ABSTRACT
The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.
Subject(s)
Autoimmune Diseases/genetics , Basic-Leucine Zipper Transcription Factors/genetics , Immunologic Deficiency Syndromes/genetics , Adrenal Cortex Hormones/therapeutic use , Adult , Autoimmune Diseases/complications , Colitis/complications , Colitis/genetics , Colitis/pathology , Female , Fever/complications , Fever/drug therapy , Fever/genetics , Haploinsufficiency , Heterozygote , Humans , Immunologic Deficiency Syndromes/complications , Lymphopenia/complications , Lymphopenia/genetics , Male , Middle Aged , Mutation , Pancytopenia/complications , Pancytopenia/drug therapy , Pancytopenia/genetics , Pedigree , Polymorphism, Single Nucleotide , Recurrence , Respiratory Tract Infections/complications , Respiratory Tract Infections/diagnostic imaging , Respiratory Tract Infections/genetics , Splenomegaly/complications , Splenomegaly/genetics , Syndrome , Tomography, X-Ray Computed , Young AdultABSTRACT
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor expressed in hematopoietic and non-hematopoietic cells. Activation of the AhR by xenobiotics, microbial metabolites, and natural substances induces immunoregulatory responses. Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disorder of the pancreas driven by autoimmunity. Although AhR activation generally suppresses pathogenic autoimmune responses, the roles played by the AhR in AIP have been poorly defined. In this study, we examined how AhR activation affected the development of experimental AIP caused by the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Experimental AIP was induced in MRL/MpJ mice by repeated injections of polyinosinic-polycytidylic acid. Activation of the AhR by indole-3-pyruvic acid and indigo naturalis, which were supplemented in the diet, inhibited the development of experimental AIP, and these effects were independent of the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Interaction of indole-3-pyruvic acid and indigo naturalis with AhRs robustly augmented the production of IL-22 by pancreatic islet α cells. The blockade of IL-22 signaling pathways completely canceled the beneficial effects of AhR ligands on experimental AIP. Serum IL-22 concentrations were elevated in patients with type 1 AIP after the induction of remission with prednisolone. These data suggest that AhR activation suppresses chronic fibroinflammatory reactions that characterize AIP via IL-22 produced by pancreatic islet α cells.
ABSTRACT
BACKGROUND: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited. OBJECTIVES: This study sought to describe NRH prevalence, associated features, and impact in patients with XLA. METHODS: Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons. RESULTS: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per µL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002). CONCLUSIONS: NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.
Subject(s)
Agammaglobulinemia/complications , Genetic Diseases, X-Linked/complications , Hyperplasia/etiology , Adolescent , Adult , Agammaglobulinaemia Tyrosine Kinase/genetics , Agammaglobulinemia/blood , Agammaglobulinemia/genetics , Agammaglobulinemia/pathology , Genetic Diseases, X-Linked/blood , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/pathology , Humans , Hyperplasia/blood , Hyperplasia/genetics , Hyperplasia/pathology , Liver/pathology , Male , Mutation , Platelet Count , Retrospective Studies , Young AdultABSTRACT
T cell antigen receptor (TCR) signaling is essential for the differentiation and maintenance of effector regulatory T (Treg) cells. However, the contribution of individual TCR-dependent genes in Treg cells to the maintenance of immunotolerance remains largely unknown. Here we demonstrate that Treg cells lacking E protein undergo further differentiation into effector cells that exhibit high expression of effector Treg signature genes, including IRF4, ICOS, CD103, KLRG-1, and RORγt. E protein-deficient Treg cells displayed increased stability and enhanced suppressive capacity. Transcriptome and ChIP-seq analyses revealed that E protein directly regulates a large proportion of the genes that are specific to effector Treg cell activation, and importantly, most of the up-regulated genes in E protein-deficient Treg cells are also TCR dependent; this indicates that E proteins comprise a critical gene regulatory network that links TCR signaling to the control of effector Treg cell differentiation and function.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation/immunology , Receptors, Antigen, T-Cell/immunology , Signal Transduction , T-Lymphocytes, Regulatory/immunology , Animals , Gene Regulatory Networks , Homeostasis , Mice , T-Lymphocytes, Regulatory/cytologyABSTRACT
Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a recently defined disease form known as IgG4-related disease (AIP/IgG4-RD). AIP/IgG4-RD is characterized by elevated systemic IgG4 antibody concentrations and lesional tissues infiltrated by IgG4-expressing plasmacytes. In addition, recent studies have revealed that, in common with other autoimmune diseases, such as systemic lupus erythematosus (SLE) and psoriasis, AIP/IgG4-RD is associated with increased type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs). However, unlike SLE, AIP/IgG4-RD is characterized by elevated IFN-I-dependent IL-33 production, the latter emerging as an important contributor to inflammation and fibrotic responses characterizing this disease. On this basis, we propose that blockade of the IFN-I/IL-33 axis might constitute a successful approach to treating this unique type of autoimmunity.
