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1.
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
2.
Medicine (Baltimore) ; 99(6): e18926, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028400

RESUMO

Lymphoid follicles/aggregates in gastric biopsies have been traditionally linked to Helicobacter pylori gastritis, and less commonly to other inflammatory and neoplastic conditions. The frequency of such aggregates in normal stomachs has yet to be adequately evaluated. This is especially relevant when it comes to diagnosing non-specific chronic gastritis in biopsy specimens with chronic inflammation but no evidence of H pylori infection. Sleeve gastrectomies represent an opportunity to study adequately preserved gastric mucosa in patients who are otherwise asymptomatic and lack a history of gastric disease.To study sleeve gastrectomy specimens to quantify the amount of lymphoid follicles/aggregates and lymphocytic infiltration in normal stomachs.Sixty-eight bariatric sleeve gastrectomies and 13 control specimens from Whipple resections were examined for multiple histologic features including type, quantity, and distribution of chronic inflammation and lymphoid follicles/aggregates. Presence of H pylori was documented by both Hematoxylin and eosin-stained (H&E) and immunohistochemistry (IHC). Clinical information including age, sex, medication intake, prior endoscopy, and/or H pylori infection was recorded. The patient population was divided in 2 groups, H pylori negative versus H pylori positive, and statistical analysis was performed by a biostatistician.Two hundred sixty three fundic sections from 68 bariatric patients were examined. Fifty three patients were found to be H pylori-negative, compared with 15 who were positive for H pylori. Among the H pylori-negative group, the average number of lymphoid aggregates was 3.33, compared with an average of 6.26 in the H pylori positive group (the difference was statistically significant with a P-value of .008). The average number of plasma cells per high power field was 2.15 in the H pylori negative group, compared and average of 5.07 in the H pylori positive group (the difference was also statistically significant with a P-value <.001). Clinically, 10 of the 53 H pylori-negative patients had esophagogastroduodenoscopy (EGD) that showed endoscopic mild non-erosive gastric erythema. The remaining had no documentation of symptoms or medication intake, including Non-steroidal anti-inflammatory drugs (NSAIDs) and Proton Pump Inhibitors (PPI).Our results suggest that the presence of lymphoid aggregates and plasma cells infiltration can be a normal finding in otherwise normal gastric mucosa, though more pronounced in H pylori infected patients.


Assuntos
Mucosa Gástrica/patologia , Gastrite/patologia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Tecido Linfoide/citologia , Plasmócitos/citologia , Estudos de Casos e Controles , Feminino , Gastrectomia , Gastrite/diagnóstico , Humanos , Masculino
3.
Nat Commun ; 11(1): 234, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932605

RESUMO

Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface.


Assuntos
Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Osteoprotegerina/metabolismo , Animais , Anticorpos Antibacterianos/imunologia , Ceco/citologia , Ceco/imunologia , Ceco/metabolismo , Ceco/microbiologia , Diferenciação Celular , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Homeostase , Imunidade nas Mucosas , Imunoglobulina G/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoprotegerina/genética , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Salmonella typhimurium/patogenicidade , Transdução de Sinais
4.
Am J Pathol ; 190(1): 252-269, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31585070

RESUMO

The mouse lymph node (LN) can provide a niche to grow metanephric kidney to maturity. Here, we show that signaling through the lymphotoxin-ß receptor (LTßR) is critical for kidney organogenesis both in the LN and the omentum. By transplanting kidney rudiments either in the LNs of mice undergoing LTßR antagonist treatment or in the omenta of Ltbr knockout (Ltbr-/-) mice, the host LTßR signals were found to be crucial for obtaining a well-vascularized kidney graft. Indeed, defective LTßR signaling correlated with decreased expression of endothelial and angiogenic markers in kidney grafts as well as structural alterations. Because the number of glomerular endothelial cells expressing the LTßR target nuclear factor κB-inducing kinase (NIK) decreased in the absence of a functional LTßR, it was speculated that an LTßR/NIK axis mediated the angiogenetic signals required for successful ectopic kidney organogenesis, given the established role of NIK in neovascularization. However, the transplantation of kidney rudiments in omenta of Nik-/- mice revealed that NIK is dispensable for ectopic kidney vascular integration and maturation. Finally, defective LTßR signaling impaired compensatory glomerular adaptation to renal mass reduction, indicating that kidney regeneration approaches, besides whole kidney reconstruction, might benefit from the presence of LTßR signals.


