RESUMO
Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DCs) and monocytes, but the extent of their heterogeneity and distinct markers for subset identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we identified distinct markers to delineate monocytes from conventional DC2 (cDC2s). Using CD88 and CD89 for monocytes and HLA-DQ and FcεRIα for cDC2s allowed for their specific identification in blood and tissues. We also showed that cDC2s could be subdivided into phenotypically and functionally distinct subsets based on CD5, CD163, and CD14 expression, including a distinct subset of circulating inflammatory CD5-CD163+CD14+ cells related to previously defined DC3s. These inflammatory DC3s were expanded in systemic lupus erythematosus patients and correlated with disease activity. These findings further unravel the heterogeneity of DC subpopulations in health and disease and may pave the way for the identification of specific DC subset-targeting therapies.
Assuntos
Biomarcadores/sangue , Células Dendríticas/imunologia , Inflamação/sangue , Inflamação/imunologia , Leucócitos Mononucleares/imunologia , Fagócitos/imunologia , Antígenos CD/sangue , Antígenos CD/imunologia , Células Cultivadas , Citometria de Fluxo/métodos , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Monócitos/imunologia , Fenótipo , Análise de Célula ÚnicaRESUMO
Antibody-based immunotherapy is a promising strategy in cancer treatment. Antibodies can directly inhibit tumor growth, induce complement-dependent cytotoxicity and induce Fc receptor-mediated elimination of tumor cells by macrophages and natural killer cells. Until now, however, neutrophils have been largely overlooked as potential effector cells, even though they are the most abundant type of immune cells in the circulation. Neutrophils display heterogeneity, especially in the context of cancer. Therefore, their role in cancer is debated. Nevertheless, neutrophils possess natural anti-tumor properties and appropriate stimulation, i.e. specific targeting via antibody therapy, induces potent tumor cell killing, especially via targeting of the immunoglobulin A Fc receptor (FcαRI, CD89). In this review we address the mechanisms of tumor cell killing by neutrophils and the role of neutrophils in induction of anti-tumor immunity. Moreover, possibilities for therapeutic targeting are discussed.
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Neoplasias , Neutrófilos , Citotoxicidade Celular Dependente de Anticorpos , Humanos , Imunoglobulina A , Imunoterapia , Receptores Fc/fisiologiaRESUMO
Patients with inflammatory bowel disease (IBD) produce enhanced immunoglobulin A (IgA) against the microbiota compared to healthy individuals, which has been correlated with disease severity. Since IgA complexes can potently activate myeloid cells via the IgA receptor FcαRI (CD89), excessive IgA production may contribute to IBD pathology. However, the cellular mechanisms that contribute to dysregulated IgA production in IBD are poorly understood. Here, we demonstrate that intestinal FcαRI-expressing myeloid cells (i.e., monocytes and neutrophils) are in close contact with B lymphocytes in the lamina propria of IBD patients. Furthermore, stimulation of FcαRI-on monocytes triggered production of cytokines and chemokines that regulate B-cell differentiation and migration, including interleukin-6 (IL6), interleukin-10 (IL10), tumour necrosis factor-α (TNFα), a proliferation-inducing ligand (APRIL), and chemokine ligand-20 (CCL20). In vitro, these cytokines promoted IgA isotype switching in human B cells. Moreover, when naïve B lymphocytes were cultured in vitro in the presence of FcαRI-stimulated monocytes, enhanced IgA isotype switching was observed compared to B cells that were cultured with non-stimulated monocytes. Taken together, FcαRI-activated monocytes produced a cocktail of cytokines, as well as chemokines, that stimulated IgA switching in B cells, and close contact between B cells and myeloid cells was observed in the colons of IBD patients. As such, we hypothesize that, in IBD, IgA complexes activate myeloid cells, which in turn can result in excessive IgA production, likely contributing to disease pathology. Interrupting this loop may, therefore, represent a novel therapeutic strategy.
