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2.
J Fr Ophtalmol ; 42(5): 517-528, 2019 May.
Artigo em Francês | MEDLINE | ID: mdl-31005284

RESUMO

The corneal limbus is a privileged region on the border between two quite different microenvironments, where corneal epithelial stem cells, numerous melanocytes, and antigen-presenting cells are all concentrated within a richly vascularized and innervated stroma. This situation within the ocular surface confers on it the key functions of barrier, epithelial renewal and defense of the cornea. As an immunological crossroads and since the corneoscleral limbus is directly exposed to external insults such as caustic agents, ultraviolet radiation, microbial agents, and allergens, it is the potential site of many tumoral, degenerative or inflammatory pathologies and may progress under certain conditions to limbal stem cell deficiency.


Assuntos
Doenças da Córnea/patologia , Limbo da Córnea/anatomia & histologia , Limbo da Córnea/patologia , Córnea/anatomia & histologia , Córnea/diagnóstico por imagem , Córnea/patologia , Doenças da Córnea/diagnóstico , Doenças da Córnea/epidemiologia , Epitélio Anterior/anatomia & histologia , Epitélio Anterior/diagnóstico por imagem , Epitélio Anterior/patologia , Infecções Oculares/diagnóstico , Infecções Oculares/patologia , Neoplasias Oculares/diagnóstico , Neoplasias Oculares/patologia , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/patologia , Limbo da Córnea/diagnóstico por imagem , Células-Tronco/patologia
3.
J Immunol ; 202(9): 2616-2627, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30910863

RESUMO

Appropriate T cell responses are controlled by strict balance between activatory and inhibitory pathways downstream of TCR. Although mice or humans with impaired TCR signaling develop autoimmunity, the precise molecular mechanisms linking reduced TCR signaling to autoimmunity are not fully understood. Engagement of TCR activates Ca2+ signaling mainly through store-operated Ca2+ entry activated by stromal interaction molecule (Stim) 1 and Stim2. Despite defective T cell activation, mice deficient in both Stim1 and Stim2 in T cells (conditional double knockout [cDKO]) developed lymphoproliferative disorders and skin inflammation with a concomitant increase in serum IgG1 and IgE levels. In cDKO mice, follicular helper T (Tfh) cells were dramatically increased in number, and they produced IL-4 spontaneously. These inflammatory symptoms were abolished by the deletion of IL-4 in cDKO mice. Tfh development and inflammatory symptoms in cDKO mice were abrogated by further deletion of NFAT2 in T cells. These findings suggest that Tfh cells spontaneously developed in the absence of Ca2+ signaling and caused unregulated type 2 responses.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Doenças do Sistema Imunitário/imunologia , Molécula 1 de Interação Estromal/deficiência , Molécula 2 de Interação Estromal/deficiência , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Sinalização do Cálcio/genética , Sinalização do Cálcio/imunologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Camundongos , Camundongos Knockout , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Dermatopatias/genética , Dermatopatias/imunologia , Dermatopatias/patologia , Linfócitos T Auxiliares-Indutores/patologia
4.
Toxicol Lett ; 304: 30-38, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30605750

RESUMO

Clinical study showed that smoking during pregnancy deceased the thymus size in newborns. However, the long-term effect remains unclear. This study was aimed to observe the effects of prenatal nicotine exposure (PNE) on the development of thymus and the T-lymphocyte subpopulation in mice offspring from the neonatal to adulthood. Both the thymus weight and cytometry data indicated that PNE caused persistent thymic hypoplasia in male offspring from neonatal to adult period and transient changes in female offspring from neonatal to prepuberal period. Flow cytometry analysis disclosed a permanent decreased proportion and number of mature CD4 single-positive (SP) T cells in thymus of both sex. In addition, the PNE male offspring showed a more serious thymus atrophy in the ovalbumin (OVA)-sensitized model. Moreover, increased autophagic vacuole and elevated mRNA expression of Beclin 1 were noted in PNE fetal thymus. In conclusion, PNE offspring showed thymus atrophy and CD 4 SP T cell reduction at different life stages. Mechanically, PNE induced excessive autophagy in fetal thymocytes might be involved in these changes. All the results provided evidence for elucidating the PNE-induced programmed immune diseases.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Doenças do Sistema Imunitário/induzido quimicamente , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Timócitos/efeitos dos fármacos , Timo/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Autofagia/efeitos dos fármacos , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Feminino , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/patologia , Masculino , Exposição Materna , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fenótipo , Gravidez , Timócitos/imunologia , Timócitos/metabolismo , Timócitos/patologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
5.
Genet Med ; 21(1): 243-251, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29921932

RESUMO

PURPOSE: The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown. METHODS: Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants. RESULTS: This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in ~50% of the patients. CONCLUSION: Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members.