Assuntos
Glomérulos Renais/transplante , Tecido Linfoide/citologia , Receptor beta de Linfotoxina/fisiologia , Neovascularização Fisiológica , Organogênese , Animais , Células Endoteliais/citologia , Glomérulos Renais/citologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/fisiologia , Regeneração , Transdução de Sinais
5.
Nature ; 574(7778): 365-371, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597962

RESUMO

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.


Assuntos
Feto/citologia , Hematopoese , Fígado/citologia , Fígado/embriologia , Células Sanguíneas/citologia , Microambiente Celular , Feminino , Feto/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Fígado/metabolismo , Tecido Linfoide/citologia , Análise de Célula Única , Células-Tronco/metabolismo
6.
Fish Shellfish Immunol ; 95: 44-80, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31604150

RESUMO

Evaluating studies over the past almost 40 years, this review outlines the current knowledge and research gaps in the use of isolated leucocytes in salmonid immunology understanding. This contribution focuses on the techniques used to isolate salmonid immune cells and popular immunological assays. The paper also analyses the use of leucocytes to demonstrate immunomodulation following dietary manipulation, exposure to physical and chemical stressors, effects of pathogens and parasites, vaccine design and application strategies assessment. We also present findings on development of fish immune cell lines and their potential uses in aquaculture immunology. The review recovered 114 studies, where discontinuous density gradient centrifugation (DDGC) with Percoll density gradient was the most popular leucocyte isolation method. Fish head kidney (HK) and peripheral blood (PB) were the main sources of leucocytes, from rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar). Phagocytosis and respiratory burst were the most popular immunological assays. Studies used isolated leucocytes to demonstrate that dietary manipulations enhance fish immunity, while chemical and physical stressors suppress immunity. In addition, parasites, and microbial pathogens depress fish innate immunity and induce pro-inflammatory cytokine gene transcripts production, while vaccines enhance immunity. This review found 10 developed salmonid cell lines, mainly from S. salar and O. mykiss HK tissue, which require fish euthanisation to isolate. In the face of high costs involved with density gradient reagents, the application of hypotonic lysis in conjunction with mico-volume blood methods can potentially reduce research costs, time, and using nonlethal and ethically flexible approaches. Since the targeted literature review for this study retrieved no metabolomics study of leucocytes, indicates that this approach, together with traditional technics and novel flow cytometry could help open new opportunities for in vitro studies in aquaculture immunology and vaccinology.


Assuntos
Rim Cefálico/imunologia , Leucócitos/imunologia , Tecido Linfoide/imunologia , Oncorhynchus mykiss/imunologia , Salmo salar/imunologia , Animais , Aquicultura , Linhagem Celular , Centrifugação com Gradiente de Concentração , Dieta/veterinária , Citometria de Fluxo , Rim Cefálico/citologia , Técnicas Imunológicas , Tecido Linfoide/citologia , Fagocitose
7.
Eur J Histochem ; 63(3)2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31577110

RESUMO

The evolutionary initiation of the appearance in lymphomyeloid tissue of the hemopoietic stem cell in the earliest (most primitive) vertebrate model, i.e. the elasmobranch (chondroichthyan) Torpedo marmorata Risso, has been studied. The three consecutive developmental stages of torpedo embryos were obtained by cesarean section from a total of six pregnant torpedoes. Lymphomyeloid tissue was identified in the Leydig organ and epigonal tissue. The sections were treated with monoclonal anti-CD34 and anti-CD38 antibodies to detect hematopoietic stem cells. At stage I (2-cm-long embryos with external gills) and at stage II (3-4 cm-long embryos with a discoidal shape and internal gills), some lymphoid-like cells that do not demonstrate any immunolabeling for these antibodies are present. Neither CD34+ nor CD38+ cells are identifiable in lymphomyeloid tissue of stage I and stage II embryos, while a CD34+CD38- cell was identified in the external yolk sac of stage II embryo. The stage III (10-11-cm-long embryos), the lymphomyeloid tissue contained four cell populations, respectively CD34+CD38-, CD34+CD38+, CD34-CD38+, and CD34-CD38- cells. The spleen and lymphomyeloid tissue are the principal sites for the development of hematopoietic progenitors in embryonic Torpedo marmorata Risso. The results demonstrated that the CD34 expression on hematopoietic progenitor cells and its extraembryonic origin is conserved throughout the vertebrate evolutionary scale.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Sistema Hematopoético/citologia , Tecido Linfoide/citologia , Torpedo/embriologia , ADP-Ribosil Ciclase 1/metabolismo , Animais , Antígenos CD34/metabolismo , Esôfago/citologia , Feminino , Imuno-Histoquímica , Masculino , Gravidez , Ratos
8.
Anat Histol Embryol ; 48(5): 476-485, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31305954