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Doenças Inflamatórias Intestinais , Interleucina-10 , Linfócitos B , Citocinas , Humanos , Imunoglobulina A , Switching de Imunoglobulina , Isotipos de Imunoglobulinas , Interleucina-6 , Ligantes , Monócitos , Fator de Necrose Tumoral alfaRESUMO
Immunoglobulin (Ig) A is the most abundant antibody isotype present at mucosal surfaces and the second most abundant in human serum. In addition to preventing pathogen entry at mucosal surfaces, IgA can control and eradicate bacterial and viral infections through a variety of antibody-mediated innate effector cell mechanisms. The role of mucosal IgA in infection (e.g. neutralization) and in inflammatory homeostasis (e.g. allergy and autoimmunity) has been extensively investigated; by contrast, serum IgA is comparatively understudied. IgA binding to fragment crystallizable alpha receptor plays a dual role in the activation and inhibition of innate effector cell functions. Mounting evidence suggests that serum IgA induces potent effector functions against various bacterial and some viral infections including Neisseria meningitidis and rotavirus. Furthermore, in the era of immunotherapy, serum IgA provides an interesting alternative to classical IgG monoclonal antibodies to treat cancer and infectious pathogens. Here we discuss the role of serum IgA in infectious diseases with reference to bacterial and viral infections and the potential for IgA as a monoclonal antibody therapy.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Transmissíveis/imunologia , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Neoplasias/imunologia , Receptores Fc/fisiologia , Motivos de Aminoácidos/imunologia , Anticorpos Monoclonais/imunologia , Antígenos CD/imunologia , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Humanos , Imunoglobulina A/química , Fragmentos Fc das Imunoglobulinas/fisiologia , Receptores Fc/sangue , Receptores Fc/química , Receptores Fc/imunologiaRESUMO
The current gold-standard diagnostic technique for IgA nephropathy (IgAN), the leading form of primary glomerulonephritis, is renal biopsy. CD89 (the main IgA receptor) is expressed on the surface of monocytes and plays a role in disease pathogenesis. Immunocomplexes formed by sCD89 (soluble form) and Gd-IgA1 are related to disease prognosis. We hypothesize that reduced CD89 surface expression on monocytes may be a marker of disease severity. We aimed to analyze leukocyte subpopulations in peripheral blood and CD89 surface expression on monocytes in a prospective study of 22 patients and 12 healthy subjects (HS). Leukocyte subpopulations and CD89 expression were analyzed by flow cytometry. IgAN patients had a higher percentage of activated and effector memory CD4+ and CD8+ T lymphocytes, a lower percentage of transitional B lymphocytes and plasmablasts, and a higher percentage of CD56dimCD16+ NK cells and myeloid dendritic cells compared with HS. Correlations between reduced CD89 expression levels on nonclassical monocytes, histological findings of a poor prognosis on renal biopsy and baseline renal function were observed. IgAN patients show a characteristic immunological pattern in peripheral blood. A reduced expression level of CD89 on nonclassical monocytes identifies patients with a worse renal prognosis.
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Glomerulonefrite por IGA/imunologia , Fluorescência , Galactose/sangue , Humanos , Imunoglobulina A/sangue , Imunofenotipagem , Leucócitos/imunologiaRESUMO
Immunoglobulin A (IgA) is the most prevalent antibody at mucosal sites, and has an important role in defense by preventing invasion of pathogens. Traditionally, IgA has been thought of as a non-inflammatory antibody that helps to maintain homeostasis in the mucosa. However, in the last decade it has become clear that IgA is a very potent stimulus to initiate pro-inflammatory cellular processes, especially after triggering the IgA Fc receptor (FcαRI) on neutrophils. It was furthermore described that FcαRI acts as a regulator between anti- and pro-inflammatory responses of IgA. Although neutrophil activation is beneficial in (mucosal) infections, abnormal or excessive IgA immune complexes can induce disproportionate neutrophil migration and in this way initiate a perpetuating neutrophil recruitment and activation loop, which will result in severe tissue damage. Increasing evidence on this process plays a detrimental role in several diseases, including autoimmune IgA blistering diseases, a subtype of rheumatoid arthritis and ulcerative colitis. Inhibiting FcαRI-mediated activation may dampen inflammation in these patients. This process also opens up the possibility of targeting FcαRI in antibody immunotherapy of cancer. Thus, interfering with IgA-mediated FcαRI activation may represent an attractive novel therapeutic strategy for multiple maladies.
