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1.
Int Arch Allergy Immunol ; 181(1): 31-42, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31694023

RESUMO

Irritable bowel syndrome (IBS) is a functional gastrointestinal disease and the most common cause of prolonged abdominal pain and bowel disturbances in the developed world. While initially thought to be functional or psychosomatic in nature, IBS is now recognized as a heterogeneous group of conditions. A subset of IBS patients and patients with allergic diseases share some characteristic inflammatory features. In fact, atopic children show an increased likelihood of developing IBS as adults. Given these findings, a subset of IBS may be suffering from allergy-related gut diseases. In this review, we present the allergy-related comorbidities of IBS, including genetic, environmental, and immunologic factors. We discuss studies demonstrating an increased sensitization of IBS patients to aeroallergens compared to food allergens. We then postulate potential pathophysiological mechanisms underlying both IBS and aeroallergens in the gut, followed by potential implications in the screening and treatment of allergies in IBS patients.


Assuntos
Gastroenteropatias/imunologia , Hipersensibilidade/imunologia , Inflamação/imunologia , Síndrome do Intestino Irritável/imunologia , Poluição do Ar , Alérgenos/imunologia , Animais , Criança , Comorbidade , Gastroenteropatias/epidemiologia , Humanos , Hipersensibilidade/epidemiologia , Síndrome do Intestino Irritável/epidemiologia , Risco
3.
Vet Immunol Immunopathol ; 210: 15-22, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30947975

RESUMO

Toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain 2 (NOD2), and TNF-α play important roles in human inflammatory bowel diseases. The aim of this study was to elucidate the relationship between Toll-like receptor 4, NOD2, and TNF-α and the severity of chronic gastrointestinal diseases in dogs. We examined the expression levels of TLR4, NOD2, and TNF-α in the stomach, duodenum, ileum, colon, and rectum obtained from 21 dogs with chronic gastrointestinal disease, including inflammatory bowel disease, high-grade lymphoma, food responsive enteropathy, chronic pancreatitis, low-grade lymphoma, inflammatory colorectal polyp, and chronic colitis. Next, we demonstrated whether there is good correlation between the expression levels of TLR4, NOD2, and TNF-α and the histopathological analysis of each sample. We found that the level of TLR4 expression in the ileum of dogs with chronic gastrointestinal disease was positively associated with the histopathological severity. We also found that the level of NOD2 expression in the duodenum, stomach, and rectum was positively associated with the histopathological severity. However, there was no correlation between TNF-α expression in the 5 regions tested in this study and the histopathological severity. These findings indicate that TLR4 and NOD2 are remarkably associated with the severity of chronic gastrointestinal disease in dogs.


Assuntos
Gastroenteropatias/imunologia , Gastroenteropatias/patologia , Proteína Adaptadora de Sinalização NOD2/genética , Receptor 4 Toll-Like/genética , Animais , Biópsia , Doença Crônica , Colo/imunologia , Colo/patologia , Cães , Duodeno/imunologia , Duodeno/patologia , Feminino , Masculino , Índice de Gravidade de Doença , Transdução de Sinais , Estômago/imunologia , Estômago/patologia , Fator de Necrose Tumoral alfa/genética
4.
Immunity ; 50(4): 778-795, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995499

RESUMO

Forty years after its naming, interleukin-1 (IL-1) is experiencing a renaissance brought on by the growing understanding of its context-dependent roles and advances in the clinic. Recent studies have identified important roles for members of the IL-1 family-IL-18, IL-33, IL-36, IL-37, and IL-38-in inflammation and immunity. Here, we review the complex functions of IL-1 family members in the orchestration of innate and adaptive immune responses and their diversity and plasticity. We discuss the varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and auto-inflammation, dysmetabolism, cardiovascular disorders, and cancer. The trans-disease therapeutic activity of anti-IL-1 strategies argues for immunity and inflammation as a metanarrative of modern medicine.


