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1.
Int Immunopharmacol ; 93: 107406, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33601246

RESUMO

In patients with COVID-19,type 2 diabetes mellitus (T2DM) can impair the function of nasal-associated lymphoid tissue (NALT) and result in olfactory dysfunction. Exploring the causative alterations of T2DM within the nasal mucosa and NALT could provide insight into the pathogenic mechanisms and bridge the gap between innate immunity and adaptive immunity for virus clearance. Here, we designed a case-control study to compare the olfactory function (OF) among the groups of normal control (NC), COVID-19 mild pneumonia (MP), and MP patients with T2DM (MPT) after a 6-8 months' recovery, in which MPT had a higher risk of hyposmia than MP and NC. No significant difference was found between the MP and NC. This elevated risk of hyposmia indicated that T2DM increased COVID-19 susceptibility in the nasal cavity with unknown causations. Therefore, we used the T2DM animal model (db/db mice) to evaluate how T2DM increased COVID-19 associated susceptibilities in the nasal mucosa and lymphoid tissues. Db/db mice demonstratedupregulated microvasculature ACE2 expression and significant alterations in lymphocytes component of NALT. Specifically, db/db mice NALT had increased immune-suppressive TCRγδ+ CD4-CD8- T and decreased immune-effective CD4+/CD8+ TCRß+ T cells and decreased mucosa-protective CD19+ B cells. These results indicated that T2DM could dampen the first-line defense of nasal immunity, and further mechanic studies of metabolic damage and NALT restoration should be one of the highest importance for COVID-19 healing.


Assuntos
/imunologia , /imunologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/virologia , Adulto , Animais , Linfócitos B/imunologia , /fisiopatologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Imunidade nas Mucosas/imunologia , Tecido Linfoide/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Animais , Mucosa Nasal/imunologia , Mucosa Olfatória/metabolismo , Fatores de Risco , Serina Endopeptidases/metabolismo , Linfócitos T/imunologia
2.
Science ; 371(6526)2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33446526

RESUMO

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.


Assuntos
Candida albicans/imunologia , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Imunidade nas Mucosas/imunologia , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Humanos , Imunidade nas Mucosas/genética , Vigilância Imunológica/genética , Vigilância Imunológica/imunologia , Interferon gama/genética , Interleucinas/genética , Janus Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Receptores de Interleucina-17/genética , Fator de Transcrição STAT1/genética , Linfócitos T/imunologia , Adulto Jovem
3.
Arch Virol ; 166(2): 545-557, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33409549

RESUMO

The use of gamma-irradiated influenza A virus (γ-Flu), retains most of the viral structural antigens, represent a promising option for vaccine development. However, despite the high effectiveness of γ-Flu vaccines, the need to incorporate an adjuvant to improve vaccine-mediated protection seems inevitable. Here, we examined the protective efficacy of an intranasal gamma-irradiated HIN1 vaccine co-administered with a plasmid encoding mouse interleukin-28B (mIL-28B) as a novel adjuvant in BALB/c mice. Animals were immunized intranasally three times at one-week intervals with γ-Flu, alone or in combination with the mIL-28B adjuvant, followed by viral challenge with a high lethal dose (10 LD50) of A/PR/8/34 (H1N1) influenza virus. Virus-specific antibody, cellular and mucosal responses, and the balance of cytokines in the spleen IFN-γ, IL-12, and IL-4) and in lung homogenates (IL-6 and IL-10) were measured by ELISA. The lymphoproliferative activity of restimulated spleen cells was also determined by MTT assay. Furthermore, virus production in the lungs of infected mice was estimated using the Madin-Darby canine kidney (MDCK)/hemagglutination assay (HA). Our data showed that intranasal immunization with adjuvanted γ-Flu vaccine efficiently promoted humoral, cellular, and mucosal immune responses and efficiently decreased lung virus titers, all of which are associated with protection against challenge. This combination also reduced IL-6 and IL-10 levels in lung homogenates. The results suggest that IL-28B can enhance the ability of the vaccine to elicit virus-specific immune responses and could potentially be used as an effective adjuvant.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Citocinas/imunologia , Imunidade Celular/imunologia , Imunidade nas Mucosas/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Infecções por Orthomyxoviridae/imunologia , Administração Intranasal/métodos , Animais , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Cães , Feminino , Imunização/métodos , Vacinas contra Influenza/imunologia , Pulmão/imunologia , Pulmão/virologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/virologia , Vacinação/métodos
4.
Methods Mol Biol ; 2182: 153-160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32894494

RESUMO

A simple procedure for obtaining outer membrane vesicles from Salmonella enterica and the use of hydrogels as vaccine delivery system is described. A heat treatment in saline solution of whole bacteria rendered the release of outer membrane vesicles containing relevant antigenic components. The immunogenicity of these antigens when administered by the intranasal route may be improved after embedment into hydrogels to increase residence half-time and thus activate the mucosal immune system.