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Antígenos CD/metabolismo , Imunoglobulina A/metabolismo , Receptores Fc/metabolismo , Animais , Antígenos CD/química , Antígenos CD/genética , Regulação da Expressão Gênica , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/terapia , Imunidade nas Mucosas , Imunoglobulina A/química , Imunoglobulina A/imunologia , Imunoterapia , Ligantes , Mucosa/imunologia , Mucosa/metabolismo , Mucosa/microbiologia , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/terapia , Especificidade de Órgãos/genética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Receptores Fc/química , Receptores Fc/genética , Transdução de SinaisRESUMO
The cross-linking of the IgA Fc receptor (FcαRI) by IgA induces release of the chemoattractant LTB4, thereby recruiting neutrophils in a positive feedback loop. IgA autoantibodies of patients with autoimmune blistering skin diseases therefore induce massive recruitment of neutrophils, resulting in severe tissue damage. To interfere with neutrophil mobilization and reduce disease morbidity, we developed a panel of specific peptides mimicking either IgA or FcαRI sequences. CLIPS technology was used to stabilize three-dimensional structures and to increase peptides' half-life. IgA and FcαRI peptides reduced phagocytosis of IgA-coated beads, as well as IgA-induced ROS production and neutrophil migration in in vitro and ex vivo (human skin) experiments. Since topical application would be the preferential route of administration, Cetomacrogol cream containing an IgA CLIPS peptide was developed. In the presence of a skin permeation enhancer, peptides in this cream were shown to penetrate the skin, while not diffusing systemically. Finally, epitope mapping was used to discover sequences important for binding between IgA and FcαRI. In conclusion, a cream containing IgA or FcαRI peptide mimetics, which block IgA-induced neutrophil activation and migration in the skin may have therapeutic potential for patients with IgA-mediated blistering skin diseases.
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Antígenos CD/química , Autoanticorpos/química , Imunoglobulina A/química , Ativação de Neutrófilo/efeitos dos fármacos , Peptidomiméticos/imunologia , Peptidomiméticos/metabolismo , Receptores Fc/química , Administração Tópica , Antígenos CD/imunologia , Antígenos CD/metabolismo , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Doenças Autoimunes/terapia , Cetomacrogol/administração & dosagem , Cetomacrogol/química , Mapeamento de Epitopos , Meia-Vida , Humanos , Doenças do Sistema Imunitário/imunologia , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Transtornos Leucocíticos/imunologia , Leucotrieno B4/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Biblioteca de Peptídeos , Peptidomiméticos/química , Fagocitose , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Receptores Fc/imunologia , Receptores Fc/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Absorção Cutânea , Dermatopatias/imunologia , Dermatopatias/terapiaRESUMO
BACKGROUND: Neutrophils participate in the first line of defense by executing several killing mechanisms, including phagocytosis, degranulation and the release of neutrophil extracellular traps. Additionally, they can orchestrate the adaptive immune system by secreting cytokines and chemokines. Opsonization with antibodies aids in the recognition of pathogens, via binding to Fc receptors on the neutrophil surface. Immunoglobulin A (IgA) is the most abundant antibody at mucosal sites and has multiple functions in homeostasis and immunity. Neutrophils and IgA can interact via the IgA Fc receptor Fc?RI (CD89), leading to pro- or anti-inflammatory responses. AIMS: The aim of this review is to give a concise overview of the interplay between IgA, Fc?RI and neutrophils and to explore potential therapies for autoimmune diseases and cancer. RESULTS: Crosslinking of FcαRI by IgA-immune complexes yields potent neutrophil activation and pro-inflammatory effector functions, including the recruitment of neutrophils. This can lead to neutrophil accumulation and tissue destruction during IgA-autoantibody mediated diseases. Conversely, for cancer treatment, the myriad of powerful neutrophil effector functions after targeting FcαRI may contribute to effective immunotherapy. CONCLUSION: By interfering with or actively promoting the interaction between IgA and FcαRI, therapies for multiple maladies could be developed.