Assuntos
Imunidade Adaptativa/imunologia , Citocinas/fisiologia , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-1/fisiologia , Animais , Doenças Cardiovasculares/imunologia , Citocinas/genética , Citocinas/imunologia , Gastroenteropatias/imunologia , Hematopoese/imunologia , Humanos , Interleucina-1/imunologia , Linfócitos/imunologia , Camundongos , Camundongos Knockout , Família Multigênica , Neoplasias/imunologia , Doenças Neurodegenerativas/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia
5.
Int J Mol Sci ; 20(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995806

RESUMO

The intestinal epithelium constitutes an indispensable single-layered barrier to protect the body from invading pathogens, antigens or toxins. At the same time, beneficial nutrients and water have to be absorbed by the epithelium. To prevent development of intestinal inflammation or tumour formation, intestinal homeostasis has to be tightly controlled and therefore a strict balance between cell death and proliferation has to be maintained. The proinflammatory cytokine tumour necrosis factor alpha (TNFα) was shown to play a striking role for the regulation of this balance in the gut. Depending on the cellular conditions, on the one hand TNFα is able to mediate cell survival by activating NFκB signalling. On the other hand, TNFα might trigger cell death, in particular caspase-dependent apoptosis but also caspase-independent programmed necrosis. By regulating these cell death and survival mechanisms, TNFα exerts a variety of beneficial functions in the intestine. However, TNFα signalling is also supposed to play a critical role for the pathogenesis of inflammatory bowel disease (IBD), infectious diseases, intestinal wound healing and tumour formation. Here we review the literature about the physiological and pathophysiological role of TNFα signalling for the maintenance of intestinal homeostasis and the benefits and difficulties of anti-TNFα treatment during IBD.


Assuntos
Gastroenteropatias/imunologia , Homeostase , Intestinos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Anticorpos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Infecções Bacterianas/patologia , Descoberta de Drogas , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/patologia , Homeostase/efeitos dos fármacos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Viroses/tratamento farmacológico , Viroses/imunologia , Viroses/patologia
6.
Toxins (Basel) ; 11(4)2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30970547

RESUMO

Shigella species and Shiga toxin-producing Escherichia coli (STEC) are agents of bloody diarrhea that may progress to potentially lethal complications such as diarrhea-associated hemolytic uremic syndrome (D+HUS) and neurological disorders. The bacteria share the ability to produce virulence factors called Shiga toxins (Stxs). Research over the past two decades has identified Stxs as multifunctional toxins capable of inducing cell stress responses in addition to their canonical ribotoxic function inhibiting protein synthesis. Notably, Stxs are not only potent inducers of cell death, but also activate innate immune responses that may lead to inflammation, and these effects may increase the severity of organ injury in patients infected with Stx-producing bacteria. In the intestines, kidneys, and central nervous system, excessive or uncontrolled host innate and cellular immune responses triggered by Stxs may result in sensitization of cells to toxin mediated damage, leading to immunopathology and increased morbidity and mortality in animal models (including primates) and human patients. Here, we review studies describing Stx-induced innate immune responses that may be associated with tissue damage, inflammation, and complement activation. We speculate on how these processes may contribute to immunopathological responses to the toxins.


Assuntos
Imunidade Inata/efeitos dos fármacos , Toxinas Shiga/toxicidade , Animais , Gastroenteropatias/imunologia , Síndrome Hemolítico-Urêmica/imunologia , Humanos , Nefropatias/imunologia
7.
Nat Biotechnol ; 37(5): 527-530, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936561

RESUMO

Oral antibodies that interfere with gastrointestinal targets and can be manufactured at scale are needed. Here we show that a single-gene-encoded monomeric immunoglobulin A (IgA)-like antibody, composed of camelid variable single domain antibodies (VHH) fused to IgA Fc (mVHH-IgA), prevents infection by enterotoxigenic Escherichia coli (F4-ETEC) in piglets. The mVHH-IgA can be produced in soybean seeds or secreted from the yeast Pichia pastoris, freeze- or spray-dried and orally delivered within food.