Assuntos
Proteínas da Membrana Bacteriana Externa/química , Proteínas da Membrana Bacteriana Externa/imunologia , Hidrogéis/química , Vacinas/química , Vacinas/imunologia , Administração Intranasal/métodos , Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Imunidade nas Mucosas/imunologia , Imunogenicidade da Vacina/imunologia , Salmonella enterica/imunologia
5.
Mol Immunol ; 130: 64-68, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33360378

RESUMO

The monomorphic MHC-class I-like molecule, MR1, presents small metabolites to T cells. MR1 is the restriction element for microbe-reactive mucosal-associated invariant T (MAIT) cells. MAIT cells have limited TCR usage, including a semi-invariant TCR alpha chain and express high levels of CD161 and CD26. In addition to microbial lumazine metabolites, recent studies have demonstrated that MR1 is able to capture a variety of diverse chemical entities including folate-derivatives, a number of drug-like and other synthetic small molecules, and as yet undefined compounds of self-origin. This capacity of MR1 to bind distinct ligands likely accounts for the recent identification of additional, non-canonical, subsets of MR1-restricted T (MR1T) cells. These subsets can be defined based on their ability to recognize diverse microbes as well as their reactivity to non-microbial cell-endogenous ligands, including tumor-associated antigens. Herein, we will discuss our current understanding of MR1T cell diversity in terms of TCR usage, ligand recognition and functional attributes.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariáveis Associadas à Mucosa/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/fisiologia , Subpopulações de Linfócitos T/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade nas Mucosas/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Receptores de Antígenos de Linfócitos T/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta
8.
Nature ; 584(7820): 274-278, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760003

RESUMO

Colonization by the microbiota causes a marked stimulation of B cells and induction of immunoglobulin, but mammals colonized with many taxa have highly complex and individualized immunoglobulin repertoires1,2. Here we use a simplified model of defined transient exposures to different microbial taxa in germ-free mice3 to deconstruct how the microbiota shapes the B cell pool and its functional responsiveness. We followed the development of the immunoglobulin repertoire in B cell populations, as well as single cells by deep sequencing. Microbial exposures at the intestinal mucosa generated oligoclonal responses that differed from those of germ-free mice, and from the diverse repertoire that was generated after intravenous systemic exposure to microbiota. The IgA repertoire-predominantly to cell-surface antigens-did not expand after dose escalation, whereas increased systemic exposure broadened the IgG repertoire to both microbial cytoplasmic and cell-surface antigens. These microbial exposures induced characteristic immunoglobulin heavy-chain repertoires in B cells, mainly at memory and plasma cell stages. Whereas sequential systemic exposure to different microbial taxa diversified the IgG repertoire and facilitated alternative specific responses, sequential mucosal exposure produced limited overlapping repertoires and the attrition of initial IgA binding specificities. This shows a contrast between a flexible response to systemic exposure with the need to avoid fatal sepsis, and a restricted response to mucosal exposure that reflects the generic nature of host-microbial mutualism in the mucosa.


Assuntos
Linfócitos B/citologia , Linfócitos B/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Simbiose/imunologia , Administração Intravenosa , Administração Oral , Animais , Clostridiales/imunologia , Clostridiales/isolamento & purificação , Escherichia coli/imunologia , Escherichia coli/isolamento & purificação , Feminino , Vida Livre de Germes , Imunoglobulina A/química , Imunoglobulina A/imunologia , Imunoglobulina G/química , Imunoglobulina G/imunologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Memória Imunológica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasmócitos/citologia , Plasmócitos/imunologia , Priming de Repetição
9.
Life Sci ; 261: 118343, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32858038