RESUMO

The proximal caecum in quails consists of lymphoid and non-lymphoid structures. The caecal tonsils in the proximal part of the caecum are units of gut-associated lymphoid tissue in poultry. This study aimed to examine the histological characteristics of the proximal caecum, as well as compositions of dendritic cells (DCs) and antigen-presenting cells (APCs) in the caecal tonsil of quails. Tissue sections were stained with Crossman's triple, periodic acid-Schiff, Gordon and Sweet's silver, Congo red and methyl green-pyronin dyes, as well as immunohistochemically by the streptavidin-biotin-peroxidase complex method. Caecal lymphoid tissue was located in the lamina propria and submucosa. Germinative centres were observed within the lymphoid tissue. Reticular fibres were mainly distributed in the border area of the germinal centre with only a few fibres scattered in the centre. Plasma cells were observed in the subepithelial region and germinal centres. Eosinophil granulocytes were prevalent in the lymphoid tissue. Additionally, CD83-immunoreactive DCs and MHC class II immunoreactive APCs were present in the subepithelial area and diffuse lymphoid tissue. While DCs were seen in the germinal centres of tonsillar units, APCs were rarely present in the germinal centres, but they were noticed around the germinal centres. In conclusion, the histological structure of the proximal caecum in quails and the distributions of some immunological cells in the caecal tonsils were revealed. Therefore, the defensive role of the caecal tonsils in the digestive system may be better understood, and comparative studies may be carried out.


Assuntos
Ceco , Tecido Linfoide/citologia , Tonsila Palatina , Animais , Células Apresentadoras de Antígenos/metabolismo , Biomarcadores , Ceco/anatomia & histologia , Ceco/citologia , Ceco/imunologia , Coturnix , Células Dendríticas/metabolismo , Tecido Linfoide/metabolismo , Tonsila Palatina/anatomia & histologia , Tonsila Palatina/citologia , Tonsila Palatina/imunologia
9.
Int J Mol Sci ; 20(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035605

RESUMO

Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen-activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focus on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSP-mediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR, and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study have the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.


Assuntos
Fosfatases de Especificidade Dupla/metabolismo , Imunomodulação , Proteínas Quinases/metabolismo , Transdução de Sinais , Animais , Evolução Biológica , Células Sanguíneas/metabolismo , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Proteoma , Proteômica/métodos
10.
Vet Immunol Immunopathol ; 211: 44-48, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084893