Assuntos
Doenças Transmissíveis/tratamento farmacológico , Gastroenteropatias/tratamento farmacológico , Imunoglobulina A/uso terapêutico , Anticorpos de Domínio Único/uso terapêutico , Administração Oral , Animais , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/microbiologia , Escherichia coli/patogenicidade , Alimentos , Gastroenteropatias/imunologia , Gastroenteropatias/prevenção & controle , Gastroenteropatias/veterinária , Humanos , Imunoglobulina A/imunologia , Anticorpos de Domínio Único/imunologia , Suínos
8.
Microb Pathog ; 131: 135-143, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30914387

RESUMO

Gastrointestinal Infectious diseases (GIDs) are the second cause of death worldwide. T helper17 cells (Th17) play an important role in GIDs through production of IL-17A, IL-17F, and IL-22 cytokines. Because of their increased activities in GID, Th17 and its inflammatory cytokines can inhibit the progression and eliminate the infection. Actually, although Th17 have the best performance in the acute phase, regulatory T cells (Treg cells) are enhanced in the chronic phase and infection progress through its suppressive function. In addition, Treg cells prevent undesirable inflammatory damages developed by immune system components. On the other hand, miRNAs have important roles in the regulation of immune responses to eliminate bacterial infections and protect host organisms from harmful effects. Actually, miRNAs can reinforce innate and adaptive immunity to remove infections. Of note, miRNAs can develop a regulatory network with the immune system. Additionally, miRNAs can also serve in favor of bacteria to reduce immune responses. Therefore, balance of immune responses in Treg and Th17 cells can influence outcome of many infectious diseases. In conclusion, there is an imbalance in the Treg/Th17 ratio in GIDs; importantly, sets of miRNAs, particularly miR155 and miR146, were determined to be involved clearly in GIDs.


Assuntos
Gastroenteropatias/imunologia , MicroRNAs/imunologia , MicroRNAs/fisiologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Citocinas/metabolismo , Progressão da Doença , Gastroenteropatias/microbiologia , Imunidade , Interleucina-17/imunologia
9.
Expert Rev Gastroenterol Hepatol ; 13(5): 437-445, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30900475

RESUMO

INTRODUCTION: Primary atopic disorders can be classified as heritable genetic disorders presenting with deregulated pathogenic allergic effector responses irrespective of sensitization. In the last decade, there are parallel rises in the burden of atopic and gastrointestinal (GI) diseases. Areas covered: There is increasing recognition of an association between atopy and GI disease through immune dysregulation, the microbiome and shared genetic pathways. Since the first article on atopy and the GI tract in 2014 in this journal, many more studies have shed light on the shared pathways in these diseases, particularly in the field of eosinophilic GI disease, functional GI disorders, and inflammatory bowel disease. Expert opinion: Understanding the links with common mechanisms in atopy and GI diseases that may lead to better targeting of treatment through manipulation of immune mechanisms, the microbiome, genetics, food allergens and specific GI diseases such as inflammatory bowel disease, functional GI disorders.


Assuntos
Alérgenos , Gastroenteropatias/epidemiologia , Microbioma Gastrointestinal , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Hipersensibilidade/epidemiologia , Animais , Gastroenteropatias/genética , Gastroenteropatias/imunologia , Gastroenteropatias/microbiologia , Predisposição Genética para Doença , Humanos , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Hipersensibilidade/microbiologia , Prognóstico , Fatores de Risco
10.
Am J Gastroenterol ; 114(3): 429-436, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30839392