RESUMO

INTRODUCTION: It is well known that immune system is highly specific to protect the body against various environmental pathogens. The concept of conventional vaccination has overcome the pandemic situation of several infectious diseases outbreak. AREA COVERED: The recent idea of immunization through oral route (edible vaccine) is vital alternatives over conventional vaccines. Edible vaccines are composed of antigenic protein introduced into the plant cells which induce these altered plants to produce the encoded protein. Edible vaccine has no way of forming infection and safety is assured as it only composed of antigenic protein and is devoid of pathogenic genes. Edible vaccines have significant role in stimulating mucosal immunity as they come in contact with digestive tract lining. They are safe, cost-effective, easy-to-administer and have reduced manufacturing cost hence have a dramatic impact on health care in developing countries. EXPERT OPINION: The edible vaccine might be the solution for the potential hazard associated with the parenteral vaccines. In this review we discuss the detailed study of pros, cons, mechanism of immune stimulation, various outbreaks that might be controlled by edible vaccines with the possible future research and applied application of edible vaccine.


Assuntos
Imunidade nas Mucosas/imunologia , Imunização , Vacinas de Plantas Comestíveis/administração & dosagem , Administração Oral , Animais , Análise Custo-Benefício , Humanos , Vacinas de Plantas Comestíveis/efeitos adversos , Vacinas de Plantas Comestíveis/imunologia
10.
J Vis Exp ; (160)2020 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-32597837

RESUMO

Studying isolated cells from mucosa-associated lymphoid tissues (MALT) allows understanding of immune cells response in pathologies involving mucosal immunity, because they can model host-pathogen interactions in the tissue. While isolated cells derived from tissues were the first cell culture model, their use has been neglected because tissue can be hard to obtain. In the present protocol, we explain how to easily process and culture tonsillar mononuclear cells (TMCs) from healthy human tonsils to study innate immune responses upon activation, mimicking viral infection in mucosal tissues. Isolation of TMCs from the tonsils is quick, because the tonsils barely have any epithelium and yield up to billions of all major immune cell types. This method allows detection of cytokine production using several techniques, including immunoassays, qPCR, microscopy, flow cytometry, etc., similar to the use of peripheral mononuclear cells (PBMCs) from blood. Furthermore, TMCs show a higher sensitivity to drug testing than PBMCs, which needs to be considered for future toxicity assays. Thus, ex vivo TMCs cultures are an easy and accessible mucosal model.


Assuntos
Separação Celular/métodos , Imunidade Inata/imunologia , Imunidade nas Mucosas/imunologia , Leucócitos Mononucleares/citologia , Tecido Linfoide/imunologia , Tonsila Palatina/citologia , Citometria de Fluxo , Humanos , Leucócitos Mononucleares/imunologia , Tecido Linfoide/citologia , Tonsila Palatina/imunologia
11.
Am J Gastroenterol ; 115(6): 814-822, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32250997

RESUMO

Primary sclerosing cholangitis (PSC) is a rare, immune-mediated, chronic cholestatic liver disease associated with a unique phenotype of inflammatory bowel disease that frequently manifests as pancolitis with right-sided predominance. Available data suggest a bidirectional interplay of the gut-liver axis with critical roles for the gastrointestinal microbiome and circulating bile acids (BAs) in the pathophysiology of PSC. BAs shape the gut microbiome, whereas gut microbes have the potential to alter BAs, and there are emerging data that alterations of BAs and the microbiome are not simply a consequence but the cause of PSC. Clustering of PSC in families may suggest that PSC occurs in genetically susceptible individuals. After exposure to an environmental trigger (e.g., microbial byproducts or BAs), an aberrant or exaggerated cholangiocyte-induced immune cascade occurs, ultimately leading to bile duct damage and progressive fibrosis. The pathophysiology can be conceptualized as a triad of (1) gut dysbiosis, (2) altered BA metabolism, and (3) immune-mediated biliary injury. Immune activation seems to be central to the disease process, but immunosuppression does not improve clinical outcomes or alter the natural history of PSC. Currently, orthoptic liver transplantation is the only established life-saving treatment, whereas antimicrobial therapy or fecal transplantation is an emerging therapeutic option for PSC. The beneficial effects of these microbiome-based therapies are likely mediated by a shift of the gut microbiome with favorable effects on BA metabolism. In the future, personalized approaches will allow to better target the interdependence between microbiome, immune function, and BA metabolism and potentially cure patients with PSC.