Subject(s)
Autoimmune Diseases/immunology , Dendritic Cells/immunology , Immunoglobulin G4-Related Disease/immunology , Pancreatitis/immunology , Animals , Disease Models, Animal , Humans , Interferon Type I/metabolism , Interleukin-33/metabolism , MiceABSTRACT
The intracellular sensor NOD1 has important host-defense functions relating to a variety of pathogens. Here, we showed that this molecule also participates in the induction of a noninfectious pancreatitis via its response to commensal organisms. Pancreatitis induced by high-dose cerulein (a cholecystokinin receptor agonist) administration depends on NOD1 stimulation by gut microflora. To analyze this NOD1 activity, we induced pancreatitis by simultaneous administration of a low dose of cerulein (that does not itself induce pancreatitis) and FK156, an activator of NOD1 that mimics the effect of gut bacteria that have breached the mucosal barrier. The pancreatitis was dependent on acinar cell production of the chemokine MCP-1 and the intrapancreatic influx of CCR2(+) inflammatory cells. Moreover, MCP-1 production involved activation of the transcription factors NF-κB and STAT3, each requiring complementary NOD1 and cerulein signaling. These studies indicate that gut commensals enable noninfectious pancreatic inflammation via NOD1 signaling in pancreatic acinar cells.
Subject(s)
Acinar Cells/immunology , Immunity, Mucosal/immunology , Mucous Membrane/immunology , Nod1 Signaling Adaptor Protein/immunology , Pancreatitis/immunology , Acetylmuramyl-Alanyl-Isoglutamine/adverse effects , Animals , Bacteria/immunology , Ceruletide/adverse effects , Chemokine CCL2/biosynthesis , Chemokine CCL2/immunology , Diaminopimelic Acid/adverse effects , Diaminopimelic Acid/analogs & derivatives , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mucous Membrane/microbiology , NF-kappa B/metabolism , Nod1 Signaling Adaptor Protein/metabolism , Pancreatitis/chemically induced , Receptors, CCR2/biosynthesis , Receptors, CCR2/immunology , STAT3 Transcription Factor/metabolism , Signal Transduction/immunologyABSTRACT
Cryopyrin-associated periodic syndromes (CAPS) are caused by aberrant interleukin-1ß (IL-1ß) production induced by mutations in the NLRP3 protein in humans, but the mechanisms involved remain poorly understood. Using a mouse model, we show a role for the indigenous microbiota and mast cells (MCs) in skin disease associated with mutant Nlrp3 protein. Unlike normal cells, MCs expressing mutant Nlrp3 produced IL-1ß in response to lipopolysaccharide or tumor necrosis factor-α (TNF-α). In neonatal mice, the microbiota induced TNF-α and IL-1ß and promoted skin disease. MC deficiency greatly reduced disease in Nlrp3 mutant mice, and reconstitution of MC-deficient mice with mutant MCs restored skin disease, which required the expression of IL-1ß in MCs. Surprisingly, neutralization of TNF-α abrogated IL-1ß production and skin disease in neonatal Nlrp3 mutant mice, but not in affected adult mice. Thus, the microbiota and MCs initiate cellular events leading to dysregulated IL-1ß production and skin inflammation in neonatal mice with the CAPS-associated Nlrp3 mutation.