RESUMO

BACKGROUND: Subtle histopathologic features such as eosinophilia and increased mast cells have been observed in functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and the irritable bowel syndrome (IBS). The mechanisms that drive recruitment of these cells to the gastrointestinal tract remain unexplained, largely due to the heterogeneity in phenotypes among patients diagnosed with such conditions. We aimed to systematically review the literature and collate the evidence for immune activation in FD and IBS, and where possible, detail the nature of activation. METHODS: Seven literature databases were searched using the keywords: 'functional gastrointestinal disorder', FGID, 'functional dyspepsia', 'non-ulcer dyspepsia', 'idiopathic dyspepsia', 'irritable bowel syndrome', IBS and 'immun*'. RESULTS: Fifty-one papers reporting discordant immune features met the selection criteria for this review. Changes in lymphocyte populations, including B and T lymphocyte numbers and activation status were reported in IBS and FD, in conjunction with duodenal eosinophilia in FD and increased colonic mast cells in IBS. Increases in circulating α4+ß7+ gut-homing T cells appear to be linked to the pathophysiology of both FD and IBS. Studies in the area are complicated by poor phenotyping of patients into subgroups and the subtle nature of the immune activity involved in FD and IBS. CONCLUSIONS: Alterations in proportions of gut-homing T lymphocytes in both FD and IBS indicate that a loss of mucosal homeostasis may drive the symptoms of FD and IBS. There is indirect evidence that Th17 responses may play a role in FGIDs, however the evidence for a Th2 immune phenotype in FD and IBS is limited. Although immune involvement is evident, large, well-characterised patient cohorts are required to elucidate the immune mechanisms driving the development of FGIDs.


Assuntos
Linfócitos B/imunologia , Dispepsia/imunologia , Eosinofilia/imunologia , Síndrome do Intestino Irritável/imunologia , Mastócitos/imunologia , Linfócitos T/imunologia , Colo/imunologia , Duodeno/imunologia , Gastroenteropatias/imunologia , Humanos , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Células Th17 , Células Th2
11.
J Immunol Res ; 2019: 8197048, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863783

RESUMO

Innate immunity represents the first barrier against bacterial invasion. Toll-like receptors (TLRs) belong to the large family of pattern recognition receptors (PRRs), and their activation leads to the induction of inflammatory cytokines, chemokines, antigen-presenting molecules, and costimulatory molecules. Recent studies have focused on identifying the association between TLRs and Helicobacter pylori- (H. pylori-) related diseases. Therefore, this minireview focuses on assessing the role of these TLRs in the development of H. pylori-related gastropathies. Both TLR2 and TLR were found to be involved in H. pylori LPS recognition, with contradictory results most likely due to both the inability to obtain pure LPS in experimental studies and the heterogeneity of the bacterial LPS. In addition, TLR2 was found to be the most extensively expressed gene among all the TLRs in gastric tumors. High levels of TLR4 were also associated with a higher risk of gastric cancer. TLR5 was initially associated with the recognition of H. pylori flagellin, but it seems that this bacterium has developed mechanisms to escape this recognition representing an important factor involved in the persistence of this infection and subsequent carcinogenesis. TLR9, the only TLR with both anti- and proinflammatory roles, was involved in the recognition of H. pylori DNA. The dichotomous role of TLR9, promoting or suppressing the infection, depends on the gastric environment. Recently, TLR7 and TLR8 were shown to recognize purified H. pylori RNA, thereby inducing proinflammatory cytokines. TLR1 and TLR10 gene polymorphisms were associated with a higher risk for gastric cancer in H. pylori-infected individuals. Different gene polymorphisms of these TLRs were found to be associated with gastric cancer depending mostly on ethnicity. Further studies are required in order to develop preventive and therapeutic strategies against H. pylori infections based on the functions of TLRs.