Assuntos
Anti-Infecciosos/uso terapêutico , Ácidos e Sais Biliares/metabolismo , Colangite Esclerosante/terapia , Disbiose/terapia , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/microbiologia , Colangite Esclerosante/imunologia , Colangite Esclerosante/metabolismo , Colangite Esclerosante/microbiologia , Disbiose/imunologia , Disbiose/metabolismo , Transplante de Microbiota Fecal , Humanos , Imunidade nas Mucosas/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Transplante de Fígado
12.
Immunity ; 52(3): 557-570.e6, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32160523

RESUMO

The intestine contains some of the most diverse and complex immune compartments in the body. Here we describe a method for isolating human gut-associated lymphoid tissues (GALTs) that allows unprecedented profiling of the adaptive immune system in submucosal and mucosal isolated lymphoid follicles (SM-ILFs and M-ILFs, respectively) as well as in GALT-free intestinal lamina propria (LP). SM-ILF and M-ILF showed distinct patterns of distribution along the length of the intestine, were linked to the systemic circulation through MAdCAM-1+ high endothelial venules and efferent lymphatics, and had immune profiles consistent with immune-inductive sites. IgA sequencing analysis indicated that human ILFs are sites where intestinal adaptive immune responses are initiated in an anatomically restricted manner. Our findings position ILFs as key inductive hubs for regional immunity in the human intestine, and the methods presented will allow future assessment of these compartments in health and disease.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Tecido Linfoide/imunologia , Imunidade Adaptativa/genética , Animais , Citometria de Fluxo , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/ultraestrutura , Humanos , Imunidade nas Mucosas/genética , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/ultraestrutura , Intestinos/ultraestrutura , Linfócitos/imunologia , Linfócitos/metabolismo , Tecido Linfoide/metabolismo , Tecido Linfoide/ultraestrutura , Microscopia Confocal , Microscopia Eletrônica de Varredura , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Nódulos Linfáticos Agregados/ultraestrutura , Análise de Sequência de DNA
13.
Sci Adv ; 6(5): eaax2285, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32064333

RESUMO

To be optimally effective, peptide-based vaccines need to be administered with adjuvants. Many currently available adjuvants are toxic, not biodegradable; they invariably invoke adverse reactions, including allergic responses and excessive inflammation. A nontoxic, biodegradable, biocompatible, self-adjuvanting vaccine delivery system is urgently needed. Herein, we report a potent vaccine delivery system fulfilling the above requirements. A peptide antigen was coupled with poly-hydrophobic amino acid sequences serving as self-adjuvanting moieties using solid-phase synthesis, to produce fully defined single molecular entities. Under aqueous conditions, these molecules self-assembled into distinct nanoparticles and chain-like aggregates. Following subcutaneous immunization in mice, these particles successfully induced opsonic epitope-specific antibodies without the need of external adjuvant. Mice immunized with entities bearing 15 leucine residues were able to clear bacterial load from target organs without triggering the release of soluble inflammatory mediators. Thus, we have developed a well-defined and effective self-adjuvanting delivery system for peptide antigens.


Assuntos
Sistemas de Liberação de Medicamentos , Inflamação/prevenção & controle , Vacinas de Subunidades/farmacologia , Vacinas/farmacologia , Adjuvantes Imunológicos/farmacologia , Aminoácidos/química , Aminoácidos/imunologia , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Epitopos/efeitos dos fármacos , Epitopos/imunologia , Humanos , Imunidade nas Mucosas/imunologia , Inflamação/imunologia , Camundongos , Nanopartículas/química , Vacinas/química , Vacinas/imunologia , Vacinas de Subunidades/química , Vacinas de Subunidades/imunologia
14.
Nat Rev Immunol ; 20(7): 427-441, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32015473

RESUMO

Humoral immune responses at mucosal surfaces have historically focused on IgA. Growing evidence highlights the complexity of IgA-inducing pathways and the functional impact of IgA on mucosal commensal bacteria. In the gut, IgA contributes to the establishment of a mutualistic host-microbiota relationship that is required to maintain homeostasis and prevent disease. This Review discusses how mucosal IgA responses occur in an increasingly complex humoral defence network that also encompasses IgM, IgG and IgD. Aside from integrating the protective functions of IgA, these hitherto neglected mucosal antibodies may strengthen the communication between mucosal and systemic immune compartments.


Assuntos
Anticorpos Antibacterianos/imunologia , Bactérias/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Animais , Bactérias/classificação , Humanos , Imunoglobulina A/imunologia , Imunoglobulina D/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Mucosa Intestinal/microbiologia
15.
Nature ; 578(7796): 527-539, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32103191

RESUMO

Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.