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Antígenos CD/fisiologia , Imunoglobulina A/fisiologia , Neutrófilos/imunologia , Receptores Fc/fisiologia , Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Previsões , Humanos , Imunidade Celular/imunologia , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Ativação de Neutrófilo/imunologia , Receptores Fc/imunologiaRESUMO
BACKGROUND: Soluble CD89 (sCD89)-IgA complex plays a key role in the pathogenesis of IgA nephropathy (IgAN). However, there is a lack of evidence supporting this complex as a good biomarker for disease progression. This study aimed to evaluate the usefulness of sCD89-IgA complex for risk stratification of IgAN. METHODS: A total of 326 patients with biopsy-proven IgAN were included. sCD89-IgA complex was measured by sandwich-enzyme-linked immunosorbent assay. The study endpoints were a 30% decline in estimated glomerular filtration rate (eGFR). RESULTS: sCD89-IgA complex levels were inversely and weakly associated with eGFR at the time of biopsy (r=-0.12, p=0.03). However, the significance between the two factors was lost in the multivariate linear regression after adjustment of clinical factors (ß=0.35, p=0.75). In a multivariate Cox model, the highest (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.35-1.61; p=0.45) and middle (HR, 0.93; 95% CI, 0.46-1.89; p=0.84) tertiles of sCD89-IgA complex levels were not associated with an increased risk of developing a 30% decrease in eGFR. Furthermore, the decline rates in eGFR did not differ between groups and C-statistics revealed that the sCD89-IgA complex were not superior to clinical factors in predicting disease progression. CONCLUSIONS: This study found no association between sCD89-IgA complex levels and disease progression in IgAN. Although sCD89 can contribute to the formation of immune complexes, our findings suggest that the sCD89-IgA level is not a good predictor of adverse outcomes and has limited clinical utility as a biomarker for risk stratification in IgAN.
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Antígenos CD/sangue , Glomerulonefrite por IGA/sangue , Imunoglobulina A/sangue , Receptores Fc/sangue , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/patologia , Humanos , Testes de Função Renal , Masculino , República da Coreia , Fatores de RiscoRESUMO
Immunoglobulins (Igs) play critical roles in immune defence against infectious disease. They elicit potent elimination processes such as triggering complement activation and engaging specific Fc receptors present on immune cells, resulting in phagocytosis and other killing mechanisms. Many important pathogens have evolved mechanisms to subvert or evade Ig-mediated defence. One such mechanism used by several pathogenic bacteria features proteins that bind the Ig Fc region and compromise engagement of host effector molecules. Examples include different IgA-binding proteins produced by Staphylococcus aureus, Streptococcus pyogenes, and group B streptococci, all of which interact with the same interdomain region on IgA Fc. Since this region also forms the interaction site for the major human IgA-specific Fc receptor CD89, the bacteria are able to evade CD89-mediated clearance mechanisms. Similar disruption of Ig effector function by pathogen Ig-binding proteins is evident in other species. Remarkably, all the Ig-binding proteins studied in detail to date are seen to target the CH2-CH3 domain interface in the Ig Fc region, suggesting a common mode of immune evasion. A second Ig subversion mechanism that has evolved independently in numerous pathogens involves proteases that cleave Ig molecules within their hinge regions, uncoupling the antigen recognition capability of the Fab region from clearance mechanisms elicited by the Fc region. The emerging understanding of the structural basis for the recognition of Igs as substrates for these proteases and as interaction partners for Ig-binding proteins may open up new avenues for treatment or vaccination.
