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1.
Annu Rev Immunol ; 36: 755-781, 2018 04 26.
Article in English | MEDLINE | ID: mdl-29677472

ABSTRACT

Inflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and polygenetic and epigenetic susceptibility impact on immune pathways is key for developing targeted therapies. Mechanistic understanding of polygenic IBD is complemented by Mendelian disorders that present with IBD, pharmacological interventions that cause colitis, autoimmunity, and multiple animal models. Collectively, this multifactorial pathogenesis supports a concept of immune checkpoints that control microbial-host interactions in the gut by modulating innate and adaptive immunity, as well as epithelial and mesenchymal cell responses. In addition to classical immunosuppressive strategies, we discuss how resetting the microbiota and restoring innate immune responses, in particular autophagy and epithelial barrier function, might be key for maintaining remission or preventing IBD. Targeting checkpoints in genetically stratified subgroups of patients with Mendelian disorder-associated IBD increasingly directs treatment strategies as part of personalized medicine.


Subject(s)
Disease Susceptibility/immunology , Inflammatory Bowel Diseases/etiology , Inflammatory Bowel Diseases/therapy , Animals , Biomarkers , Chronic Disease , Disease Management , Disease Models, Animal , Drug-Related Side Effects and Adverse Reactions , Dysbiosis , Gastrointestinal Microbiome , Genetic Predisposition to Disease , Humans , Inflammatory Bowel Diseases/prevention & control , Molecular Targeted Therapy , Translational Research, Biomedical
2.
Nat Immunol ; 18(7): 813-823, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28530713

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 Adult
3.
Immunity ; 50(2): 432-445.e7, 2019 02 19.
Article in English | MEDLINE | ID: mdl-30683619

ABSTRACT

Host microbial cross-talk is essential to maintain intestinal homeostasis. However, maladaptation of this response through microbial dysbiosis or defective host defense toward invasive intestinal bacteria can result in chronic inflammation. We have shown that macrophages differentiated in the presence of the bacterial metabolite butyrate display enhanced antimicrobial activity. Butyrate-induced antimicrobial activity was associated with a shift in macrophage metabolism, a reduction in mTOR kinase activity, increased LC3-associated host defense and anti-microbial peptide production in the absence of an increased inflammatory cytokine response. Butyrate drove this monocyte to macrophage differentiation program through histone deacetylase 3 (HDAC3) inhibition. Administration of butyrate induced antimicrobial activity in intestinal macrophages in vivo and increased resistance to enteropathogens. Our data suggest that (1) increased intestinal butyrate might represent a strategy to bolster host defense without tissue damaging inflammation and (2) that pharmacological HDAC3 inhibition might drive selective macrophage functions toward antimicrobial host defense.


Subject(s)
Anti-Infective Agents/pharmacology , Butyrates/pharmacology , Cell Differentiation/drug effects , Macrophages/drug effects , Monocytes/drug effects , Animals , Cell Differentiation/genetics , Cells, Cultured , Colon/drug effects , Colon/metabolism , Colon/microbiology , Cytokines/genetics , Cytokines/metabolism , Dysbiosis/microbiology , Gene Expression Regulation/drug effects , Humans , Intestines/drug effects , Intestines/microbiology , Macrophages/metabolism , Macrophages/microbiology , Mice, Inbred C57BL , Microbiota/drug effects , Microbiota/physiology , Monocytes/metabolism , Monocytes/microbiology
4.
Nature ; 597(7875): 250-255, 2021 09.
Article in English | MEDLINE | ID: mdl-34497389

ABSTRACT

The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.


Subject(s)
Aging , Enteric Nervous System/cytology , Fetus/cytology , Health , Intestines/cytology , Intestines/growth & development , Lymph Nodes/cytology , Lymph Nodes/growth & development , Adult , Animals , Child , Crohn Disease/pathology , Datasets as Topic , Enteric Nervous System/anatomy & histology , Enteric Nervous System/embryology , Enteric Nervous System/growth & development , Epithelial Cells/cytology , Female , Fetus/anatomy & histology , Fetus/embryology , Humans , Intestines/embryology , Intestines/innervation , Lymph Nodes/embryology , Lymph Nodes/pathology , Mice , Mice, Inbred C57BL , Organogenesis , Receptors, IgG/metabolism , Signal Transduction , Spatio-Temporal Analysis , Time Factors
5.
Gastroenterology ; 165(1): 44-60.e2, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37062395