Assuntos
Predisposição Genética para Doença , Testes Genéticos , Genômica , Doenças do Sistema Imunitário/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Exoma/genética , Exoma/imunologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Masculino , Mutação , Fenótipo , Análise de Sequência de DNA , Sequenciamento Completo do Exoma , Adulto Jovem
6.
Stem Cells ; 37(3): 298-305, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30395373

RESUMO

With their immunosuppressive features, human mesenchymal stromal cells (MSCs), sometimes also termed as mesenchymal stem cells, hold great potential as a cell-based therapy for various immune-mediated diseases. Indeed, MSCs have already been approved as a treatment for graft versus host disease. However, contradictory data from clinical trials and lack of conclusive proof of efficacy hinder the progress toward wider clinical use of MSCs and highlight the need for more relevant disease models. Humanized mice are increasingly used as models to study immune-mediated disease, as they simulate human immunobiology more closely than conventional murine models. With further advances in their resemblance to human immunobiology, it is very likely that humanized mice will be used more commonly as models to investigate MSCs with regard to their therapeutic safety and their immunomodulatory effect and its underlying mechanisms. Recent studies that explore the immunosuppressive features of MSCs in humanized mouse models will be discussed in this review. Stem Cells 2019;37:298-305.


Assuntos
Modelos Animais de Doenças , Doença Enxerto-Hospedeiro , Doenças do Sistema Imunitário , Imunomodulação , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Doenças do Sistema Imunitário/terapia , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/patologia , Camundongos
7.
Adv Exp Med Biol ; 1201: 93-108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31898783

RESUMO

Mesenchymal stem cells (MSCs) are multipotent cells that can self-renew and differentiate into cells of all germ layers. MSCs can be easily attracted to the site of tissue insult with high levels of inflammatory mediators. The general ability of MSCs to migrate at the sites of tissue injury suggested an innate ability for these cells to be involved in baseline tissue repair. The bone marrow is one of the primary sources of MSCs, though they can be ubiquitous. An attractive property of MSCs for clinical application is their ability to cross allogeneic barrier. However, alone, MSCs are not immune suppressive cells. Rather, they can be licensed by the tissue microenvironment to become immune suppressor cells. Immune suppressor functions of MSCs include those that blunt cytotoxicity of natural killer cells, suppression of T-cell proliferation, and "veto" function. MSCs, as third-party cells, suppress the immune response that generally recapitulates graft-versus-host disease (GvHD) responses. Based on the plastic functions of MSCs, these cells have dominated the field of cell-based therapies, such as anti-inflammatory and drug delivery. Here, we focus on the potential use of MSC for immunological disorders such as Crohn's disease and GvHD.


Assuntos
Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Doença de Crohn/imunologia , Doença de Crohn/terapia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Doenças do Sistema Imunitário/patologia , Células Matadoras Naturais/imunologia , Células-Tronco Mesenquimais/citologia
8.
Cell ; 175(4): 908-920, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388451

RESUMO

Stem cells regenerate tissues in homeostasis and under stress. By taking cues from their microenvironment or "niche," they smoothly transition between these states. Immune cells have surfaced as prominent members of stem cell niches across the body. Here, we draw parallels between different stem cell niches to explore the context-specific interactions that stem cells have with tissue-resident and recruited immune cells. We also highlight stem cells' innate ability to sense and respond to stress and the enduring memory that forms from such encounters. This fascinating crosstalk holds great promise for novel therapies in inflammatory diseases and regenerative medicine.


Assuntos
Células-Tronco/imunologia , Animais , Homeostase , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Nicho de Células-Tronco/imunologia
9.
Mol Immunol ; 103: 191-199, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30300798

RESUMO

The difficulty of studying small tissue samples and rare cell populations have been some of the main limitations in performing efficient translational studies of immune mediated diseases. Many of these conditions are grouped under the name of a single disease whilst there are strong suggestions that disease heterogeneity leads to variable disease progression as well as therapeutic responses. The recent development of single cell techniques, such as single cell RNA sequencing, gene expression profiling, or multiparametric cytometry, is likely to be a turning point. Single cell approaches provide researchers the opportunity to finally dissect disease pathology at a level that will allow mechanistic classifications and precision therapeutic strategies. In this review, we will give an overview of the current and developing repertoire of single cell techniques, the benefits and limitations of each, and provide an example of how single cell techniques can be utilized to understand complex immune mediated diseases and their translation from mouse to human.