Subject(s)
Carrier Proteins/genetics , Dermatitis/genetics , Dermatitis/immunology , Interleukin-1beta/metabolism , Mast Cells/immunology , Mast Cells/metabolism , Mutation , Animals , Caspase 1/metabolism , Dermatitis/microbiology , Female , Interleukin-1beta/immunology , Lipopolysaccharides/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein , Skin Diseases/chemically induced , Skin Diseases/genetics , Skin Diseases/immunology , Tumor Necrosis Factor-alpha/administration & dosage , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Inflammasomes are multiprotein complexes formed to regulate the maturation of pro-inflammatory caspases, in response to intracellular or extracellular stimulants. Accumulating studies showed that the inflammasomes are implicated in the pathogenesis of inflammatory bowel disease (IBD), although their activation is not a decisive factor for the development of IBD. Inflammasomes and related cytokines play an important role in the maintenance of gut immune homeostasis, while its overactivation might induce excess immune responses and consequently cause tissue damage in the gut. Emerging studies provide evidence that some genetic abnormalities might induce enhanced NLRP3 inflammasome activation and cause colitis. In these cases, the colonic inflammation can be ameliorated by blocking NLRP3 activation or its downstream cytokine IL-1ß. A number of natural products were shown to play a role in preventing colon inflammation in various experimental colitis models. On the other hand, lack of inflammasome function also causes intestinal abnormalities. Thus, an appropriate regulation of inflammasomes might be a promising therapeutic strategy for IBD intervention. This review aims at summarizing the main findings in these studies and provide an outline for further studies that might contribute to our understanding of the role of inflammasomes in the pathogenesis and therapeutic treatment of IBD.
Subject(s)
Colon/immunology , Inflammasomes/immunology , Inflammatory Bowel Diseases/immunology , Interleukin-1beta/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Animals , Colon/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Inflammatory Bowel Diseases/pathologyABSTRACT
The molecular mechanisms underlying the differentiation of interleukin 17-producing T helper cells (T(H)-17 cells) are still poorly understood. Here we show that optimal transcription of the gene encoding interleukin 17 (Il17) required a 2-kilobase promoter and at least one conserved noncoding (enhancer) sequence, CNS-5. Both cis-regulatory elements contained regions that bound the transcription factors RORgammat and Runx1. Runx1 influenced T(H)-17 differentiation by inducing RORgammat expression and by binding to and acting together with RORgammat during Il17 transcription. However, Runx1 also interacts with the transcription factor Foxp3, and this interaction was necessary for the negative effect of Foxp3 on T(H)-17 differentiation. Thus, our data support a model in which the differential association of Runx1 with Foxp3 and with RORgammat regulates T(H)-17 differentiation.
Subject(s)
Core Binding Factor Alpha 2 Subunit/metabolism , Forkhead Transcription Factors/metabolism , Gene Expression Regulation , Interleukin-17/genetics , Receptors, Retinoic Acid/metabolism , Receptors, Thyroid Hormone/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Animals , Cell Differentiation , Enhancer Elements, Genetic/genetics , Humans , Jurkat Cells , Mice , Mice, Inbred BALB C , Nuclear Receptor Subfamily 1, Group F, Member 3 , Promoter Regions, Genetic/genetics , Protein Binding , Transcription, GeneticABSTRACT
Previous studies have shown that inhibition of receptor-interacting serine/threonine kinase (RICK) (also known as RIP2) results in amelioration of experimental colitis. This role has largely been attributed to nucleotide-binding oligomerization domain 2 (NOD2) signaling since the latter is considered a major inducer of RICK activation. In this study, we explored the molecular mechanisms accounting for RICK-mediated inhibition of inflammatory bowel disease (IBD). In an initial series of studies focused on trinitrobenzene sulfonic acid (TNBS)-colitis and dextran sodium sulfate (DSS)-colitis we showed that down-regulation of intestinal RICK expression in NOD2-intact mice by intra-rectal administration of a plasmid expressing RICK-specific siRNA was accompanied by down-regulation of pro-inflammatory cytokine responses in the colon and protection of the mice from experimental colitis. Somewhat surprisingly, intra-rectal administration of RICK-siRNA also inhibited TNBS-colitis and DSS-colitis in NOD2-deficient and in NOD1/NOD2-double deficient mice. In complementary studies of humans with IBD we found that expression of RICK, cellular inhibitor of apoptosis protein 2 (cIAP2) and downstream signaling partners were markedly increased in inflamed tissue of IBD compared to controls without marked elevations of NOD1 or NOD2 expression. In addition, the increase in RICK expression correlated with disease activity and pro-inflammatory cytokine responses. These studies thus suggest that NOD1- or NOD2-independenent activation of RICK plays a major role in both murine experimental colitis and human IBD.