ABSTRACT

Recent advances in our understanding of the pathogenesis of inflammatory bowel disease (IBD) have highlighted the complex interplay between the genome, the epigenome, and the environment. Despite the exciting advances in genomics that have enabled the identification of over 200 susceptibility loci, these only account for a small proportion of the disease variance and the estimated heritability in IBD. It is likely that gene-environment (GxE) interactions contribute to "missing heritability" and these may act through epigenetic mechanisms. Several environmental factors, such as the microbiome, nutrition, and tobacco smoking, induce alterations in the epigenome of children and adults, which may impact disease susceptibility. Other mechanisms for GxE interactions are also directly pertinent in early life. We discuss a model in which environmental factors imprint disease risk in a window of susceptibility during infancy that may contribute to later disease onset, whereas other elements of the exposome act later in life and contribute directly to the pathogenesis and course of the disease. Understanding the mechanisms underlying GxE interactions may provide the basis for new therapeutic targets or preventative strategies for IBD.


Subject(s)
Epigenome , Inflammatory Bowel Diseases , Adult , Child , Humans , Genetic Predisposition to Disease , Inflammatory Bowel Diseases/genetics , Genome , Epigenesis, Genetic
6.
Clin Exp Immunol ; 217(1): 1-11, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38651248

ABSTRACT

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multicenter study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in 1 patient, respectively. In 3 patients (18.7%), no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD.


Subject(s)
Exome Sequencing , Inflammatory Bowel Diseases , Humans , Male , Female , Iran , Inflammatory Bowel Diseases/genetics , Child, Preschool , Infant , Age of Onset , Child , Genetic Testing/methods , Cohort Studies , Mutation , I-kappa B Kinase/genetics , Consanguinity , Receptors, Interleukin-10/genetics
7.
J Allergy Clin Immunol ; 151(3): 791-796.e7, 2023 03.
Article in English | MEDLINE | ID: mdl-36462957

ABSTRACT

BACKGROUND: Toll-like receptors (TLRs) are important pattern recognition receptors that sense microbes and control host defense. Myeloid differentiation protein 2 (MD2) is the indispensable coreceptor for TLR4, facilitating the binding to the gram-negative bacterial cell wall component LPS and activation of downstream signaling. OBJECTIVE: We sought to provide phenotypic and mechanistic insights into human MD2 deficiency. METHODS: To elucidate the genetic cause in a patient with very early onset inflammatory bowel disease, we performed whole-exome sequencing and studied the functional consequences of the identified mutation in LY96 (encoding for MD2) in genetically engineered induced pluripotent stem cell-derived macrophages with knockout of MD2 or knockin of the patient-specific mutation, including TLR4-mediated signaling, cytokine production, and bacterial handling. RESULTS: Whole-exome sequencing identified a homozygous in-frame deletion in the LY96 gene (c.347_349delCAA; p.Thr116del) in a patient with very early onset inflammatory bowel disease and a sibling presenting with pneumonia and otitis media. Induced pluripotent stem cell-derived macrophages with knockout of MD2 or expression of the Thr116del mutation showed impaired activation of nuclear factor kappa B and mitogen-activated protein kinase signaling as well as TLR4 endocytosis on challenge with LPS or bacteria. In addition, MD2-deficient macrophages showed decreased cytokine expression (eg, IL-6, TNF, and IL-10) in response to LPS or gram-negative but not gram-positive bacteria. CONCLUSIONS: Human MD2 deficiency causes defective TLR4 signaling in response to LPS or gram-negative bacteria. The clinical manifestations and expressivity might be variable due to unknown secondary risk factors. Because TLR4 represents a therapeutic target for multiple inflammatory conditions, our study may provide insights into potential side effects of pharmacological TLR4 targeting.