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Bactérias/imunologia , Proteínas de Bactérias/imunologia , Imunoglobulinas/imunologia , Receptores Fc/imunologia , Bactérias/classificação , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunoglobulinas/metabolismo , Modelos Moleculares , Ligação Proteica/imunologia , Conformação Proteica , Receptores Fc/química , Receptores Fc/metabolismo , Staphylococcus aureus/imunologia , Staphylococcus aureus/metabolismo , Staphylococcus aureus/fisiologia , Streptococcus agalactiae/imunologia , Streptococcus agalactiae/metabolismo , Streptococcus agalactiae/fisiologia , Streptococcus pyogenes/imunologia , Streptococcus pyogenes/metabolismo , Streptococcus pyogenes/fisiologiaRESUMO
The goal of study was better understanding of complex immune mechanisms that can help to evaluate patients with chronic urticaria (CU), especially those with unknown etiology. The study involved 55 patients with CU. Control group consisted of up to 90 healthy persons. The presence and intensity of serum IgG, IgA, IgM and IgE antibodies to common food antigens: cow's milk proteins (CMP), gliadin and phytohemagglutinin were determined by ELISA. Determination of subpopulations of immunocompetent cells was performed by flow cytometry. Significantly enhanced IgE, but also IgA immunity to CMP was found in patients with CU in comparison to healthy controls: (p < 0.000004) and (p < 0.002), respectively. Notably, in 40 out of 55 CU patients, the increased levels of some type of immunoglobulin reactivity to CMP were found. Regarding gliadin, only the levels of serum IgE anti-gliadin antibodies were significantly enhanced in patients with CU (p < 0.04). Significantly enhanced percentage of CD89+ cells accompanied with significantly lower percentage of lymphocytes and significantly higher mean fluorescence intensity of CD26 expression on lymphocytes were found in patients with CU in comparison to healthy controls (p < 0.04), (p < 0.02) and (p < 0.003), respectively. Results of this study may help in better understanding the complex immune disturbances in patients with CU.
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Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/imunologia , Alimentos/efeitos adversos , Urticária/complicações , Urticária/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alérgenos/imunologia , Animais , Estudos de Casos e Controles , Bovinos , Doença Crônica , Dipeptidil Peptidase 4/sangue , Humanos , Imunidade Humoral , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Imunofenotipagem , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Pessoa de Meia-Idade , Proteínas do Leite/imunologia , Urticária/diagnóstico , Adulto JovemRESUMO
BACKGROUND & AIMS: Anti-neutrophil cytoplasmic antibodies (ANCA) are a non-uniform family of antibodies recognizing diverse components of neutrophil granulocytes. ANCA formation might be induced by protracted bacterial infections or probably reflect an abnormal immune response to commensal microorganisms. Bacterial infections are common complications in cirrhosis with high incidence of episodes caused by enteric organisms, therefore, we sought to study the presence and clinical importance of ANCA in cirrhosis. METHODS: Sera of 385 patients with cirrhosis of different etiologies were assayed for ANCA of IgG, IgA, IgA1, IgA2, and secretory IgA subtypes by indirect immunofluorescence and ELISAs. The control group comprised 202 patients with chronic liver diseases without cirrhosis and 100 healthy subjects. In cirrhosis, a 2-year follow-up, observational study was conducted to assess a possible association between the presence of ANCA and clinically significant bacterial infections. RESULTS: Prevalence of ANCA IgA was significantly higher in cirrhosis (52.2%) compared to chronic liver diseases (18.6%) or healthy controls (0%, p<0.001 for both). ANCA IgA subtyping assays revealed marked increase in the proportion of IgA2 subtype (46% of total ANCA IgA) and presence of the secretory component concurrently. Presence of ANCA IgA was associated with disease-specific clinical characteristics (Child-Pugh stage and presence of ascites, p<0.001). During a 2-year follow-up period, risk of infections was higher among patients with ANCA IgA compared to those without (41.8% vs. 23.4%, p<0.001). ANCA IgA positivity was associated with a shorter time to the first infectious complication (pLogRank <0.001) in Kaplan-Meier analysis and was identified as an independent predictor in multivariate Cox-regression analysis (HR:1.74, 95% CI: 1.18-2.56, p=0.006). CONCLUSIONS: Presence of IgA type ANCA is common in cirrhosis. Involvement of gut mucosal immune system is in center of their formation and probably reflects sustained exposure to bacterial constituents.