Subject(s)
Inflammation/metabolism , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Animals , Humans , Inflammation/immunology , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/metabolism , Receptor-Interacting Protein Serine-Threonine Kinase 2/immunology , Signal Transduction/immunologyABSTRACT
Lymphoid tissue inducer (LTi) cells are key components of the machinery required for the construction of the lymphoid structures underlying immune responses. In this issue of Immunity, Vonarbourg et. al. (2010) describe how these cells assume several different guises, each associated with different LTi functions.
ABSTRACT
The molecular mechanisms underlying retinoic acid (RA) augmentation of T cell receptor (TCR) and transforming growth factor-ß (TGF-ß)-induced Foxp3 transcription and inhibition of the latter by cytokines such as IL-27 were here shown to be related processes involving modifications of baseline (TGF-ß-induced) phosphorylated Smad3 (pSmad3) binding to a conserved enhancer region (enhancer I). RA augmentation involved the binding of retinoic acid receptor (RAR) and retinoid X receptor (RXR) to a dominant site in enhancer I and a subordinate site in the promoter. This led to increased histone acetylation in the region of the Smad3 binding site and increased binding of pSmad3. Cytokine (IL-27) inhibition involved binding of pStat3 to a gene silencer in a second conserved enhancer region (enhancer II) downstream from enhancer I; this led to loss of pSmad3 binding to enhancer I. Thus, control of accessibility and binding of pSmad3 provides a common framework for positive and negative regulation of TGF-ß-induced Foxp3 transcription.
Subject(s)
Enhancer Elements, Genetic , Forkhead Transcription Factors/genetics , Gene Expression Regulation , Smad3 Protein/metabolism , Animals , Binding Sites , Female , Mice , Mice, Inbred C57BL , NFATC Transcription Factors/metabolism , Phosphorylation , Promoter Regions, Genetic , Protein Serine-Threonine Kinases/physiology , Receptor, Transforming Growth Factor-beta Type I , Receptors, Antigen, T-Cell/physiology , Receptors, Transforming Growth Factor beta/physiology , Retinoid X Receptors/physiology , Transcription Factor AP-1/physiology , Transcription, Genetic , Transforming Growth Factor beta/physiology , Tretinoin/pharmacologyABSTRACT
The basis of the increased risk for Crohn's disease conferred by the Atg16L1T300A polymorphism is incompletely understood. An important step forward came from the recent demonstration that the murine equivalent of Atg16L1T300A (Atg16L1T316A) exhibits increased susceptibility to caspase 3-mediated cleavage and resulting decreased levels of full-length Atg16L1 in macrophages. However, although this finding showed that this polymorphism is a loss-of-function abnormality, it did not address the possibility that this polymorphism also affects the function of a normal Atg16L1 allele in heterozygous mice. Therefore, we evaluated the function of the Atg16L1T300A polymorphism heterozygote and homozygote in knock-in (KI) mice. Surprisingly, we found that macrophages from both types of KI mice exhibit defective autophagic induction; accordingly, both types of mice exhibit defects in bacterial clearance coupled with increased inflammasome cytokine (IL-1ß) responses. Furthermore, macrophages from both types of KI mice displayed defects in TNF-α-induced Atg16L1T300A cleavage, increased retention of bacteria, bacterial dissemination, and Salmonella-induced colitis. These studies suggested that chromosomes bearing the Atg16L1T300A polymorphism can interfere with the function of the wild-type (WT) Atg16L1 allele and, thus, that the Crohn's disease risk polymorphism is a dominant-negative variant with the potential to act as a disease factor, even when present on only one chromosome. This conclusion was supported by the finding that mice bearing a WT Atg16L1 allele and a null allele (Atg16L1KO/+ mice) exhibit normal autophagic function equivalent to that of WT mice.
