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1.
Front Immunol ; 11: 1959, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849655

RESUMO

The lung is the vital target organ of coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the majority of patients the most active virus replication seems to be found in the upper respiratory tract, severe cases however suffer from SARS-like disease associated with virus replication in lung tissues. Due to the current lack of suitable anti-viral drugs the induction of protective immunity such as neutralizing antibodies in the lung is the key aim of the only alternative approach-the development and application of SARS-CoV-2 vaccines. However, past experience from experimental animals, livestock, and humans showed that induction of immunity in the lung is limited following application of vaccines at peripheral sides such as skin or muscles. Based on several considerations we therefore propose here to consider the application of a Modified Vaccinia virus Ankara (MVA)-based vaccine to mucosal surfaces of the respiratory tract as a favorable approach to combat COVID-19.


Assuntos
Betacoronavirus/química , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Glicoproteína da Espícula de Coronavírus/imunologia , Vírus Vaccinia/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Administração através da Mucosa , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Brônquios/imunologia , Infecções por Coronavirus/virologia , Humanos , Imunoglobulina A/metabolismo , Tecido Linfoide/imunologia , Plasmócitos/imunologia , Pneumonia Viral/virologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Linfócitos T/imunologia , Vacinação , Vacinas Atenuadas/imunologia
2.
Nat Commun ; 11(1): 3798, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732867

RESUMO

Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicroscopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis.


Assuntos
Células Endoteliais/citologia , Endotélio Vascular/citologia , Linfonodos/irrigação sanguínea , Linfócitos/imunologia , Células Mieloides/imunologia , Animais , Sequência de Bases , Movimento Celular/imunologia , Feminino , Perfilação da Expressão Gênica , Homeostase/imunologia , Inflamação/imunologia , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Análise de Sequência de RNA , Análise de Célula Única , Transcriptoma/genética
3.
Curr Top Microbiol Immunol ; 426: 1-19, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32588229

RESUMO

Tertiary lymphoid organs (TLOs), also known as inducible lymphoid organs, tertiary lymphoid structures, tertiary lymphoid tissues, or ectopic lymphoid organs are accumulations of cells in chronic inflammation that have been observed in most tissues in autoimmunity, infection, and cancer in mouse and man. They share many properties with secondary lymphoid organs (SLOs), particularly lymph nodes, with regard to cellular composition, function, and regulation. TLOs include T and B cells, dendritic cells, follicular dendritic cells, and many other stromal cells, and high endothelial venules (HEVs) and lymphatic vessels. They serve as sites of antigen presentation and tolerance induction; they are harmful in autoimmunity and can be both harmful and beneficial in cancer. SLO induction in ontogeny is mediated by interactions of several cell types, including CD4+ CD3- lymphoid tissue inducer (LTi) RORγt+ cells that express LTαß and interact with mesenchymal lymphoid tissue organizer (LTo) FAP+ cells in the presence of lymphatic and blood vessels. A variety of inducer cells initiate TLOs, including bona fide LTi cells, T cells, B cells, and NK cells. The mesenchymal organizer cells are less well characterized but can include FAP+ cells. Current challenges include identification of methods to inhibit TLOs in autoimmunity without affecting SLOs, and enhancement of TLOs for defense against tumors.


Assuntos
Inflamação/imunologia , Tecido Linfoide/imunologia , Animais , Humanos , Linfonodos
4.
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
5.
Mol Immunol ; 124: 42-50, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32526556

RESUMO

CD8+ T cells are crucial for immunity against viral infections, including HIV. Several characteristics of CD8+ T cells, such as polyfunctionality and cytotoxicity, have been correlated with effective control of HIV. However, most of these correlates have been established in the peripheral blood. Meanwhile, HIV primarily replicates in lymphoid tissues. Therefore, it is unclear which aspects of CD8+ T cell biology are shared and which are different between blood and lymphoid tissues in the context of HIV infection. In this review, we will recapitulate the latest advancements of our knowledge on lymphoid tissue CD8+ T cells during HIV infection and discuss the insights these advancements might provide for the development of a HIV cure.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Tecido Linfoide/imunologia , Humanos
6.
Curr Top Microbiol Immunol ; 426: 143-160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483658

RESUMO

Human-type lymphoid tissue organoids, which stably function in our body for a certain period of time or longer, may have a great potential as immune-stimulatory or immune-regulatory devices and could be utilized in the future for the treatment of various diseases such as cancer, severe infection, autoimmunity and congenital as well as acquired immunodeficiency resulting from severe infections or aging. In this review, we discuss about rationality and trials of the synthesis of immunologically functional lymphoid tissue organoids mainly in mouse. We have been recently trying to construct immunologically functioning human-type organoids, and the efforts are also briefly described.