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Infecções Bacterianas/etiologia , Infecções Bacterianas/imunologia , Imunoglobulina A/sangue , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Hepatite C Crônica/complicações , Hepatite C Crônica/imunologia , Humanos , Imunoglobulina A/classificação , Cirrose Hepática Alcoólica/complicações , Cirrose Hepática Alcoólica/imunologia , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/imunologia , Hepatopatias/complicações , Hepatopatias/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de TempoRESUMO
Recent advances in the development of therapeutic antibodies (Abs) have greatly improved the treatment of otherwise drug-resistant cancers and autoimmune diseases. Antibody activities are mediated by both their Fab and the Fc. However, therapeutic Abs base their protective mechanisms on Fc-mediated effector functions resulting in the activation of innate immune cells by FcRs. Therefore, Fc-bioengineering has been widely used to maximise the efficacy and convenience of therapeutic antibodies. Today, IgG remains the only commercially available therapeutic Abs, at the expense of other isotypes. Indeed, production, sampling, analysis and related in vivo studies are easier to perform with IgG than with IgA due to well-developed tools. However, interest in IgA is growing, despite a shorter serum half-life and a more difficult sampling and purification methods than IgG. Indeed, the paradigm that the effector functions of IgG surpass those of IgA has been experimentally challenged. Firstly, IgA has been shown to bind to its Fc receptor (FcR) on effector cells of innate immunity with greater efficiency than IgG, resulting in more robust IgA-mediated effector functions in vitro and better survival of treated animals. In addition, the two isotypes have been shown to act synergistically. From these results, new therapeutic formats of Abs are currently emerging, in particular chimeric Abs containing two tandemly expressed Fc, one from IgG (Fcγ) and one from IgA (Fcα). By binding both FcγR and FcαR on effector cells, these new chimeras showed improved effector functions in vitro that were translated in vivo. Furthermore, these chimeras retain an IgG-like half-life in the blood, which could improve Ab-based therapies, including in AIDS. This review provides the rationale, based on the biology of IgA and IgG, for the development of Fcγ and Fcα chimeras as therapeutic Abs, offering promising opportunities for HIV-1 infected patients. We will first describe the main features of the IgA- and IgG-specific Fc-mediated signalling pathways and their respective functional differences. We will then summarise the very promising results on Fcγ and Fcα containing chimeras in cancer treatment. Finally, we will discuss the impact of Fcα-Fcγ chimerism in prevention/treatment strategies against infectious diseases such as HIV-1.
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Quimerismo , Receptores de IgG , Animais , Receptores de IgG/metabolismo , Fragmentos Fc das Imunoglobulinas , Receptores Fc , Imunoglobulina G , Imunoglobulina ARESUMO
Immunoglobulin A (IgA) is generally considered as a non-inflammatory regulator of mucosal immunity, and its importance in diversifying the gut microbiota is increasingly appreciated. IgA autoantibodies have been found in several autoimmune or chronic inflammatory diseases, but their role in pathophysiology is ill-understood. IgA can interact with the Fc receptor FcαRI on immune cells. We now established a novel IgA autoimmune blistering model, which closely resembles the human disease linear IgA bullous disease (LABD) by using genetically modified mice that produce human IgA and express human FcαRI. Intravital microscopy demonstrated that presence of IgA anti-collagen XVII, - the auto-antigen in LABD-, resulted in neutrophil activation and extravasation from blood vessels into skin tissue. Continued exposure to anti-collagen XVII IgA led to massive neutrophil accumulation, severe tissue damage and blister formation. Importantly, treatment with anti-FcαRI monoclonal antibodies not only prevented disease, but was also able to resolve existing inflammation and tissue damage. Collectively, our data reveal a novel role of neutrophil FcαRI in IgA autoantibody-mediated disease and identify FcαRI as promising new therapeutic target to resolve chronic inflammation and tissue damage.