Assuntos
Gastroenteropatias/imunologia , Gastroenteropatias/microbiologia , Infecções por Helicobacter/imunologia , Receptores Toll-Like/imunologia , Animais , Grupos Étnicos , Infecções por Helicobacter/complicações , Helicobacter pylori/imunologia , Humanos , Imunidade Inata , Camundongos , Polimorfismo Genético , Receptores de Reconhecimento de Padrão/imunologia , Fatores de Risco , Transdução de Sinais , Neoplasias Gástricas/microbiologia , Receptores Toll-Like/genética
12.
J Dairy Sci ; 102(5): 4249-4263, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30852025

RESUMO

Infection of cattle with bovine paratuberculosis (i.e., Johne's disease) is caused by Mycobacterium avium ssp. paratuberculosis (MAP) and results in a chronic incurable gastroenteritis. This disease, which has economic ramifications for the cattle industry, is increasing in detected prevalence globally; subclinically infected animals can silently shed the bacterium into the environment for years, exposing contemporaries and hampering disease-control programs. The objective of the present study was to first quantify the genetic parameters for humoral response to MAP in dairy cattle. This was followed by a genome-based association analysis and subsequent downstream bioinformatic analyses from imputed whole genome sequence SNP data. After edits, ELISA test records were available on 136,767 cows; analyses were also undertaken on a subset of 33,818 of these animals from herds with at least 5 MAP ELISA-positive cows, with at least 1 of those positive cows being homebred. Variance components were estimated using univariate animal and sire linear mixed models. The heritability calculated from the animal model for humoral response to MAP using alternative phenotype definitions varied from 0.02 (standard error = 0.003) to 0.05 (standard error = 0.008). The genome-based associations were undertaken within a mixed model framework using weighted deregressed estimated breeding values as a dependent variable on 1,883 phenotyped animals that were ≥87.5% Holstein-Friesian. Putative susceptibility quantitative trait loci (QTL) were identified on Bos taurus autosome 1, 3, 5, 6, 8, 9, 10, 11, 13, 14, 18, 21, 23, 25, 26, 27, and 29; mapping the most significant SNP to genes within and overlapping these QTL revealed that the most significant associations were with the 10 functional candidate genes KALRN, ZBTB20, LPP, SLA2, FI3A1, LRCH3, DNAJC6, ZDHHC14, SNX1, and HAS2. Pathway analysis failed to reveal significantly enriched biological pathways, when both bovine-specific pathway data and human ortholog data were taken into account. The existence of genetic variation for MAP susceptibility in a large data set of dairy cows signifies the potential of breeding programs for reducing MAP susceptibility. Furthermore, the identification of susceptible QTL facilitates greater biological understanding of bovine paratuberculosis and potential therapeutic targets for future investigation. The novel molecular similarities identified between bovine paratuberculosis and human inflammatory bowel disease suggest potential for human therapeutic interventions to be translated to veterinary medicine and vice versa.


Assuntos
Doenças dos Bovinos/imunologia , Gastroenteropatias/imunologia , Imunidade Humoral/genética , Mycobacterium avium subsp. paratuberculosis/imunologia , Paratuberculose/imunologia , Animais , Cruzamento , Bovinos , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/genética , Suscetibilidade a Doenças , Ensaio de Imunoadsorção Enzimática/veterinária , Feminino , Gastroenteropatias/genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Lineares , Masculino , Paratuberculose/genética , Paratuberculose/microbiologia , Fenótipo , Locos de Características Quantitativas
13.
World J Gastroenterol ; 25(5): 552-566, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30774271

RESUMO

Despite their high prevalence, lack of understanding of the exact pathophysiology of the functional gastrointestinal disorders has restricted us to symptomatic diagnostic tools and therapies. Complex mechanisms underlying the disturbances in the bidirectional communication between the gastrointestinal tract and the brain have a vital role in the pathogenesis and are key to our understanding of the disease phenomenon. Although we have come a long way in our understanding of these complex disorders with the help of studies on animals especially rodents, there need to be more studies in humans, especially to identify the therapeutic targets. This review study looks at the anatomical features of the gut-brain axis in order to discuss the different factors and underlying molecular mechanisms that may have a role in the pathogenesis of functional gastrointestinal disorders. These molecules and their receptors can be targeted in future for further studies and possible therapeutic interventions. The article also discusses the potential role of artificial intelligence and machine learning and its possible role in our understanding of these scientifically challenging disorders.