Assuntos
Tecido Linfoide/imunologia , Organoides/imunologia , Organoides/transplante , Animais , Humanos , Tecido Linfoide/citologia , Tecido Linfoide/transplante , Organoides/citologia
7.
Curr Top Microbiol Immunol ; 426: 119-141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483659

RESUMO

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease. RA mainly affects the joints, with inflammation of the synovial membrane, characterized by hyperplasia, neo-angiogenesis, and immune cell infiltration that drives local inflammation and, if untreated, can lead to joint destruction and disability. In parallel to the well-known clinical heterogeneity, the underlying synovitis can also be significantly heterogeneous. In particular, in about 40% of patients with RA, synovitis is characterized by a dense lymphocytic infiltrate that can acquire the features of fully functional tertiary lymphoid organs (TLO). These structures amplify autoimmunity and inflammation locally associated with worse prognosis and potential implications for treatment response. Here, we will review the current knowledge on TLO in RA, with a focus on their pathogenetic and clinical relevance.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Tecido Linfoide/patologia , Autoimunidade , Humanos , Tecido Linfoide/imunologia , Neovascularização Patológica , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/patologia
8.
Curr Top Microbiol Immunol ; 426: 65-82, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32385532

RESUMO

The skin is the outermost organ of the body and is exposed to many kinds of external pathogens. To manage this, the skin contains multiple types of immune cells. To achieve sufficient induction of cutaneous adaptive immune responses, the antigen presentation/recognition in the skin is an essential process. Recent studies have expanded our knowledge of how T cells survey their cognate antigens in the skin. In addition, the formation of a lymphoid cluster, named inducible skin-associated lymphoid tissue (iSALT), has been reported during skin inflammation. Although iSALT may not be classified as a typical tertiary lymphoid organ, it provides specific antigen presentation sites in the skin. In this article, we provide an overview of the antigen presentation mechanism in the skin, with a focus on the development of iSALT and its function.


Assuntos
Imunidade Adaptativa , Tecido Linfoide/anatomia & histologia , Tecido Linfoide/imunologia , Pele/imunologia , Apresentação do Antígeno , Antígenos/imunologia , Humanos , Linfócitos T/imunologia
9.
Curr Top Microbiol Immunol ; 426: 45-63, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32385533

RESUMO

An interesting phenomenon of chronic inflammation is that the associated cytokines can simultaneously promote inflammatory cell recruitment and tissue pathology as well as tissue regeneration and development of inducible organized lymphoid tissues (tertiary lymphoid organs or TLO), demonstrating the remarkable dynamics of the immune interactions with host tissues. In mucosal tissues, chronic immune-mediated inflammation can present a mixed inflammatory pathology including neutrophil infiltrates along with the lymphocytic aggregates. The factors driving this pattern may involve effects on barrier function as well as inducible mechanisms associated with immune surveillance. The relative contribution of these factors may be important in determining the outcome, from resolution to inflammatory stalemate to progressive tissue pathology and destruction. Here, we focus on the specific impact of cytokine-driven inducible lymphoid cells and tissues on immune surveillance at mucosal surfaces, including the induction of epithelial M cells. We propose a model of chronic intestinal inflammation to assess the relative contributions of mucosal barrier integrity, M cell transcytosis of luminal microbes, and inducible lymphoid tissues.


Assuntos
Inflamação/imunologia , Inflamação/patologia , Tecido Linfoide/imunologia , Membrana Mucosa/imunologia , Membrana Mucosa/patologia , Células Epiteliais , Humanos , Linfócitos/citologia , Linfócitos/imunologia
10.
Avian Dis ; 64(1): 69-79, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32267127