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Imunoglobulina A , Receptores Fc , Animais , Anticorpos Monoclonais/uso terapêutico , Autoanticorpos , Inflamação/tratamento farmacológico , CamundongosRESUMO
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and one of the leading causes of renal failure worldwide. The pathophysiology of IgAN involves nephrotoxic IgA1-immune complexes. These complexes are formed by galactose-deficient (Gd) IgA1 with autoantibodies against the hinge region of Gd-IgA1 as well as soluble CD89, an immune complex amplifier with an affinity for mesangial cells. These multiple molecular interactions result in the induction of the mesangial IgA receptor, CD71, injuring the kidney and causing disease. This review features recent immunological and microbiome studies that bring new microbiota-dependent mechanisms developing the disease based on data from IgAN patients and a humanized mouse model of IgAN. Dysbiosis of the microbiota in IgAN patients is also discussed in detail. Highlights of this review underscore that nephrotoxic IgA1 in the humanized mice originates from mucosal surfaces. Fecal microbiota transplantation (FMT) experiments in mice using stools from patients reveal a possible microbiota dysbiosis in IgAN with the capacity to induce progression of the disease whereas FMT from healthy hosts has beneficial effects in mice. The continual growth of knowledge in IgAN patients and models can lead to the development of new therapeutic strategies targeting the microbiota to treat this disease.
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INTRODUCTION: Most bispecific antibody (BsAb) therapies focus on stimulating the adaptive immune system, in particular T cells, to promote tumor cell killing. Another method to promote tumor eradication is through the engagement of myeloid cells, including macrophages and neutrophils, which are abundantly present and possess intrinsic cytotoxic mechanisms for tumor cell killing, making them interesting effector cells to recruit for BsAb therapy. AREAS COVERED: In this review, we describe the evolving knowledge of the role of macrophages and neutrophils in cancer in scientific literature. Moreover, we address the BsAbs that have been developed over the years to recruit these cell types as effector cells in immunotherapy of cancer. This includes the discussion of BsAbs that target Fc receptors (i.e. FcγR and FcαRI) to induce antibody-dependent cellular phagocytosis (ADCP) by macrophages or trogoptosis via neutrophils, as well as BsAbs that interfere with checkpoint inhibition, including the SIRPα-CD47 pathway. EXPERT OPINION: Elucidating the complexity of macrophage and neutrophil heterogeneity in cancer may help to specifically enlist the cytotoxic ability of these cells through targeting Fc receptors and checkpoint pathways, which may further enhance anti-cancer immunity.
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Anticorpos Biespecíficos , Antineoplásicos , Neoplasias , Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Humanos , Imunoterapia/métodos , Células Mieloides/patologia , Fagocitose , Receptores FcRESUMO
Both IgA nephropathy and IgA vasculitis, formerly known as Henoch-SchÓ§nlein purpura, are immune deposition diseases. IgA nephropathy is caused by the deposition of aberrantly formed poly-IgA complexes from blood circulation to the kidney glomerulus; IgA vasculitis is characterized by IgA-dominant immune deposits to small vessels of the skin and other organs, including the kidney. Therefore, measuring the disease-causing poly-IgA contents in the plasma is needed to study these conditions. However, while clinical tests for the level of total plasma IgA are routinely performed, methods for specific detection of poly-IgA contents are unavailable in clinical medicine. In this protocol, we describe a practical solution for measuring poly-IgA in patient samples. The new method is based on the biological selectivity of IgA Fcα receptor I (FcαRI/CD89) toward poly-IgA species, in contrast to its relatively low affinity for normal monomeric IgA. By devising recombinant CD89 ectodomain as the "capturing" probe, we validated the feasibility of the assay for measuring plasma poly-IgA levels in a 96-well format. The methodology was able to differentiate plasma samples of IgA nephropathy, or related IgA vasculitis, from those of other autoimmune kidney disease types or from healthy controls. Moreover, the measured poly-IgA indices not only correlated with the severity of IgA nephropathy, but the levels also trended lower following corticosteroid or immunosuppressant treatments of patients. Therefore, we anticipate the new assay will provide useful measurements of the IgA nephropathy disease activity index for stratifying disease severity or for evaluating treatment response. Graphical abstract.