Assuntos
Perfilação da Expressão Gênica/métodos , Doenças do Sistema Imunitário/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Animais , Epigenômica/métodos , Humanos , Doenças do Sistema Imunitário/patologia , Espectrometria de Massas/métodos , Proteoma/genética , Proteoma/metabolismo , Proteômica/métodos
11.
J Clin Pathol ; 71(12): 1033-1040, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30275102

RESUMO

'Apoptotic colopathy' is an umbrella term signifying a pattern of injury where the gastrointestinal biopsy shows a colitic picture with apoptosis as the predominant histological feature. Although the entities within apoptotic colopathy share a common histological feature- 'apoptosis', there is a list of varied clinical differential diagnoses that produce this similar histological pattern of injury. These include graft-versus-host disease, drug-induced injury due to multiple drugs (in particular, mycophenolate mofetil, check point inhibitor therapy and some others), infections (particularly cytomegalovirus, adenovirus and some others), immune disorders and other miscellaneous causes. However, the management of these varied differentials is strikingly different, thus necessitating an algorithmic approach for accurate diagnosis and optimal patient management. A definitive diagnosis requires interpretation of varied histological findings in the appropriate clinical context including clinical history, drug history and laboratory findings. This review will focus on the histopathological findings of varied entities that can manifest as 'apoptotic colopathy' on assessment of colonic biopsies.


Assuntos
Apoptose , Colite/diagnóstico , Doenças do Colo/diagnóstico , Doença Enxerto-Hospedeiro/diagnóstico , Doenças do Sistema Imunitário/diagnóstico , Viroses/diagnóstico , Biópsia , Colite/induzido quimicamente , Colite/patologia , Doenças do Colo/patologia , Diagnóstico Diferencial , Doença Enxerto-Hospedeiro/patologia , Humanos , Doenças do Sistema Imunitário/patologia , Viroses/patologia
12.
Front Immunol ; 9: 1900, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30166988

RESUMO

Trauma remains a leading cause of death worldwide. Hemorrhagic shock and direct injury to vital organs are responsible for early mortality whereas most delayed deaths are secondary to complex pathophysiological processes. These processes result from imbalanced systemic reactions to the multiple aggressions associated with trauma. Trauma results in the uncontrolled local and systemic release of endogenous mediators acting as danger signals [damage-associated molecular patterns (DAMPs)]. Their recognition by the innate immune system triggers a pro-inflammatory immune response paradoxically associated with concomitant immunosuppression. These responses, ranging in intensity from inappropriate to overwhelming, promote the propagation of injuries to remote organs, leading to multiple organ failure and death. Some of the numerous DAMPs released after trauma trigger the assembly of intracellular multiprotein complexes named inflammasomes. Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1ß and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. Following trauma-induced DAMP(s) recognition, inflammasomes participate in multiple ways in the development of exaggerated systemic and organ-specific inflammatory response, contributing to organ damage. Inflammasomes are involved in the innate responses to traumatic brain injury and contribute to the development of acute respiratory distress syndrome. Inflammasomes may also play a role in post-trauma immunosuppression mediated by dysregulated monocyte functions. Characterizing the involvement of inflammasomes in the pathogenesis of post-trauma syndrome is a key issue as they may be potential therapeutic targets. This review summarizes the current knowledge on the roles of inflammasomes in trauma.


Assuntos
Alarminas/metabolismo , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/metabolismo , Inflamassomos/metabolismo , Ferimentos e Lesões/complicações , Animais , Coagulação Sanguínea , Plaquetas/metabolismo , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/patologia , Imunidade Inata , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia
13.
Front Immunol ; 9: 2056, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30254638