RESUMO

The development of immunocompetence in chicks after hatching is not fully understood. However, detailed knowledge of immunocompetence and maturation processes in day-old chicks (DOCs) and juvenile chickens (Gallus gallus domesticus) is necessary to implement enhanced immunization strategies. For viral diseases, this especially includes the development of cellular immunity focusing on T-cell-dependent responses. In the current study, we investigated T-cell subsets in blood and lymphoid tissues of 1-to-21-day-old chickens concerning their cellular composition and localization. We detected an increase of T-cell frequencies in blood and spleen and a shift of the CD8α dimer expression toward a CD8αß expression on the surface of T cells with increasing age. A relocalization of lymphocytes into antigen presentation structures within the spleen was affirmed. In addition, changes in basal messenger RNA (mRNA) level, with increasing IL2 and IFNγ mRNA levels at different ages were measured. These detected changes suggest an improved T-cell-dependent antiviral response with increasing age in chickens. To confirm this finding on a functional level, we conducted a transfer experiment: adult and, as a negative control, neonatal naïve lymphocytes were transferred into DOCs. Afterward, the protection induced by these transferred cells was verified by a sublethal infection by using a highly pathogenic avian influenza virus with neuraminidase deletion, H5Ndel. Previous experiments have shown that adult animals survive infection with this virus strain, while naïve DOCs show severe symptoms or even die. As a result, the transfer of adult, but not neonatal lymphocytes, confers protection to DOCs against the infection, demonstrating functional differences in lymphocytes from chicks of different ages. Collectively, these data reveal the inability of chicks to mount an effective, cellular antiviral response in the first 3 wk of life. Therefore, we propose that the observed maturation of both the innate and the adaptive arms of the immune system early in development is mandatory for controlling influenza infection in chickens, as well as for an effective vaccination with replication-competent viral vaccine strains.


Assuntos
Sangue/imunologia , Galinhas/imunologia , Imunidade Celular , Imunocompetência , Virus da Influenza A Subtipo H5N1/imunologia , Tecido Linfoide/imunologia , Linfócitos T/fisiologia , Fatores Etários , Animais , Feminino , Masculino
11.
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
12.
Immunity ; 52(3): 452-463, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32187516

RESUMO

The intestines have the essential but challenging mission of absorbing nutrients, restricting damage from food-derived toxins, promoting colonization by symbionts, and expelling pathogens. These processes are often incompatible with each other and must therefore be prioritized in view of the most crucial contemporary needs of the host. Recent work has shown that tissue-resident innate lymphoid cells (ILCs) constitute a central sensory module allowing adaptation of intestinal organ function to changing environmental input. Here, we propose a conceptual framework positing that the various types of ILC act in distinct modules with intestinal epithelial cells, collectively safeguarding organ function. Such homeostasis-promoting circuitry has high potential to be plumbed for new therapeutic approaches to the treatment of immune-mediated inflammatory diseases.


Assuntos
Células Epiteliais/imunologia , Homeostase/imunologia , Imunidade Inata/imunologia , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Células Epiteliais/metabolismo , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Linfócitos/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Modelos Imunológicos
13.
J Virol ; 94(11)2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32213610

RESUMO

Ebola virus (EBOV) continues to pose a significant threat to human health, as evidenced by the 2013-2016 epidemic in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. EBOV causes hemorrhagic fever, organ damage, and shock culminating in death, with case fatality rates as high as 90%. This high lethality combined with the paucity of licensed medical countermeasures makes EBOV a critical human pathogen. Although EBOV infection results in significant damage to the liver and the adrenal glands, little is known about the molecular signatures of injury in these organs. Moreover, while changes in peripheral blood cells are becoming increasingly understood, the host responses within organs and lymphoid tissues remain poorly characterized. To address this knowledge gap, we tracked longitudinal transcriptional changes in tissues collected from EBOV-Makona-infected cynomolgus macaques. Following infection, both liver and adrenal glands exhibited significant and early downregulation of genes involved in metabolism, coagulation, hormone synthesis, and angiogenesis; upregulated genes were associated with inflammation. Analysis of lymphoid tissues showed early upregulation of genes that play a role in innate immunity and inflammation and downregulation of genes associated with cell cycle and adaptive immunity. Moreover, transient activation of innate immune responses and downregulation of humoral immune responses in lymphoid tissues were confirmed with flow cytometry. Together, these data suggest that the liver, adrenal gland, and lymphatic organs are important sites of EBOV infection and that dysregulating the function of these vital organs contributes to the development of Ebola virus disease.IMPORTANCE Ebola virus (EBOV) remains a high-priority pathogen since it continues to cause outbreaks with high case fatality rates. Although it is well established that EBOV results in severe organ damage, our understanding of tissue injury in the liver, adrenal glands, and lymphoid tissues remains limited. We begin to address this knowledge gap by conducting longitudinal gene expression studies in these tissues, which were collected from EBOV-infected cynomolgus macaques. We report robust and early gene expression changes within these tissues, indicating they are primary sites of EBOV infection. Furthermore, genes involved in metabolism, coagulation, and adaptive immunity were downregulated, while inflammation-related genes were upregulated. These results indicate significant tissue damage consistent with the development of hemorrhagic fever and lymphopenia. Our study provides novel insight into EBOV-host interactions and elucidates how host responses within the liver, adrenal glands, and lymphoid tissues contribute to EBOV pathogenesis.