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IgA Nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by the mesangial deposition of abnormally glycosylated IgA1 (Gd-IgA). The production of Gd-IgA occurs in mucose-associated lymphoid tissue (MALT). The microbiota plays a role in MALT modulation. Rifaximin (NORMIX®), a non-absorbable oral antibiotic, induces positive modulation of the gut microbiota, favoring the growth of bacteria beneficial to the host. Here, we evaluate the effect of rifaximin on a humanized mice model of IgAN (α1KI-CD89Tg). Methods: The α1KI-CD89Tg mice were treated by the vehicle (olive oil) or rifaximin (NORMIX®). Serum levels of hIgA, hIgA1-sCD89, and mIgG-hIgA1 immune complexes were determined. Glomerular hIgA1 deposit and CD11b+ cells recruitment were revealed using confocal microscopy. Furthermore, the mRNA of the B-Cell Activating Factor (BAFF), polymeric immunoglobulin receptor (pIgR), and Tumor Necrosing Factor-α (TNF-α) in gut samples were detected by qPCR. Results: Rifaximin treatment decreased the urinary protein-to-creatinine ratio, serum levels of hIgA1-sCD89 and mIgG-hIgA1 complexes, hIgA1 glomerular deposition, and CD11b+ cell infiltration. Moreover, rifaximin treatment decreased significantly BAFF, pIgR, and TNF-α mRNA expression. Conclusions: Rifaximin decreased the IgAN symptoms observed in α1KI-CD89Tg mice, suggesting a possible role for it in the treatment of the disease.
RESUMO
Mucosal surfaces constitute the frontiers of the body and are the biggest barriers of our body for the outside world. Immunoglobulin A (IgA) is the most abundant antibody class present at these sites. It passively contributes to mucosal homeostasis via immune exclusion maintaining a tight balance between tolerating commensals and providing protection against pathogens. Once pathogens have succeeded in invading the epithelial barriers, IgA has an active role in host-pathogen defense by activating myeloid cells through divers receptors, including its Fc receptor, FcαRI (CD89). To evade elimination, several pathogens secrete proteins that interfere with either IgA neutralization or FcαRI-mediated immune responses, emphasizing the importance of IgA-FcαRI interactions in preventing infection. Depending on the IgA form, either anti- or pro-inflammatory responses can be induced. Moreover, the presence of excessive IgA immune complexes can result in continuous FcαRI-mediated activation of myeloid cells, potentially leading to severe tissue damage. On the one hand, enhancing pathogen-specific mucosal and systemic IgA by vaccination may increase protective immunity against infectious diseases. On the other hand, interfering with the IgA-FcαRI axis by monovalent targeting or blocking FcαRI may resolve IgA-induced inflammation and tissue damage. This review describes the multifaceted role of FcαRI as immune regulator between anti- and pro-inflammatory responses of IgA, and addresses potential novel therapeutic strategies that target FcαRI in disease.
RESUMO
New evidence has been emerging that antibodies can be protective in various experimental models of tuberculosis. Here, we report on protection against multidrug-resistant Mycobacterium tuberculosis (MDR-TB) infection using a combination of the human monoclonal IgA 2E9 antibody against the alpha-crystallin (Acr, HspX) antigen and mouse interferon-gamma in mice transgenic for the human IgA receptor, CD89. The effect of the combined mucosal IgA and IFN-γ; treatment was strongest (50-fold reduction) when therapy was applied at the time of infection, but a statistically significant reduction of lung bacterial load was observed even when the therapy was initiated once the infection had already been established. The protection involving enhanced phagocytosis and then neutrophil mediated killing of infected cells was IgA isotype mediated, because treatment with an IgG version of 2E9 antibody was not effective in human IgG receptor CD64 transgenic mice. The Acr antigen specificity of IgA antibodies for protection in humans has been indicated by their elevated serum levels in latent tuberculosis unlike the lack of IgA antibodies against the virulence-associated MPT64 antigen. Our results represent the first evidence for potential translation of mucosal immunotherapy for the management of MDR-TB.