Subject(s)
Lipopolysaccharides , Toll-Like Receptor 4 , Humans , Cytokines/metabolism , Lipopolysaccharides/pharmacology , Lymphocyte Antigen 96/metabolism , Signal Transduction , Toll-Like Receptor 4/genetics , Toll-Like Receptors/metabolism
8.
J Allergy Clin Immunol ; 151(3): 783-790.e5, 2023 03.
Article in English | MEDLINE | ID: mdl-36462956

ABSTRACT

BACKGROUND: Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins. OBJECTIVE: We sought to report phenotype and cellular function of individuals with complete TLR4 deficiency. METHODS: We performed genome sequencing and investigated exome and genome sequencing databases. Cellular responses were studied on primary monocytes, macrophages, and neutrophils, as well as cell lines using flow cytometry, reporter, and cytokine assays. RESULTS: We identified 2 individuals in a family of Qatari origin carrying a homozygous stop codon variant p.Q188X in TLR4 presenting with a variable phenotype (asymptomatic and inflammatory bowel disease consistent with severe perianal Crohn disease). A third individual with homozygous p.Y794X was identified in a population database. In contrast to hypomorphic polymorphisms p.D299G and p.T399I, the variants p.Q188X and p.Y794X completely abrogated LPS-induced cytokine responses whereas TLR2 response was normal. TLR4 deficiency causes a neutrophil CD62L shedding defect, whereas antimicrobial activity toward intracellular Salmonella was intact. CONCLUSIONS: Biallelic TLR4 deficiency in humans causes an inborn error of immunity in responding to LPS. This complements the spectrum of known primary immunodeficiencies, in particular myeloid differentiation primary response 88 (MYD88) or the IL-1 receptor-associated kinase 4 (IRAK4) deficiency that are downstream of TLR4 and TLR2 signaling.


Subject(s)
Toll-Like Receptor 2 , Toll-Like Receptor 4 , Humans , Toll-Like Receptor 4/genetics , Toll-Like Receptor 2/genetics , Lipopolysaccharides/pharmacology , Toll-Like Receptors/metabolism , Cytokines/metabolism , Myeloid Differentiation Factor 88/genetics
9.
Gut ; 72(4): 654-662, 2023 04.
Article in English | MEDLINE | ID: mdl-36191961

ABSTRACT

OBJECTIVE: Loss-of-function mutations in genes generating reactive oxygen species (ROS), such as NOX1, are associated with IBD. Mechanisms whereby loss of ROS drive IBD are incompletely defined. DESIGN: ROS measurements and single-cell transcriptomics were performed on colonoids stratified by NOX1 genotype and TNFα stimulation. Clustering of epithelial cells from human UC (inflamed and uninflamed) scRNASeq was performed. Validation of M cell induction was performed by immunohistochemistry using UEA1 (ulex europaeus agglutin-1 lectin) and in vivo with DSS injury. RESULTS: TNFα induces ROS production more in NOX1-WT versus NOX1-deficient murine colonoids under a range of Wnt-mediated and Notch-mediated conditions. scRNASeq from inflamed and uninflamed human colitis versus TNFα stimulated, in vitro colonoids defines substantially shared, induced transcription factors; NOX1-deficient colonoids express substantially lower levels of STAT3 (signal transducer and activator of transcription 3), CEBPD (CCAAT enhancer-binding protein delta), DNMT1 (DNA methyltransferase) and HIF1A (hypoxia-inducible factor) baseline. Subclustering unexpectedly showed marked TNFα-mediated induction of M cells (sentinel cells overlying lymphoid aggregates) in NOX1-deficient colonoids. M cell induction by UEA1 staining is rescued with H2O2 and paraquat, defining extra- and intracellular ROS roles in maintenance of LGR5+ stem cells. DSS injury demonstrated GP2 (glycoprotein-2), basal lymphoplasmacytosis and UEA1 induction in NOX1-deficiency. Principal components analyses of M cell genes and decreased DNMT1 RNA velocity correlate with UC inflammation. CONCLUSIONS: NOX1 deficiency plus TNFα stimulation contribute to colitis through dysregulation of the stem cell niche and altered cell differentiation, enhancing basal lymphoplasmacytosis. Our findings prioritise ROS modulation for future therapies.


Subject(s)
Colitis , Inflammatory Bowel Diseases , Mice , Humans , Animals , Reactive Oxygen Species/metabolism , Tumor Necrosis Factor-alpha/adverse effects , M Cells , NADPH Oxidase 1/genetics , NADPH Oxidase 1/metabolism , Hydrogen Peroxide/adverse effects , Colitis/chemically induced
10.
Hum Mol Genet ; 30(14): 1273-1282, 2021 06 26.
Article in English | MEDLINE | ID: mdl-33822054

ABSTRACT

Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.