RESUMO

Regulatory B cells that produce IL-10 are now recognized as an important component of the immune system. We previously confirmed that IL-10 secreting CD21+ regulatory B cells (Breg cells) were present in ovine jejunal Peyer's patches (JPP) and this IL-10 production suppressed IL-12 and IFN-γ secretion. It is not known, however, whether ovine Breg cells are restricted to JPP or are present in other lymphoid tissues. Therefore, CD21+ B cells were purified from sheep JPP and from a variety of mucosal and systemic lymphoid tissues using magnetic cell sorting. Purified CD21+ B cells were stimulated with a TLR9-agonist, CpG oligodeoxynucleotide (CpG ODN), and the frequency of spontaneous and inducible (i) IL-10-secreting B cells was evaluated by ELISPOT. Spontaneous IL-10 secreting CD21+ B cells were present in mucosal (jejunal PP, parabronchial lymph nodes (LN), mesesnteric LN, and palatine tonsils) and systemic (spleen and blood) lymphoid tissues. Mucosal lymphoid tissues (parabronchial and mesenteric LNs and JPP) had the highest frequency of cells spontaneously secreting IL-10 while tonsils had the lowest. The frequency of B cells spontaneously secreting IL-10 was lowest in blood and spleen. There was large inter-animal variation in the frequency of CD21+ B cells spontaneously secreting IL-10 and no significant difference was detected following CpG ODN stimulation. When comparing within individual animals there was, however, a consistent increase in the frequency of CD21+ cells secreting IL-10 following CpG ODN stimulation versus stimulation with GpC control ODN. The presence of inducible (i)Breg cells in ovine mucosal tissues supports previous evidence from mice indicating that B cells have the capacity to modulate inflammatory responses. The presence of iBreg cells in ruminants may also provide a novel therapeutic target for both immunomodulatory drugs and vaccines designed to control antigen-specific mucosal inflammation.


Assuntos
Linfócitos B Reguladores/imunologia , Tecido Linfoide/citologia , Ovinos/imunologia , Animais , Linfócitos B Reguladores/efeitos dos fármacos , Linfócitos B Reguladores/fisiologia , ELISPOT/veterinária , Feminino , Citometria de Fluxo/veterinária , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Tecido Linfoide/imunologia , Masculino , Mesentério/citologia , Mesentério/imunologia , Oligodesoxirribonucleotídeos/farmacologia , Baço/citologia , Baço/imunologia
11.
Viruses ; 11(3)2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893756

RESUMO

Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Recent discoveries have demonstrated that tissue-resident lymphocyte subsets, comprised of innate lymphoid cells (ILCs) and unconventional T cells, have vital roles in the initiation of primary antiviral responses. Via direct and indirect mechanisms, ILCs and unconventional T cell subsets play a critical role in the ability of the immune system to mount an effective antiviral response through potent early cytokine production. In this review, we will summarize the current knowledge of tissue-resident lymphocytes during initial viral infection and evaluate their redundant or nonredundant contributions to host protection or virus-induced pathology.


Assuntos
Imunidade Inata , Tecido Linfoide/citologia , Subpopulações de Linfócitos T/imunologia , Viroses/imunologia , Animais , Diferenciação Celular/imunologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Tecido Linfoide/imunologia , Camundongos
12.
Vet Immunol Immunopathol ; 208: 1-5, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30712787

RESUMO

M cells play a pivotal role in the induction of immune responses within the mucosa-associated lymphoid tissues. M cells exist principally in the follicle-associated epithelium (FAE) of the isolated solitary lymphoid follicles as well as in the lymphoid follicles of nasopharynx-associated lymphoid tissue and gut associated lymphoid tissue (GALT). Through lymphatic cannulation it is possible to investigate local immune responses induced following nasal Ag delivery in sheep. Hence, identifying sheep M cell markers would allow the targeting of M cells to offset the problem of trans-epithelial Ag delivery associated with inducing mucosal immunity. Sheep cDNA from the tonsils of the oropharynx and nasopharynx was PCR amplified using Glycoprotein-2 (GP2)-specific primers and expressed as a poly-His-tagged recombinant sheep GP2 (56 kDa) in HEK293 cells. The recombinant GP2 protein was purified using Ni-NTA affinity chromatography and polyclonal serum against the protein was raised in rats. The antiserum recognized the recombinant sheep GP2 and purified rat IgG against GP2 stained M cells in sections of sheep tonsils from nasopharynx and oropharynx. M cells were found to be present in epithelium of the palatine tonsils (oropharynx), pharyngeal tonsils as well as tubal tonsils (nasopharynx). They were also present in the FAE of the scattered lymphoid follicles over the base of the nasopharynx. Thus, GP2 has been identified to be an important M cell marker of nasopharynx and oropharynx-associated lymphoid tissues in sheep.