Assuntos
Glândulas Suprarrenais , Ebolavirus , Regulação Viral da Expressão Gênica/imunologia , Doença pelo Vírus Ebola , Fígado , Tecido Linfoide , Doenças dos Macacos , Transcrição Genética/imunologia , Glândulas Suprarrenais/imunologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/virologia , Animais , Ebolavirus/imunologia , Ebolavirus/metabolismo , Feminino , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/metabolismo , Doença pelo Vírus Ebola/patologia , Doença pelo Vírus Ebola/veterinária , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Tecido Linfoide/virologia , Macaca fascicularis , Masculino , Doenças dos Macacos/imunologia , Doenças dos Macacos/metabolismo , Doenças dos Macacos/patologia , Doenças dos Macacos/virologia
14.
PLoS One ; 15(2): e0228463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027689

RESUMO

Infection with Brucella abortus causes contagious zoonosis, brucellosis, and leads to abortion in animals and chronic illness in humans. Chitosan nanoparticles (CNs), biocompatible and nontoxic polymers, acts as a mucosal adjuvant. In our previous study, B. abortus malate dehydrogenase (Mdh) was loaded in CNs, and it induced high production of pro-inflammatory cytokines in THP-1 cells and systemic IgA in BALB/C mice. In this study, the time-series gene expression analysis of nasal-associated lymphoid tissue (NALT) was performed to identify the mechanism by which Mdh affect the target site of nasal immunization. We showed that intranasal immunization of CNs-Mdh reduced cell viability of epithelial cells and muscle cells at first 1 h, then induced cellular movement of immune cells such as granulocytes, neutrophils and lymphocytes at 6h, and activated IL-6 signaling pathway at 12h within NALT. These activation of immune cells also promoted signaling pathway for high-mobility group box 1 protein (HMGB1), followed by the maturation of DCs required for mucosal immunity. The CNs also triggered the response to other organism and inflammatory response, showing it is immune-enhancing adjuvant. The ELISA showed that significant production of specific IgA was detected in the fecal excretions and genital secretions from the CNs-Mdh-immunized group after 2 weeks-post immunization. Collectively, these results suggest that B. abortus Mdh-loaded CNs triggers activation of HMGB1, IL-6 and DCs maturation signaling within NALT and induce production of systemic IgG and IgA.


Assuntos
Formação de Anticorpos/fisiologia , Brucella abortus/imunologia , Brucelose/prevenção & controle , Imunização/métodos , Tecido Linfoide/imunologia , Malato Desidrogenase/imunologia , Administração Intranasal , Animais , Formação de Anticorpos/efeitos dos fármacos , Brucella abortus/metabolismo , Brucelose/imunologia , Quitosana/administração & dosagem , Quitosana/química , Quitosana/imunologia , Quitosana/farmacologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Feminino , Imunidade nas Mucosas/efeitos dos fármacos , Imunogenicidade da Vacina , Tecido Linfoide/efeitos dos fármacos , Malato Desidrogenase/administração & dosagem , Malato Desidrogenase/metabolismo , Malato Desidrogenase/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia
15.
Gene ; 739: 144496, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32088242