RESUMO

Background: One of the greatest challenges for medicine is to find a safe and effective treatment for immune-related diseases. However, due to the low efficacy of the treatment available and the occurrence of serious adverse effects, many groups are currently searching for alternatives to the traditional therapy. In this regard, the use of human mesenchymal stem cells (hMSCs) represents a great promise for the treatment of a variety of immune-related diseases due to their potent immunomodulatory properties. The main objective of this study is, therefore, to present and summarize, through a systematic review of the literature, in vivo studies in which the efficacy of the administration of hMSCs for the treatment of immune-related diseases was evaluated. Methods: The article search was conducted in PubMed/MEDLINE, Scopus and Web of Science databases. Original research articles assessing the therapeutic potential of hMSCs administration for the in vivo treatment immune-related diseases, published from 1984 to December 2017, were selected and evaluated. Results: A total of 132 manuscripts formed the basis of this systematic review. Most of the studies analyzed reported positive results after hMSCs administration. Clinical effects commonly observed include an increase in the survival rates and a reduction in the severity and incidence of the immune-related diseases studied. In addition, hMSCs administration resulted in an inhibition in the proliferation and activation of CD19+ B cells, CD4+ Th1 and Th17 cells, CD8+ T cells, NK cells, macrophages, monocytes, and neutrophils. The clonal expansion of both Bregs and Tregs cells, however, was stimulated. Administration of hMSCs also resulted in a reduction in the levels of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-1, IL-2, IL-12, and IL-17 and in an increase in the levels of immunoregulatory cytokines such as IL-4, IL-10, and IL-13. Conclusions: The results obtained in this study open new avenues for the treatment of immune-related diseases through the administration of hMSCs and emphasize the importance of the conduction of further studies in this area.


Assuntos
Citocinas/imunologia , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Leucócitos Mononucleares/imunologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Humanos , Doenças do Sistema Imunitário/patologia , Leucócitos Mononucleares/patologia , Células-Tronco Mesenquimais/patologia
15.
Int J Cancer ; 143(10): 2449-2457, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30238973

RESUMO

Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses. It is unlikely that prior therapy is solely responsible for SPC risk. To investigate risk of SPC after diagnosis of non-Hodgkin lymphoma (NHL) and 10 of its subtypes we conducted a novel bidirectional analysis, SPCs after NHL and NHL as SPC. Using the Swedish Family-Cancer Database, we identified 19,833 individuals with primary NHL diagnosed between 1993 and 2015. We calculated relative risks (RRs) of SPCs in NHL survivors and, for bi-directional analysis, risk of NHL as SPC. The overall RRs were significantly bidirectionally increased for NHL and 7 cancers. After diagnosis of NHL risks were increased for upper aerodigestive tract (RR = 1.96), colorectal (1.35), kidney (3.10), bladder (1.54) and squamous cell skin cancer (SCC) (4.12), melanoma (1.98) and Hodgkin lymphoma (9.38). The concordance between RRs for each bidirectional association between NHL and 31 different cancers was highly significant (r = 0.86, p < 0.0001). Melanoma was bidirectionally associated with all 10 subtypes of NHL. The observed bidirectional associations between NHL and cancer suggest that therapy-related carcinogenic mechanisms cannot solely explain the findings. Considering that skin SCC and melanoma are usually treated by surgery and that these cancers and NHL are most responsive of any cancer to immune suppression, the consistent bidirectional results provide population-level evidence that immune suppressed state is a key underlying mechanism in the context of SPCs. Furthermore, the quantified risks for NHL subtypes have direct clinical application in the management of NHL patients.


Assuntos
Doenças do Sistema Imunitário/epidemiologia , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/imunologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/imunologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/patologia , Risco , Suécia/epidemiologia
16.
Cytokine ; 111: 112-118, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30138899

RESUMO

The immuno-inflammatory origin of schizophrenia in a subset of patients is viewed as a key element of an overarching etiological construct. Despite substantial research, the immune components exerting major effect are yet to be fully clarified. Disrupted T cell networks have consistently been linked to the pathogenesis of schizophrenia. Amongst the Th cell subsets, the Th17 cells have emerged as a paradigmatic lineage with significant functional implications in a vast number of immune mediated diseases including brain disorders such as schizophrenia. The present study was aimed at examining the functional role of the Th17 pathway in schizophrenia. To address this, genotyping of IL17A (rs2275913; G197A) Single Nucleotide Polymorphism was carried out by the PCR-RFLP method in 221 schizophrenia patients and 223 healthy control subjects. Gene expression of two transcription factors STAT3 and RORC was quantified in a subset of drug naïve schizophrenia patients (n = 56) and healthy controls (n = 52) by TaqMan assay. The plasma levels of fifteen cytokines belonging to Th17 pathway were estimated in a subset of drug naïve schizophrenia patients (n = 61) and healthy controls (n = 50) by using Bio-Plex Pro Human Th17 cytokine assays. The AA genotype was associated with higher total score of bizarre behaviour and apathy in female schizophrenia patients. A high gene expression level of RORC was observed in drug naïve schizophrenia patients. In addition, significantly elevated plasma levels of IL-6 and IL-22, and reduced levels of IL-1ß and IL-17F were noted in schizophrenia patients. Taken together, these findings indicate a dysregulated Th17 pathway in schizophrenia patients.