Assuntos
Disbiose/fisiopatologia , Gastroenteropatias/fisiopatologia , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/inervação , Sistema Hipotálamo-Hipofisário/fisiopatologia , Animais , Antibacterianos/uso terapêutico , Diagnóstico por Computador/métodos , Disbiose/imunologia , Disbiose/microbiologia , Disbiose/terapia , Gastroenteropatias/diagnóstico , Gastroenteropatias/imunologia , Gastroenteropatias/terapia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/patologia , Trato Gastrointestinal/fisiopatologia , Humanos , Sistema Hipotálamo-Hipofisário/diagnóstico por imagem , Aprendizado de Máquina , Vias Neurais/fisiopatologia , Neuroimagem/métodos , Probióticos/administração & dosagem , Nervo Vago/fisiopatologia
14.
Am J Gastroenterol ; 114(4): 648-655, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30747770

RESUMO

OBJECTIVES: Common variable immunodeficiency (CVID) is associated with a spectrum of autoimmune complications. We studied the prevalence of gastrointestinal (GI) manifestations and infections in patients with CVID. METHODS: Complete clinical data of 132 Finnish patients with CVID (106 probable and 26 possible CVID) followed up between 2007 and 2016 were collected to a structured database. Data on endoscopies, histology, and laboratory studies were retrieved from patient files. RESULTS: Most common referral indications were diarrhea and/or weight loss (47%-67%). Patients with probable CVID had higher fecal calprotectin and α1-antitrypsin and lower blood vitamin B12 than patients with possible CVID. Gastroscopy and colonoscopy were done to 71 (67%) and 63 (59%) patients with probable CVID, respectively. Endoscopies showed that 15% of them had chronic active gastritis and 17% atrophic gastritis and 3% had gastric adenocarcinoma. A celiac sprue-like condition was found in 7 patients (10%), of whom 3 responded to a gluten-free diet. Colonoscopies demonstrated unspecific colitis (14%), ulcerative colitis (8%), microscopic colitis (10%), and Crohn's disease (2%). Colonic polyps were noted in 30% of patients, and 3% had lower GI malignancies. Thirty-five patients with CVID had bacterial or parasitic gastroenteritis; chronic norovirus was detected in 4 patients with probable CVID. Patients with GI inflammation had higher levels of fecal calprotectin and blood CD8 T lymphocytes but lower counts of CD19CD27 memory B cells and/or CD19 B cells. Immunophenotype with low B-cell counts was associated with higher fecal calprotectin levels. DISCUSSION: Patients with CVID had a high prevalence of GI manifestations and infections of the GI tract. GI inflammation was associated with a distinct immunophenotype and elevated fecal calprotectin.


Assuntos
Imunodeficiência de Variável Comum/complicações , Gastroenteropatias/etiologia , Gastroenteropatias/imunologia , Biomarcadores/metabolismo , Feminino , Finlândia/epidemiologia , Gastroenteropatias/epidemiologia , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Prevalência
17.
Int Immunopharmacol ; 67: 54-61, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30530169

RESUMO

Complement activation is associated with regional inflammation during acute gastrointestinal injury (AGI). This study is designed to explore how intracellular C3 activation in Paneth cells (PCs) affects regeneration of intestinal epithelium during AGI. AGI was induced in wildtype C57BL/6 mice, with sham operation employed as control. Exogenous C3 (1 mg, I.P.) was applied at 6 h post-surgery. Intestinal crypts harvested from ileum were cultured with presence or absence of C3 (20 µg/ml), with small interfering RNA against BST1 and complement activation inhibitor selectively applied in vitro. The intestinal integrity, percentage of PCs and intestinal stem cells (ISCs) were evaluated. Importantly, cADPR, C3 fragments, and S6-related proteins were detected in PCs to inspect the mammalian target of rapamycin complex 1 (mTORC1) signaling. AGI caused breakdown of intestinal mucosa integrity and regional inflammation. Exogenous C3 by itself failed to promote the growth of intestinal epithelium, but distinctly enhanced the activity of PCs via intracellular activation, which subsequently supported the expansion of ISCs inside of intestinal crypts. Inhibition of C3 activation was associated with decreased expressions of S6, S6K1 and cADPR, with blocking BST1 found to depress cADPR only. Collectively, these data confirmed intracellular activation of C3 in PCs enhanced expansion of ISCs in response to acute injury. The mTORC1 signaling pathway in PCs contributed to this crosstalk during exogenous C3 treatment.