RESUMO

Early larval developmental stages of fish are highly susceptible to opportunistic pathogens until the complete maturation of the lymphoid organs. Knowledge of the expression pattern of important markers of adaptive immune system during the ontogenetic development is essential before vaccinating the fish. In the present study, Pterophyllum scalare (angelfish) was taken to explore the relative expression profile of developmental markers of adaptive immunity, recombination activating gene-2 (RAG-2) and immunoglobulin M (IgM). The fishes were bred and early developmental stages (0-45 days post-hatched) were used to assess the expression profile. The genes, RAG-2 and IgM were cloned and sequenced with the base pair lengths of 1958 bp and 225 bp respectively. The mRNA expression of RAG-2 appeared at insignificant level at the first day of hatching, but the expression was significantly increased from 24 dph (days post-hatching) onwards and reached its peak at 27 dph. The results proved that the maturation of lymphoid organs was completed at 27 dph as the respective protein is involved in the V(D)J recombination, important for the maturation of lymphoid organs. A similar trend was also observed in the mRNA transcript levels of IgM gene and a significantly high expression was detected from 27 dph onwards. The present study suggested that the suitable time for vaccination in P. scalare could be taken at 27 dph, as the maturation and development of lymphoid organs is completed thus helps in stimulating the adaptive response of immunity against any pathogen.


Assuntos
Imunidade Adaptativa/genética , Ciclídeos/genética , Proteínas de Ligação a DNA/imunologia , Vacinação/veterinária , Animais , Ciclídeos/imunologia , Clonagem Molecular , Proteínas de Ligação a DNA/genética , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Rim/imunologia , Tecido Linfoide/imunologia , Baço/imunologia
16.
PLoS One ; 15(2): e0229743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106280

RESUMO

Thymocyte selection-associated high-mobility group box (TOX) is a DNA-binding factor that is able to regulate transcription by modifying local chromatin structure and modulating the formation of multi-protein complexes. TOX has multiple roles in the development of the adaptive immune system including development of CD4 T cells, NK cells and lymph node organogenesis. However very few antibodies recognizing this molecule have been reported and no extensive study of the expression of TOX in reactive and neoplastic lymphoid tissue has been performed to date. In the present study, we have investigated TOX expression in normal and neoplastic lymphoid tissues using a novel rat monoclonal antibody that recognizes its target molecule in paraffin-embedded tissue sections. A large series of normal tissues and B- and T-cell lymphomas was studied, using whole sections and tissue microarrays. We found that the majority of precursor B/T lymphoblastic, follicular and diffuse large B-cell lymphomas, nodular lymphocyte-predominant Hodgkin lymphomas and angioimmunoblastic T-cell lymphomas strongly expressed the TOX protein. Burkitt and mantle cell lymphomas showed TOX expression in a small percentage of cases. TOX was not found in the majority of chronic lymphocytic leukemia, myelomas, marginal zone lymphomas and classical Hodgkin lymphomas. In conclusion, we describe for the first time the expression of TOX in normal and neoplastic lymphoid tissues. The co-expression of TOX and PD-1 identified in normal and neoplastic T cells is consistent with recent studies identifying TOX as a critical regulator of T-cell exhaustion and a potential immunotherapy target. Its differential expression may be of diagnostic relevance in the differential diagnosis of follicular lymphoma, the identification of the phenotype of diffuse large B-cell lymphoma and the recognition of peripheral T-cell lymphoma with a follicular helper T phenotype.


Assuntos
Anticorpos Monoclonais Murinos/imunologia , Subpopulações de Linfócitos B/imunologia , Proteínas de Grupo de Alta Mobilidade/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Especificidade de Anticorpos , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma de Células T/imunologia , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
17.
Proc Natl Acad Sci U S A ; 117(8): 4292-4299, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32034098

RESUMO

The migratory patterns of virus-specific CD8 T cells during chronic viral infection are not well understood. To address this issue, we have done parabiosis experiments during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. We found that despite the high frequency of virus-specific CD8 T cells in both lymphoid and nonlymphoid tissues there was minimal migration of virus-specific CD8 T cells between the chronically infected conjoined parabiont mice. This was in contrast to parabionts between mice that had undergone an acute LCMV infection where virus-specific CD8 T cells established equilibrium demonstrating circulation of memory T cells generated after viral clearance. We have identified a population of PD-1+ TCF1+CXCR5+Tim-3- stemlike virus-specific CD8 T cells that reside in lymphoid tissues and act as resource cells for maintaining the T cell response during chronic infection. These are the cells that proliferate and give rise to the more terminally differentiated PD-1+ CXCR5-Tim-3+ CD8 T cells. Both the stemlike CD8 T cells and their terminally differentiated progeny showed minimal migration during chronic infection and the few LCMV-specific CD8 T cells that were present in circulation were the recently emerging progeny from the stemlike CD8 T cells. The PD-1+ TCF1+CXCR5+ stemlike CD8 T cells were truly resident in lymphoid tissues and did not circulate in the blood. We propose that this residency in specialized niches within lymphoid tissues is a key aspect of their biology and is essential for maintaining their quiescence and stemlike program under conditions of a chronic viral infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Tecido Linfoide/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Feminino , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Memória Imunológica , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/genética , Tecido Linfoide/virologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/genética , Receptores CXCR5/genética , Receptores CXCR5/imunologia
18.
Vet Res ; 51(1): 19, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093775