Subject(s)
Autophagy-Related Proteins/genetics , Autophagy/genetics , Colitis/genetics , Crohn Disease/genetics , Macrophages/physiology , Salmonella Infections/genetics , Salmonella/physiology , Animals , Apoptosis , Bacteriolysis/genetics , Colitis/microbiology , Gene Knock-In Techniques , Heterozygote , Homozygote , Humans , Interleukin-1beta/metabolism , Mice , Mice, Inbred C57BL , Mutation/genetics , Polymorphism, Genetic , Tumor Necrosis Factor-alpha/metabolismABSTRACT
In previous studies, we found that human IgG4-related autoimmune pancreatitis (AIP) and murine AIP are driven by activation of plasmacytoid dendritic cells (pDCs) producing IFN-α. In the present studies we examined additional roles of pDC-related mechanisms in AIP pathogenesis, particularly those responsible for induction of fibrosis. We found that in murine AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid) not only the pancreatic infiltration of immune cells but also the development of fibrosis were markedly reduced by the depletion of pDCs or blockade of type I IFN signaling; moreover, such treatment was accompanied by a marked reduction of pancreatic expression of IL-33. Conversely, polyinosinic-polycytidylic acid-induced inflamed pancreatic tissue in murine AIP exhibited increased expression of type I IFNs and IL-33 (and downstream IL-33 cytokines such as IL-13 and TGF-ß1). pDCs stimulated by type I IFN were the source of the IL-33 because purified populations of these cells isolated from the inflamed pancreas produced a large amount of IL-33 upon activation by TLR9 ligands, and such production was abrogated by the neutralization of type I IFN. The role of IL-33 in murine AIP pathogenesis was surprisingly important because blockade of IL-33 signaling by anti-ST2 Ab attenuated both pancreatic inflammation and accompanying fibrosis. Finally, whereas patients with both conventional pancreatitis and IgG4-related AIP exhibited increased numbers of acinar cells expressing IL-33, only the latter also exhibited pDCs producing this cytokine. These data thus suggest that pDCs producing IFN-α and IL-33 play a pivotal role in the chronic fibro-inflammatory responses underlying murine AIP and human IgG4-related AIP.
Subject(s)
Autoimmune Diseases/immunology , Dendritic Cells/immunology , Interferon-alpha/immunology , Interleukin-33/immunology , Pancreatitis/immunology , Acinar Cells/immunology , Animals , Autoimmune Diseases/physiopathology , Dendritic Cells/metabolism , Fibrosis/immunology , Humans , Immunoglobulin G/immunology , Interferon-alpha/biosynthesis , Interferon-alpha/genetics , Interleukin-33/biosynthesis , Interleukin-33/genetics , Mice , Pancreas/cytology , Pancreas/immunology , Pancreas/pathology , Pancreatitis/physiopathology , Poly I-C/administration & dosage , Toll-Like Receptor 9/immunologyABSTRACT
Common variable immunodeficiency (CVID), the most common symptomatic primary antibody deficiency, is accompanied in some patients by a duodenal inflammation and malabsorption syndrome known as CVID enteropathy (E-CVID).The goal of this study was to investigate the immunological abnormalities in CVID patients that lead to enteropathy as well as the contribution of intestinal microbiota to this process.We found that, in contrast to noE-CVID patients (without enteropathy), E-CVID patients have exceedingly low levels of IgA in duodenal tissues. In addition, using transkingdom network analysis of the duodenal microbiome, we identified Acinetobacter baumannii as a candidate pathobiont in E-CVID. Finally, we found that E-CVID patients exhibit a pronounced activation of immune genes and down-regulation of epithelial lipid metabolism genes. We conclude that in the virtual absence of mucosal IgA, pathobionts such as A. baumannii, may induce inflammation that re-directs intestinal molecular pathways from lipid metabolism to immune processes responsible for enteropathy.