Assuntos
Doenças do Sistema Imunitário , Interleucina-6 , Interleucinas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Polimorfismo de Nucleotídeo Único , Células Th17 , Adolescente , Adulto , Feminino , Genótipo , Humanos , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/sangue , Interleucinas/genética , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/sangue , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Esquizofrenia/sangue , Esquizofrenia/genética , Esquizofrenia/imunologia , Esquizofrenia/patologia , Fatores Sexuais , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/fisiologia
17.
J Immunol ; 201(5): 1442-1451, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30012848

RESUMO

Phenotypic differences among substrains of laboratory mice due to spontaneous mutations or pre-existing genetic variation confound the interpretation of targeted mutagenesis experiments and contribute to challenges with reproducibility across institutions. Notably, C57BL/6 Hsd mice and gene-targeted mice that have been backcrossed to this substrain have been reported to harbor a duplication in exons 28 and 29 of Dock2 In this study, we demonstrate the presence of this Dock2 variant in the widely used Nod2-/- mice. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic innate immune receptor associated with inflammatory bowel disease susceptibility. Consistent with a role of NOD2 in an immunological disorder, Nod2-/- mice bred at our institution displayed multiple B cell defects including deficiencies in recirculating B cells, marginal zone B cells, and B1a cells in vivo, as well as defects in class switch recombination in vitro. However, we found that these effects are due to the Dock2 variant and are independent of Nod2 deletion. Despite originating from the same gene-targeted founder mice, Nod2-/- mice from another source did not harbor the Dock2 variant or B cell defects. Finally, we show that Dock2-/- mice display the same B cell defects as mice harboring the Dock2 variant, confirming that the variant is a loss-of-function mutation and is sufficient to explain the alterations to the B cell compartment observed in Nod2-/- mice. Our findings highlight the effects of confounding mutations from widely used inbred strains on gene-targeted mice and reveal new functions of DOCK2 in B cells.


Assuntos
Linfócitos B/imunologia , Proteínas Ativadoras de GTPase , Doenças do Sistema Imunitário , Mutação , Proteína Adaptadora de Sinalização NOD2/deficiência , Animais , Linfócitos B/patologia , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/imunologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Camundongos , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/imunologia
18.
Int J Biol Macromol ; 114: 1049-1055, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29626602

RESUMO

In vivo an ecological network of polysaccharides utilization by gut microbiota is not only an intense competition but also an impressive cooperation pattern. The present study evaluated the in vivo protective effect of combined fungal polysaccharides (CFP) from Cordyceps sinensis and Ganoderma atrum on colon immune dysfunction, induced by 150mg/kg cyclophosphamide (CP). The results showed that C. sinensis polysaccharides (CSP) significantly promoted microbial-derived butyrate to improve histone h3 acetylation mediating regulatory T (Treg) cell specific Foxp3, as well as significantly restored CP-induced elevation of interleukin (IL)-17 and IL-21. Additionally, G. atrum polysaccharides (PSG) significantly down-regulated MyD88, as well as significantly increased IL-10 and TGF-ß3. Furthermore, CFP balanced the disequilibrium of cytokines secretion and Foxp3/RORγt ratio related Treg/T helper 17 (Th17) balance, as well as down-regulated the TLR-mediated inflammatory signaling pathway and promoted secretory immunoglobulin A (sIgA) secretion to suppress colonic inflammation. Therefore, our results typically contribute to understand the in vivo immunoregulatory function of fungal polysaccharides compounds, involving microbial-associated inflammatory signals and specific metabolic products.