Assuntos
Complemento C3/metabolismo , Gastroenteropatias/imunologia , Mucosa Intestinal/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Celulas de Paneth/fisiologia , Ferimentos e Lesões/imunologia , Animais , Autorrenovação Celular , Células Cultivadas , ADP-Ribose Cíclica/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/cirurgia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases S6 Ribossômicas/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais , Ferimentos e Lesões/cirurgia
18.
Pediatr Allergy Immunol ; 30(2): 149-158, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30403301

RESUMO

The rise in food allergy has been described as the "second wave" of the allergy epidemic, with some developed countries reporting a prevalence of 10% of challenge-proven food allergies. Recognition of the Allergic March has played a crucial role in identifying causality in allergic conditions, linking atopic dermatitis to food allergy and food allergy to other atopic disorders, thereby highlighting opportunities in prevention and the importance of early intervention. This publication will establish the value of weaving the less well-understood, non-IgE-mediated food allergy into the Allergic March and mapping its progression through childhood and its associated co-morbidities. The proposed non-IgE-mediated Allergic March highlights the concomitant presentation of gastrointestinal symptoms and atopic dermatitis as early presenting symptoms in confirmed non-IgE-mediated allergies and the later development of atopic co-morbidities, including asthma and allergic rhinitis, similar to the IgE-mediated Allergic March. This publication highlights recent observations of a link between non-IgE-mediated food allergy in early childhood and functional gastrointestinal disorders in later life and also the reported occurrence of extra-intestinal manifestations at later ages. Although significant limitations exist in regard to the proposed evolution of the Allergic March model, the authors hope that this publication will influence the management of non-IgE-mediated gastrointestinal allergies and inform future research and interventions.


Assuntos
Hipersensibilidade Alimentar/diagnóstico , Gastroenteropatias/imunologia , Asma/complicações , Asma/imunologia , Criança , Pré-Escolar , Dermatite Atópica/complicações , Dermatite Atópica/imunologia , Progressão da Doença , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/imunologia , Gastroenteropatias/complicações , Humanos , Imunoglobulina E , Lactente , Rinite Alérgica/complicações , Rinite Alérgica/imunologia
19.
Brain Behav Immun ; 75: 192-199, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30394313