Assuntos
Doenças Inflamatórias Intestinais/genética , Animais , Citocinas/imunologia , Exoma/genética , Fibrose/imunologia , Fibrose/patologia , Predisposição Genética para Doença , Homeostase , Humanos , Imunidade Celular , Imunidade Humoral , Imunidade Inata , Imunidade nas Mucosas/genética , Imunidade nas Mucosas/imunologia , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Análise de Célula Única
16.
Reumatol. clín. (Barc.) ; 16(1): 49-55, ene.-feb. 2020. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-194261

RESUMO

Existe una búsqueda urgente de alternativas a los antibióticos para prevenir infecciones, debido al aumento acelerado de la resistencia a los antibióticos. Esto es más grave para los pacientes con infecciones recurrentes que tienen que ser tratados con varios ciclos de antibióticos al año, lo que incrementa el riesgo de resistencia a los antibióticos, que puede ser potencialmente mortal. En los últimos años se ha demostrado que el uso de vacunas profilácticas por vía mucosa para estos pacientes es una alternativa potencialmente beneficiosa y segura para prevenir infecciones. El nuevo conocimiento sobre la inmunidad de las mucosas y la inmunidad entrenada, una forma de memoria de la inmunidad innata que puede mejorar la respuesta a diferentes amenazas por infecciones, ha hecho más fácil expandir su utilización. La aplicación clínica de la inmunidad entrenada de estos fármacos podría explicar sus efectos simultáneos pro-tolerogénicos y potenciadores en diversas células inmunitarias para diferentes infecciones. En esta revisión describimos los mecanismos inmunomoduladores de las vacunas polibacterianas de la mucosa, su conexión con la inmunidad entrenada y su utilidad en la prevención de infecciones recurrentes en pacientes inmunocomprometidos


An urgent search is currently underway for alternatives to antibiotics to prevent infections, due to the accelerated evolution and increase in antibiotic resistance. This problem is more serious for patients with recurrent infections, since they have to use many cycles of antibiotics per year, so the risk for antibiotic resistance is higher and can be life-threatening. In recent years, the use of prophylactic vaccines via the mucosal route for these patients with recurrent infections has been demonstrated as a potentially beneficial and safe alternative to prevent infections. The new knowledge about mucosal immunity and trained immunity, a form of innate immunity memory that can enhance the response to different infectious threads, has made it easier to extend its use. The application of the new concepts of trained immunity may explain the simultaneous pro-tolerogenic and boosting effect or effects of these drugs on diverse immune cells for different infections. In this review, we describe the immunomodulatory mechanisms of mucosal polybacterial vaccines and their connection with trained immunity and its utility in the prevention of recurrent infections in immunosuppressed patients


Assuntos
Humanos , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/uso terapêutico , Imunidade nas Mucosas/imunologia , Imunomodulação , Doenças Autoimunes/imunologia , Infecções/imunologia , Prevenção Secundária
17.
PLoS One ; 15(1): e0218905, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935222

RESUMO

The innate immune response induced by type I interferons (IFNs) plays a critical role in the establishment of HIV infection. IFNs are induced early in HIV infection and trigger an antiviral defense program by signaling through the IFNα/ß receptor (IFNAR), which consists of two subunits, IFNAR1 and IFNAR2. Changes in IFNAR expression in HIV target cells, as well as other immune cells, could therefore have important consequences for initial HIV spread. It was previously reported that IFNAR2 expression is increased in peripheral blood CD4+ CXCR4+ T cells of HIV+ patients compared to HIV uninfected controls, suggesting that HIV infection may alter the IFN responsiveness of target cells. However, the earliest immune cells affected by HIV in vivo reside in the gut-associated lymphoid tissue (GALT). To date, it remains unknown if IFNAR expression is altered in GALT immune cells in the context of HIV infection and exposure to IFNs, including the 12 IFNα subtypes. Here, we analyzed the expression of surface bound and soluble IFNAR2 on Lamina propria mononuclear cells (LPMCs) isolated from the GALT of HIV- individuals and in plasma samples of HIV+ patients. IFNAR2 expression varied between different T cells, B cells and natural killer cells, but was not altered following HIV infection. Furthermore, expression of the soluble IFNAR2a isoform was not changed in HIV+ patients compared to healthy donors, nor in LPMCs after HIV-1 infection ex vivo. Even though the 12 human IFNα subtypes trigger different biological responses and vary in their affinity to both receptor subunits, stimulation of LPMCs with different recombinant IFNα subtypes did not result in any significant changes in IFNAR2 surface expression. Our data suggests that potential changes in the IFN responsiveness of mucosal immune cells during HIV infection are unlikely dictated by changes in IFNAR2 expression.