Subject(s)
MTOR Inhibitors , Neoplastic Syndromes, Hereditary , Bone Morphogenetic Protein Receptors, Type I , Colectomy , Gastrointestinal Hemorrhage , Humans , Intestinal Polyposis/congenital , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/pathology , Neoplastic Syndromes, Hereditary/surgery , PTEN Phosphohydrolase/genetics , TOR Serine-Threonine Kinases/genetics
11.
Hum Genet ; 142(5): 599-611, 2023 May.
Article in English | MEDLINE | ID: mdl-35761107

ABSTRACT

Over 100 genes are associated with monogenic forms of inflammatory bowel disease (IBD). These genes affect the epithelial barrier function, innate and adaptive immunity in the intestine, and immune tolerance. We provide an overview of newly discovered monogenic IBD genes and illustrate how a recently proposed taxonomy model can integrate phenotypes and shared pathways. We discuss how functional understanding of genetic disorders and clinical genomics supports personalised medicine for patients with monogenic IBD.


Subject(s)
Inflammatory Bowel Diseases , Precision Medicine , Humans , Genetic Predisposition to Disease , Inflammatory Bowel Diseases/genetics , Intestines , Phenotype
12.
Hum Genet ; 142(5): 697-704, 2023 May.
Article in English | MEDLINE | ID: mdl-36773065

ABSTRACT

Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome of hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context of a specific variant in the PMM2 promotor, either in homozygosity, or compound heterozygous with a deleterious PMM2 variant. Here, we describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6, and 10 years of age. In each case, intestinal inflammation coincided with the unusual finding of gastric antral foveolar hyperplasia. IBD disease was of variable severity at onset but well controlled with conventional and first-line biologic treatment approaches. The organ-level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A). Analysis of published transcriptomic data suggests that IBD most likely arises due to an impact on epithelial cellular function. We identify a specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology.


Subject(s)
Congenital Disorders of Glycosylation , Hyperinsulinism , Inflammatory Bowel Diseases , Polycystic Kidney Diseases , Humans , Hyperplasia/genetics
13.
J Clin Immunol ; 44(1): 30, 2023 12 22.
Article in English | MEDLINE | ID: mdl-38133879

ABSTRACT

Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a molecular classification for 59 reported rare IL6ST pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of IL6ST variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian IL6ST coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights IL6ST as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations.


Subject(s)
Cytokine Receptor gp130 , Interleukin-11 , Job Syndrome , Humans , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/metabolism , Cytokines/genetics , Cytokines/metabolism , Interleukin-11/metabolism , Interleukin-6/metabolism , Receptors, Cytokine/genetics , Receptors, Cytokine/metabolism , STAT3 Transcription Factor/metabolism
14.
J Clin Immunol ; 43(2): 495-511, 2023 02.
Article in English | MEDLINE | ID: mdl-36370291

ABSTRACT

Balancing natural selection is a process by which genetic variants arise in populations that are beneficial to heterozygous carriers, but pathogenic when homozygous. We systematically investigated the prevalence, structural, and functional consequences of pathogenic IL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in the IL10RA gene. Since the majority of these IL10RA variants have not been functionally characterized, we performed a systematic screening of their impact on STAT3 phosphorylation upon IL-10 stimulation. Based on the geographic accumulation of confirmed pathogenic IL10RA variants in East Asia and in Northeast China, the distribution of infectious disorders worldwide, and the functional evidence of IL-10 signaling in the pathogenesis, we identify Schistosoma japonicum infection as plausible selection pressure driving variation in IL10RA. Consistent with this is a partially augmented IL-10 response in peripheral blood mononuclear cells from heterozygous variant carriers. A parasite-driven heterozygote advantage through reduced IL-10 signaling has implications for health care utilization in regions with high allele frequencies and potentially indicates pathogen eradication strategies that target IL-10 signaling.