Assuntos
Proteínas Ligadas por GPI/genética , Tecido Linfoide/imunologia , Nasofaringe/imunologia , Orofaringe/imunologia , Animais , Biomarcadores , Proteínas Ligadas por GPI/imunologia , Células HEK293 , Humanos , Imunidade nas Mucosas/imunologia , Tecido Linfoide/citologia , Nasofaringe/citologia , Orofaringe/citologia , Tonsila Palatina/citologia , Tonsila Palatina/imunologia , Ovinos/imunologia
13.
Methods Mol Biol ; 1930: 75-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30610601

RESUMO

In order to mount a potent immune response, immune cells must move actively through tissues. As an example, T-cell need to migrate within lymph nodes in order to scan the surface of many dendritic cells and recognize rare expressed antigens. The recent development of improved imaging approaches, such as two-photon microscopy, and the use of powerful mouse models have shed light on some of the mechanisms that regulate the migration of immune cells in many organs. Whereas such systems have provided valuable insights, they do not always predict human responses. In human, our knowledge in the field mainly comes from a description of fixed tissue samples. However, these studies lack a temporal dimension since samples have been fixed. In order to overcome some of these limitations, we describe, in this methodology chapter, an experimental system of fresh human adenoid slices to monitor the dynamics of resident T-lymphocytes that have been stained with directly-coupled fluorescent antibodies. Combined with confocal fluorescent imaging, this preparation offers an effective approach to imaging immune cells in a three-dimensional (3D) human lymphoid tissue environment.


Assuntos
Movimento Celular , Rastreamento de Células/métodos , Tecido Linfoide/citologia , Microscopia Confocal/métodos , Imagem Molecular/métodos , Linfócitos T/citologia , Linfócitos T/fisiologia , Células Cultivadas , Humanos , Transdução de Sinais
14.
Int J Mol Sci ; 20(1)2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30577453

RESUMO

Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The "M" in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.


Assuntos
Imunidade Adaptativa , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/etiologia , Verrugas/diagnóstico , Verrugas/etiologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Gerenciamento Clínico , Humanos , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/terapia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Doenças da Imunodeficiência Primária , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Verrugas/metabolismo , Verrugas/terapia
15.
J Vis Exp ; (141)2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30531718

RESUMO

Marginal zone B cells (MZBs) are a population of B cells that reside in the mouse splenic marginal zones that envelop follicles. To reach the follicles, MZBs must migrate up the shear force of blood flow. We present here a method for analyzing this flow-induced MZB migration in vitro. First, MZBs are isolated from the mouse spleen. Second, MZBs are settled on integrin ligands in flow chamber slides, exposed to shear flow, and imaged under a microscope while migrating. Third, images of the migrating MZBs are processed using the MTrack2 automatic cell tracking plugin for ImageJ, and the resulting cell tracks are quantified using the Ibidi chemotaxis tool. The migration data reveal how fast the cells move, how often they change direction, whether the shear flow vector affects their migration direction, and which integrin ligands are involved. Although we use MZBs, the method can easily be adapted for analyzing migration of any leukocyte that responds to the force of shear flow.


Assuntos
Linfócitos B/fisiologia , Movimento Celular/fisiologia , Quimiotaxia/fisiologia , Imagem com Lapso de Tempo/métodos , Animais , Linfócitos B/química , Células Cultivadas , Tecido Linfoide/química , Tecido Linfoide/citologia , Tecido Linfoide/fisiologia , Camundongos , Baço/química , Baço/citologia , Baço/fisiologia
16.
JCI Insight ; 3(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30429372

RESUMO

Tissue-resident memory T cells (TRMs) accelerate pathogen clearance through rapid and enhanced functional responses in situ. TRMs are prevalent in diverse anatomic sites throughout the human lifespan, yet their phenotypic and functional diversity has not been fully described. Here, we identify subpopulations of human TRMs based on the ability to efflux fluorescent dyes [efflux(+) TRMs] located within mucosal and lymphoid sites with distinct transcriptional profiles, turnover, and functional capacities. Compared with efflux(-) TRMs, efflux(+) TRMs showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling in response to homeostatic cytokines. Moreover, upon activation, efflux(+) TRMs secreted lower levels of inflammatory cytokines such as IFN-γ and IL-2 and underwent reduced degranulation. Interestingly, analysis of TRM subsets following activation revealed that both efflux(+) and efflux(-) TRMs undergo extensive transcriptional changes following TCR ligation but retain core TRM transcriptional properties including retention markers, suggesting that TRMs carry out effector function in situ. Overall, our results suggest a model for tissue-resident immunity wherein heterogeneous subsets have differential capacities for longevity and effector function.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Corantes Fluorescentes , Humanos , Tecido Linfoide/citologia , Mitocôndrias/metabolismo , Modelos Imunológicos , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Distribuição Tecidual , Transcriptoma
17.
J Vis Exp ; (139)2018 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-30272663

