave the way for new diagnostic tools and therapeutic strategies.


Assuntos
Anafilaxia/imunologia , Doenças Autoimunes/imunologia , Armadilhas Extracelulares/imunologia , Hipersensibilidade/imunologia , Neutrófilos/imunologia , Anafilaxia/diagnóstico , Anafilaxia/terapia , Animais , Complexo Antígeno-Anticorpo/imunologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Autoimunidade , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/terapia
18.
Sci Rep ; 9(1): 20126, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882893

RESUMO

Complications of chronic liver diseases - particularly hepatocellular carcinoma (HCC) - are a major cause of mortality worldwide. Several studies have shown that high or increasing levels of serum Squamous Cell Carcinoma Antigen-Immunoglobulin M complex (SCCA-IgM) are associated with development of HCC in patients with advanced liver disease and worse survival in patients with liver cancer. The aim of the present study was to assess, in patients with advanced liver disease, differences in long-term clinical outcomes in relation to baseline levels of serum SCCA-IgM. Ninety one consecutive outpatients with liver cirrhosis of different etiologies, without hepatocellular carcinoma at presentation, were enrolled from April 2007 to October 2012 in a prospective study. For a median time of 127 months, patients were bi-annually re-evaluated. SCCA-IgM complex levels were determined with a validated enzyme-linked immunosorbent assay. The results provided evidence that serum SCCA-IgM is a predictor of overall survival. The best cut-off to discriminate both HCC-free and overall survival rates was 120 AU/mL. Patients with baseline values higher than this threshold showed a substantial increase in both HCC incidence rate and all-cause mortality rate. In conclusion, a single measurement of serum SCCA-IgM helps to identify those patients with liver cirrhosis with increased risks of HCC development and mortality.


Assuntos
Complexo Antígeno-Anticorpo/sangue , Complexo Antígeno-Anticorpo/imunologia , Antígenos de Neoplasias/imunologia , Imunoglobulina M/imunologia , Cirrose Hepática/sangue , Cirrose Hepática/mortalidade , Serpinas/imunologia , Adulto , Idoso , Antígenos de Neoplasias/sangue , Biomarcadores , Carcinoma Hepatocelular , Feminino , Humanos , Imunoglobulina M/sangue , Cirrose Hepática/etiologia , Hepatopatias , Neoplasias Hepáticas , Masculino , Pessoa de Meia-Idade , Prognóstico , Serpinas/sangue , Análise de Sobrevida
19.
Arthritis Res Ther ; 21(1): 259, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783909

RESUMO

INTRODUCTION: Immune complexes are of importance in systemic lupus erythematosus pathogenesis, and autoantibodies are believed to participate in immune complex formation. Quantification of autoantibody levels in circulating IC might be of prognostic value. METHODS: A C1q-binding-eluting technique was applied to purify immune complexes from 55 belimumab-treated systemic lupus erythematosus patients during a 24-month follow-up. Autoantibodies in serum and in solubilized immune complexes were quantified using addressable laser bead immunoassay. We investigated whether levels of autoantibodies in immune complexes associate with disease activity and response to belimumab treatment. RESULTS: High baseline anti-double-stranded DNA and anti-histone levels in immune complexes associated with attainment of zero scores in clinical systemic lupus erythematosus disease activity index 2000 during the 24-month follow-up (p = 0.003 and p = 0.048, respectively). Low complement levels associated with high serum anti-double-stranded DNA and anti-ribosomal P levels (p = 0.003 and p = 0.008, respectively) and high anti-double-stranded DNA (p = 0.002) but not anti-ribosomal P levels in immune complexes. Anti-SSA/SSB serum levels were lower in patients attaining lupus low disease activity state at month 6; these associations were stronger for corresponding immune complex levels. Serum levels of most autoantibodies had declined at month 3, whereas autoantibody levels in immune complexes, except for anti-double-stranded DNA, showed a more gradual decline over 1-2 years. Serum anti-double-stranded DNA levels decreased in all patients irrespective of systemic lupus erythematosus disease activity index 2000=0 attainment, whereas immune complex levels decreased only in achievers. CONCLUSION: Immune complex levels of autoantibodies against double-stranded DNA and the SSA/SSB complex show more specific associations with treatment outcome compared with serum levels in belimumab-treated systemic lupus erythematosus patients. Characterization of autoantibody content in circulating immune complexes could prove useful in treatment evaluation in systemic lupus erythematosus and other immune complex-associated diseases.


Assuntos
Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo Antígeno-Anticorpo/imunologia , DNA/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Adulto , Anticorpos Antinucleares/sangue , Feminino , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
20.
J Immunotoxicol ; 16(1): 191-200, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31684787

RESUMO

In preclinical toxicity studies, species-foreign proteins administered to animals frequently leads to formation of anti-drug antibodies (ADA). Such antibodies may form circulating immune complexes (CIC) with the administered protein. These CIC can activate the classical complement pathway, thereby forming complement-bound CIC (cCIC); if large of amounts of CIC or cCIC is formed, the clearance mechanism may become saturated which potentially leads to vascular immune complex (IC) deposition and inflammation. Limited information is available on the effect of different treatment related procedures as well as biomarkers of IC-related vascular disease. In order to explore the effect of different dose regimens on IC formation and deposition, and identification of possible biomarkers of IC deposition and IC-related pathological changes, C57BL/6J and BALB/c mice were dosed subcutaneously twice weekly with bovine serum albumin (BSA) for 13 weeks without adjuvant. After 6 and 13 weeks, CIC and cCIC were detected in plasma; after 13 weeks, IC deposition was detected in kidney glomeruli. In particular immunohistochemistry double-staining was shown to be useful for detection of IC deposition. Increasing dosing frequency or changing BSA dose level on top of an already established CIC and cCIC response did not cause changes in IC deposition, but CIC and cCIC concentrations tended to decrease with increased dose level, and increased cCIC formation was observed after more frequent dosing. The presence of CIC in plasma was associated with glomerular IC deposits in the dose regimen study; however, the use of CIC or cCIC as potential biomarkers for IC deposition and IC-related pathological changes, needs to be explored further.


Assuntos
Complexo Antígeno-Anticorpo/análise , Glomerulonefrite/imunologia , Soroalbumina Bovina/toxicidade , Vasculite Sistêmica/imunologia , Animais , Complexo Antígeno-Anticorpo/imunologia , Biomarcadores/análise , Via Clássica do Complemento/efeitos dos fármacos , Via Clássica do Complemento/imunologia , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Glomerulonefrite/sangue , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/diagnóstico , Humanos , Imuno-Histoquímica , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Masculino , Camundongos , Soroalbumina Bovina/administração & dosagem , Soroalbumina Bovina/imunologia , Vasculite Sistêmica/sangue , Vasculite Sistêmica/induzido quimicamente , Vasculite Sistêmica/diagnóstico , Testes de Toxicidade/métodos
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