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) affects 1% of children and has no cure. Gastrointestinal (GI) problems are common in children with ASD, and although gut microbiota is known to play an important role in ASD through the gut-brain axis, the specific mechanism is unknown. Recent evidence suggests that gut microbiota may participate in the pathogenesis of ASD through immune- and inflammation-mediated pathways. Here, we identified potentially immunogenic epitopes derived from gut microbiota in stool samples from ASD children with and without GI problems and typically developing (TD) children. METHODS: Candidate gut microbiota-associated epitopes (MEs) were identified by blast shotgun metagenomic sequencing of fecal samples from 43 ASD children (19 with and 24 without GI involvement) and 31 sex- and age-matched typically developing (TD) children. Potentially immunogenic epitopes were screened against a predictive human Immune Epitope Database. The composition and abundance of candidate MEs were compared between the three groups of children. RESULTS: MEs identified in ASD children with GI problems were significantly more diverse than those in TD children. ME composition could discriminate between the three groups of children. We identified 34 MEs that were significantly more or less abundant in ASD children than TD children, most (29/34) of the differences in MEs were reduced in ASD and associated with abnormal gut IgA level and altered gut microbiota composition, these MEs were limited effected by clinical factors such as age, gender, and GI problems, of which eleven MEs were pathogenic microorganisms peptides with strong T or B cell response, nine MEs showed high homology to peptides from human self proteins associated with autoimmune disease occurrence, eliciting immune attack against hematopoietic stem cells and inhibition antigen binding. We also found that the abundance of five MEs were increased in ASD, including three human self proteins, gap junction alpha-1 (GJA1), paired box protein Pax-3 (PAX3) and eyes absent homolog 1 isoform 4 (EYA1) which associated with cancer, and a ME with homology to a Listeriolysin O peptide from the pathogenic bacterium Listeria monocytogenes was significantly increased in ASD children compared with TD children. CONCLUSIONS: Our findings demonstrate the abnormal of MEs composition in the gut of children with ASD, moreover, the abnormality in MEs composition was associated with abnormal gut IgA levels and altered gut microbiota composition, this abnormality also suggests that there may be abnormalities in intestinal immunity in children with ASD; In all, thirty-four MEs identified were potential biomarker of ASD, and alterations in MEs may contribute to abnormalities in gut immunity and/or homeostasis in ASD children. Further study of the MEs identified here may advance our understanding of the pathogenesis of ASD.


Assuntos
Transtorno do Espectro Autista/microbiologia , Gastroenteropatias/imunologia , Microbioma Gastrointestinal/imunologia , Transtorno do Espectro Autista/fisiopatologia , Criança , Desenvolvimento Infantil , Pré-Escolar , Conexina 43/imunologia , Epitopos/imunologia , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/fisiologia , Humanos , Imunidade , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Proteínas Nucleares/imunologia , Fator de Transcrição PAX3/imunologia , Proteínas Tirosina Fosfatases/imunologia
20.
Digestion ; 100(1): 1-14, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30384361

RESUMO

BACKGROUND: IgG4-related diseases are a rare but an important entity. Due to the variable clinical presentation, this multiorgan disease was attributed to single-organ systems for many years. Also, it often remains a challenge to differentiate between IgG4-related diseases and malignancies. The pathogenesis seems to be a mixture of Th1- and Th2- immune responses, whereas the role of the non-pathogenic IgG4 antibodies is still unclear. Histopathological characteristics are a lymphoplasmacellular infiltrate with IgG4+ plasma cells, a storiform fibrosis and an obliterative phlebitis. This can lead to the functional destruction of every organ affected. In most cases, glucocorticoid treatment leads to remission and is used as maintenance therapy as well. Immune modulatory therapies are employed in case of steroid resistance. However, a majority of patients achieve remission without any therapy. SUMMARY: In this study, we review the current state-of-the-art regarding pathophysiology, diagnostics, organ manifestation and therapeutic approaches. Key Messages: While the diagnosis of IgG4-related diseases is still challenging, there have been significant improvements in diagnostic as well as in therapeutic approaches. This is partially due to a better understanding of the pathophysiology of the disease but also due to improved imaging modalities and novel, more targeted therapies.


Assuntos
Gastroenteropatias/terapia , Doença Relacionada a Imunoglobulina G4/terapia , Imunoglobulina G/sangue , Imunossupressores/uso terapêutico , Ductos Biliares/imunologia , Ductos Biliares/patologia , Produtos Biológicos/uso terapêutico , Diagnóstico Diferencial , Gastroenteropatias/diagnóstico , Gastroenteropatias/imunologia , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina G/imunologia , Doença Relacionada a Imunoglobulina G4/diagnóstico , Doença Relacionada a Imunoglobulina G4/imunologia , Fígado/imunologia , Fígado/patologia , Pâncreas/imunologia , Pâncreas/patologia , Indução de Remissão/métodos
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