Assuntos
Colo/imunologia , Doenças do Colo/prevenção & controle , Cordyceps/química , Polissacarídeos Fúngicos , Ganoderma/química , Doenças do Sistema Imunitário/prevenção & controle , Animais , Colo/patologia , Doenças do Colo/imunologia , Doenças do Colo/patologia , Citocinas/imunologia , Feminino , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/farmacologia , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
19.
J Biol Regul Homeost Agents ; 32(1): 37-45, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29504363

RESUMO

Regulated-on-activation, normal T cell expressed and secreted (also called RANTES, CCL5 or R/C) is a chemotactic cytokine that plays a key role in recruiting immune cells to inflammatory sites. R/C is involved in the pathogenesis of many systemic immune-mediated diseases (SIDs) and is upregulated in fatty-degenerative osteolysis jawbone (FDOJ) cavitations. Surgical cleaning of degenerative areas reduces the source of chronic R/C but might not be sufficient to re-establish the altered immunological patterns. The aim of the present study was to collect clinical data from patients suffering from sids who underwent dental surgery of FDOJ areas (n=46), by measuring R/C serum levels at the first visit (V0) prior to surgery, and at the second visit (V1). The majority of patients (n=41) were treated one month with ultra-low dose RANTES (27CH), a medicine used in micro-immunotherapy, while five patients were not. Mean and standard deviation of R/C serum levels at V0 in treated and untreated patients were respectively 48.5±25.8ng/ml and 42.48±22.22ng/ ml. Untreated patients had a tendency towards higher R/C levels at V1 (68.36±30.7ng/ml; p=0.062), while an opposite tendency was observed in treated patients (40.9±20.3ng/ml; p=0.129). Investigators observed that a cut-off set at 40ng/ml at V0 seemed to be predictive of the efficacy of the dental surgery/treatment (p=0.0013, n=26) and that gender could influence R/C levels and patient's responsiveness. The Authors, being aware that this is a preliminary follow-up, wanted to lay the basis for forthcoming studies, in which a larger cohort of patients and well-defined inclusion/exclusion criteria will be established.


Assuntos
Quimiocina CCL5/administração & dosagem , Doenças do Sistema Imunitário , Doenças Maxilomandibulares , Complicações Pós-Operatórias , Feminino , Seguimentos , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Doenças Maxilomandibulares/tratamento farmacológico , Doenças Maxilomandibulares/imunologia , Doenças Maxilomandibulares/patologia , Masculino , Osteólise , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/patologia
20.
Metallomics ; 10(3): 463-473, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29485154

RESUMO

Coal mining is one of the economic activities with the greatest impact on environmental quality. At all stages contaminants are released as particulates such as coal dust. The first aim of this study was to obtain an aqueous coal dust extract and characterize its composition in terms of trace elements by ICP-MS. In addition, the developmental toxicity of the aqueous coal extract was evaluated using zebrafish (Danio rerio) after exposure to different concentrations (0-1000 ppm; µg mL-1) to establish acute toxicity, morphology and transcriptome changes. Trace elements within the aqueous coal dust extract present at the highest concentrations (>10 ppb) included Sr, Zn, Ba, As, Cu and Se. In addition, Cd and Pb were found in lower concentrations. No significant difference in mortality was observed (p > 0.05), but a delay in hatching was found at 0.1 and 1000 ppm (p < 0.05). No significant differences in morphological characteristics were observed in any of the treatment groups (p > 0.05). Transcriptomic results of zebrafish larvae revealed alterations in 77, 61 and 1376 genes in the 1, 10, and 100 ppm groups, respectively. Gene ontology analysis identified gene alterations associated with the development and function of connective tissue and the hematological system, as well as pathways associated with apoptosis, the cell cycle, transcription, and oxidative stress including the MAPK signaling pathway. In addition, altered genes were associated with cancer; connective tissue, muscular, and skeletal disorders; and immunological and inflammatory diseases. Overall, this is the first study to characterize gene expression alterations in response to developmental exposure to aqueous coal dust residue from coal mining with transcriptome results signifying functions and systems to target in future studies.


Assuntos
Carvão Mineral/toxicidade , Tecido Conjuntivo/patologia , Poeira/análise , Regulação da Expressão Gênica no Desenvolvimento , Doenças Hematológicas/patologia , Doenças do Sistema Imunitário/patologia , Inflamação/patologia , Peixe-Zebra/crescimento & desenvolvimento , Animais , Tecido Conjuntivo/efeitos dos fármacos , Tecido Conjuntivo/metabolismo , Poluentes Ambientais/toxicidade , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/genética , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/genética , Inflamação/induzido quimicamente , Inflamação/genética , Transcriptoma , Peixe-Zebra/genética
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