RESUMO

For evaluation of a new therapeutic agent for immunotherapy or vaccination, analysis of immune cell activation in lymphatic tissues is essential. Here, we investigated immunological effects of a novel lipid-DNA immunostimulant in nanoparticle form from different administration routes in the mouse: oral, intranasal, subcutaneous, footpad, intraperitoneal, and intravenous. These injections will directly influence the immune response, and harvesting lymphatic tissues and analysis of dendritic cell (DC) activation in the tissues are crucial parts of these evaluations. The extraction of mediastinal lymph nodes (mLNs) is important but quite complex because of the size and location of this organ. A stepwise procedure for harvesting the inguinal lymph node (iLN), mLN, and spleen and analyzing DC activation by flow cytometry is described.


Assuntos
Adjuvantes Imunológicos/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Tecido Linfoide/citologia , Adjuvantes Imunológicos/química , Animais , DNA/química , Citometria de Fluxo , Injeções , Lipídeos/química , Tecido Linfoide/imunologia , Camundongos , Nanopartículas/química
18.
Front Immunol ; 9: 2375, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30369933

RESUMO

CD1d-restricted Natural Killer T (NKT) cells are regarded as sentinels of tissue integrity by sensing local cell stress and damage. This occurs via recognition of CD1d-restricted lipid antigens, generated by stress-related metabolic changes, and stimulation by inflammatory cytokines, such as IL-12 and IL-18. Increasing evidence suggest that this occurs mainly upon NKT cell interaction with CD1d-expressing cells of the Mononuclear Phagocytic System, i.e., monocytes, macrophages and DCs, which patrol parenchymatous organs and mucosae to maintain tissue homeostasis and immune surveillance. In this review, we discuss critical examples of this crosstalk, presenting the known underlying mechanisms and their effects on both cell types and the environment, and suggest that the interaction with CD1d-expressing mononuclear phagocytes in tissues is the fundamental job of NKT cells.


Assuntos
Comunicação Celular , Suscetibilidade a Doenças , Sistema Fagocitário Mononuclear/imunologia , Sistema Fagocitário Mononuclear/metabolismo , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Especificidade de Órgãos/imunologia , Fagócitos/imunologia , Fagócitos/metabolismo , Microambiente Tumoral
19.
Int J Mol Sci ; 19(10)2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30347676

RESUMO

Multiple sclerosis (MS) is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease. This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and experimental autoimmune encephalomyelitis (EAE). The curation of this literature has identified that central nervous system (CNS) infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation. This demonstrates that TFH cells and their products are promising targets for therapies in MS.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Tecido Linfoide/citologia , Esclerose Múltipla/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Humanos
20.
Nat Commun ; 9(1): 3857, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30242242

RESUMO

Human memory B cells and marginal zone (MZ) B cells share common features such as the expression of CD27 and somatic mutations in their IGHV and BCL6 genes, but the relationship between them is controversial. Here, we show phenotypic progression within lymphoid tissues as MZ B cells emerge from the mature naïve B cell pool via a precursor CD27-CD45RBMEM55+ population distant from memory cells. By imaging mass cytometry, we find that MZ B cells and memory B cells occupy different microanatomical niches in organised gut lymphoid tissues. Both populations disseminate widely between distant lymphoid tissues and blood, and both diversify their IGHV repertoire in gut germinal centres (GC), but nevertheless remain largely clonally separate. MZ B cells are therefore not developmentally contiguous with or analogous to classical memory B cells despite their shared ability to transit through GC, where somatic mutations are acquired.


Assuntos
Linfócitos B , Tecido Linfoide/citologia , Humanos , Memória Imunológica , Tecido Linfoide/imunologia , Fenótipo
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