RESUMO

Marek's disease (MD) is a contagious disease of domestic chickens caused by MD viruses. MD has been controlled primarily by vaccinations, yet sporadic outbreaks of MD take place worldwide. Commonly used MD vaccines include HVT, SB-1 and CVI988/Rispens and their efficacies are reportedly dependent of multiple factors including host genetics. Our previous studies showed protective efficacy of a MD vaccine can differ drastically from one chicken line to the next. Advanced understanding on the underlying genetic and epigenetic factors that modulate vaccine efficacy would greatly improve the strategy in design and development of more potent vaccines. Two highly inbred lines of White Leghorn were inoculated with HVT and CVI988/Rispens. Bursa samples were taken 26 days post-vaccination and subjected to small RNA sequencing analysis to profile microRNAs (miRNA). A total of 589 and 519 miRNAs was identified in one line, known as line 63, 490 and 630 miRNAs were identified in the other, known as line 72, in response to HVT or CVI988/Rispens inoculation, respectively. HVT and CVI988/Rispens induced mutually exclusive 4 and 13 differentially expressed (DE) miRNAs in line 63 birds in contrast to a non-vaccinated group of the same line. HVT failed to induce any DE miRNA and CVI988/Rispens induced a single DE miRNA in line 72 birds. Thousands of target genes for the DE miRNAs were predicted, which were enriched in a variety of gene ontology terms and pathways. This finding suggests the epigenetic factor, microRNA, is highly likely involved in modulating vaccine protective efficacy in chicken.


Assuntos
Bolsa de Fabricius/metabolismo , Galinhas/imunologia , Regulação da Expressão Gênica , Tecido Linfoide/metabolismo , Vacinas contra Doença de Marek/metabolismo , MicroRNAs/genética , Animais , Bolsa de Fabricius/imunologia , Tecido Linfoide/imunologia , Vacinas contra Doença de Marek/administração & dosagem , MicroRNAs/metabolismo
19.
Sci Rep ; 10(1): 2919, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076025

RESUMO

Oral rabies vaccination (ORV) is highly effective in foxes and raccoon dogs, whereas for unknown reasons the efficacy of ORV in other reservoir species is less pronounced. To investigate possible variations in species-specific cell tropism and local replication of vaccine virus, different reservoir species including foxes, raccoon dogs, raccoons, mongooses, dogs and skunks were orally immunised with a highly attenuated, high-titred GFP-expressing rabies virus (RABV). Immunofluorescence and RT-qPCR screenings revealed clear differences among species suggesting host specific limitations to ORV. While for responsive species the palatine tonsils (tonsilla palatina) were identified as a main site of virus replication, less virus dissemination was observed in the tonsils of rather refractory species. While our comparison of vaccine virus tropism emphasizes the important role that the tonsilla palatina plays in eliciting an immune response to ORV, our data also indicate that other lymphoid tissues may have a more important role than originally anticipated. Overall, these data support a model in which the susceptibility to oral live RABV vaccine infection of lymphatic tissue is a major determinant in vaccination efficacy. The present results may help to direct future research for improving vaccine uptake and efficacy of oral rabies vaccines under field conditions.


Assuntos
Reservatórios de Doenças/virologia , Tecido Linfoide/imunologia , Membrana Mucosa/imunologia , Vacinas Antirrábicas/imunologia , Raiva/imunologia , Vacinação , Administração Oral , Animais , Anticorpos Antivirais/imunologia , Raposas/imunologia , Raposas/virologia , Proteínas de Fluorescência Verde/metabolismo , Tecido Linfoide/virologia , Membrana Mucosa/virologia , Especificidade de Órgãos , Tonsila Palatina/imunologia , Tonsila Palatina/virologia , RNA Viral/genética , Raiva/sangue , Raiva/veterinária , Raiva/virologia , Vírus da Raiva/fisiologia , Especificidade da Espécie , Tropismo , Carga Viral , Replicação Viral/fisiologia
20.
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
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