Assuntos
Infecções por HIV/genética , Imunidade Inata/genética , Receptor de Interferon alfa e beta/genética , Antivirais/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Imunidade nas Mucosas/imunologia , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Tecido Linfoide/imunologia , Tecido Linfoide/virologia , Transdução de Sinais/efeitos dos fármacos
18.
Curr Top Microbiol Immunol ; 426: 21-43, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31974759

RESUMO

Pulmonary respiration inevitably exposes the mucosal surface of the lung to potentially noxious stimuli, including pathogens, allergens, and particulates, each of which can trigger pulmonary damage and inflammation. As inflammation resolves, B and T lymphocytes often aggregate around large bronchi to form inducible Bronchus-Associated Lymphoid Tissue (iBALT). iBALT formation can be initiated by a diverse array of molecular pathways that converge on the activation and differentiation of chemokine-expressing stromal cells that serve as the scaffolding for iBALT and facilitate the recruitment, retention, and organization of leukocytes. Like conventional lymphoid organs, iBALT recruits naïve lymphocytes from the blood, exposes them to local antigens, in this case from the airways, and supports their activation and differentiation into effector cells. The activity of iBALT is demonstrably beneficial for the clearance of respiratory pathogens; however, it is less clear whether it dampens or exacerbates inflammatory responses to non-infectious agents. Here, we review the evidence regarding the role of iBALT in pulmonary immunity and propose that the final outcome depends on the context of the disease.


Assuntos
Brônquios/imunologia , Imunidade nas Mucosas/imunologia , Respiração/imunologia , Humanos , Linfócitos/imunologia
19.
Clin Immunol ; 212: 108347, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31978558

RESUMO

Galactose-deficient immunoglobulin A1 (Gd-IgA1) was recently identified as a critical effector molecule in the pathogenesis of IgA nephropathy (IgAN). Gd-IgA1 is produced by the mucosal immune system. IgAN is thought to develop because of the deposition of a circulating immune-complex containing Gd-IgA1 in the kidney. Multicentric Castleman's disease (MCD) is a rare non-neoplastic lymphoproliferative disorder. As an etiology model, hypercytokinemia, including increased levels of interleukin-6, is the primary pathogenesis of many MCD cases. Here, we present two cases of mesangial proliferative glomerulonephritis with MCD. According to renal biopsy findings, one was diagnosed with non-IgAN and the other with IgAN. Surprisingly, in both cases, Gd-IgA1 was produced by plasma cells in the lymph nodes, suggesting that Gd-IgA1 production alone does not cause IgAN; rather, it may be produced without induction by mucosal immunity. Our findings demonstrate the diversity of the development of IgAN and help to reconsider the onset mechanism of IgAN.


Assuntos
Hiperplasia do Linfonodo Gigante/imunologia , Glomerulonefrite por IGA/imunologia , Glomerulonefrite Membranoproliferativa/imunologia , Imunoglobulina A/imunologia , Plasmócitos/imunologia , Proteína C-Reativa/imunologia , Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/patologia , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/patologia , Glomerulonefrite Membranoproliferativa/complicações , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Hipergamaglobulinemia/imunologia , Imunidade nas Mucosas/imunologia , Interleucina-6/imunologia , Linfadenopatia/imunologia , Masculino , Pessoa de Meia-Idade
20.
Eur J Immunol ; 50(3): 317-325, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31986556

RESUMO

Humans are constantly exposed to fungi, either in the form of commensals at epithelial barriers or as inhaled spores. Innate immune cells play a pivotal role in maintaining commensal relationships and preventing skin, mucosal, or systemic fungal infections due to the expression of pattern recognition receptors that recognize fungal cell wall components and modulate both their activation status and the ensuing adaptive immune response. Commensal fungi also play a critical role in the modulation of homeostasis and disease susceptibility at epithelial barriers. This review will outline cellular and molecular mechanisms of anti-fungal innate immunity focusing on C-type lectin receptors and their relevance in the context of host-fungi interactions at skin and mucosal surfaces in murine experimental models as well as patients susceptible to fungal infections.


Assuntos
Fungos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Imunidade nas Mucosas/imunologia , Lectinas Tipo C/imunologia , Micoses/imunologia , Animais , Humanos
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