Subject(s)
Common Variable Immunodeficiency/immunology , Duodenitis/immunology , Gastrointestinal Microbiome/immunology , Immunity, Mucosal/immunology , Immunoglobulin A/immunology , Interferons/immunology , Malabsorption Syndromes/immunology , Acinetobacter baumannii , Common Variable Immunodeficiency/complications , Down-Regulation , Duodenitis/etiology , Duodenitis/microbiology , Female , Gastrointestinal Microbiome/genetics , Gene Expression , Humans , Inflammation , Lipid Metabolism/genetics , Malabsorption Syndromes/etiology , Malabsorption Syndromes/microbiology , Male , RNA, Bacterial/genetics , RNA, Ribosomal, 16S/geneticsSubject(s)
Diabetes Mellitus, Type 1 , Gastrointestinal Microbiome , Microbiota , Antimicrobial Cationic Peptides , Antimicrobial Peptides , Autoimmunity , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/immunology , Humans , Infant, Newborn , CathelicidinsABSTRACT
The role of immunologic factors in the development of gastrointestinal (GI) neoplasia, made evident from the high degree of association of chronic intestinal or gastric inflammation with the development of cancer, has attracted much attention because it promises new ways of treating disease. Here we develop the idea that immunologic factors influence the appearance of GI cancer on two levels: (i) a basic and initiating level during which the epithelial cell is induced to undergo pre-cancerous molecular changes that render it prone to further cancer progression; and (ii) a secondary level that builds on this vulnerability and drives the cell into frank malignancy. This secondary level is uniquely dependent on a single epithelial cell signaling pathway centered on STAT3, and it is this pathway upon which stimulation of mucosal cytokine production and microbiota effects converge.
Subject(s)
Gastrointestinal Neoplasms/immunology , Gastrointestinal Neoplasms/pathology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/pathology , Inflammation/immunology , Animals , Cell Transformation, Neoplastic/immunology , Cell Transformation, Neoplastic/pathology , Chronic Disease , Humans , STAT3 Transcription Factor/metabolism , Signal Transduction/immunologyABSTRACT
Over the last decade, it has become apparent that the complex interactions between components of the mucosal microflora and the mucosal immune system can involve either direct contact with dendritic cells in the lamina propria or, alternatively, contact with epithelial cells lining the mucosa that then influence the function of dendritic cells. Although in some cases these interactions involve signaling specific to particular organisms and in others, to classes of organisms, a common theme is that signaling is invariably channeled through receptors that address many organisms or all organisms such as the pattern-recognition receptors TLR and NLR. Here, I review this information with the intention of identifying how the mucosal microflora influences specific functions of the mucosal immune system such the production of particular cytokines as well as broader functions such as the maintenance of mucosal immune homeostasis and host defense.
Subject(s)
Dendritic Cells/immunology , Immunity, Mucosal , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Animals , Cytokines/biosynthesis , Cytokines/immunology , Homeostasis , Humans , Signal TransductionABSTRACT
Missense mutations of the gene encoding NLRP3 are associated with autoinflammatory disorders characterized with excessive production of interleukin-1beta (IL-1beta). Here we analyzed the immune responses of gene-targeted mice carrying a mutation in the Nlrp3 gene equivalent to the human mutation associated with Muckle-Wells Syndrome. We found that antigen-presenting cells (APCs) from such mice produced massive amounts of IL-1beta upon stimulation with microbial stimuli in the absence of ATP. This was likely due to a diminished inflammasome activation threshold that allowed a response to the small amount of agonist. Moreover, the Nlrp3 gene-targeted mice exhibited skin inflammation characterized by neutrophil infiltration and a Th17 cytokine-dominant response, which originated from hematopoietic cells. The inflammation of Nlrp3 gene-targeted mice resulted from excess IL-1beta production from APCs, which augmented Th17 cell differentiation. These results demonstrate that the NLRP3 mutation leads to inflammasome hyperactivation and consequently Th17 cell-dominant immunopathology in autoinflammation.