Subject(s)
Interleukin-10 , Leukocytes, Mononuclear , Humans , Receptors, Interleukin-10/genetics , Interleukin-10/genetics , Interleukin-10 Receptor alpha Subunit/genetics , Selection, Genetic
15.
Clin Gastroenterol Hepatol ; 21(10): 2639-2648.e6, 2023 09.
Article in English | MEDLINE | ID: mdl-36336312

ABSTRACT

BACKGROUND & AIMS: In this nationwide study from the Israeli Inflammatory Bowel Disease Research Nucleus, we aimed to describe the incidence of very early onset inflammatory bowel diseases (VEOIBDs) with a focus on infantile-onset disease and to compare management and disease course with older children. METHODS: Data were retrieved from the 4 Israeli Health Maintenance Organizations covering 98% of the population. Pediatric-onset IBD was categorized as follows: adolescent onset (10 to <18 y), early onset (6 to <10 y), VEOIBD (0 to <6 y), toddler onset (2 to <6 y), and infantile onset (<2 y). RESULTS: A total of 5243 children with 35,469 person-years of follow-up evaluation, were diagnosed with IBD during 2005 to 2020: 4444 (85%) with adolescent onset, 548 (10%) with early onset, and 251 (4.8%) with VEOIBD, of whom 81 (1.5%) had infantile onset. The incidence of pediatric-onset IBD increased from 10.8 per 100,000 in 2005 to 15.3 per 100,000 in 2019 (average annual percentage change, 2.8%; 95% CI, 2.2%-3.4%), but that of VEOIBD remained stable (average annual percentage change, 0%; 95% CI, -2.5% to 2.6%). The infantile-onset and toddler-onset groups were treated less often with biologics (36% and 35%, respectively) vs the early onset (57%) and adolescent-onset groups (53%; P < .001). The time to steroid dependency was shorter in infantile-onset (hazard ratio [HR], 2.1; 95% CI, 1.5-2.9) and toddler-onset disease (HR, 1.6; 95% CI, 1.2-2.0) vs early onset and adolescent-onset disease, but time to hospitalizations, time to surgery, and growth delay were worse only in infantile-onset disease. In a multivariable model, infantile-onset patients had a higher risk for surgery (HR, 1.4; 95% CI, 1.1-1.9) and hospitalization (HR, 1.7; 95% CI, 1.2-2.4) than the toddler-onset group. CONCLUSIONS: The incidence of VEOIBD remained stable. Infantile-onset IBD had worse outcomes than older children, while toddler onset had mostly similar outcomes, despite less frequent use of biologics.


Subject(s)
Biological Products , Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Adolescent , Humans , Child , Crohn Disease/epidemiology , Incidence , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/epidemiology , Inflammatory Bowel Diseases/therapy , Intestines , Colitis, Ulcerative/epidemiology
16.
Gastroenterology ; 162(3): 859-876, 2022 03.
Article in English | MEDLINE | ID: mdl-34780721

ABSTRACT

BACKGROUND & AIMS: Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis. METHODS: To build a taxonomy model, we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by (1) overlapping syndromic features, (2) response to hematopoietic stem cell transplantation, (3) bulk RNA-sequencing of 32 tissues, (4) single-cell RNA-sequencing of >50 cell subsets from the intestine of healthy individuals and patients with IBD (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4). RESULTS: Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8+ T cells, neutrophils, epithelial subsets, and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mammalian target of rapamycin activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD. CONCLUSION: Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses.


Subject(s)
Inflammatory Bowel Diseases/classification , Inflammatory Bowel Diseases/genetics , Age of Onset , Antiporters/genetics , Cells, Cultured , Classification , Gene Expression Profiling , Genetic Association Studies , Genotype , Glucose-6-Phosphatase/genetics , Glucose-6-Phosphate/metabolism , Humans , Inflammatory Bowel Diseases/metabolism , Macrophages , Metabolomics , Monosaccharide Transport Proteins/genetics , Penetrance , Phenotype , Signal Transduction/genetics
17.
PLoS Comput Biol ; 18(6): e1010112, 2022 06.
Article in English | MEDLINE | ID: mdl-35731827

ABSTRACT

Cell-cell communication is mediated by many soluble mediators, including over 40 cytokines. Cytokines, e.g. TNF, IL1ß, IL5, IL6, IL12 and IL23, represent important therapeutic targets in immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease (IBD), psoriasis, asthma, rheumatoid and juvenile arthritis. The identification of cytokines that are causative drivers of, and not just associated with, inflammation is fundamental for selecting therapeutic targets that should be studied in clinical trials. As in vitro models of cytokine interactions provide a simplified framework to study complex in vivo interactions, and can easily be perturbed experimentally, they are key for identifying such targets. We present a method to extract a minimal, weighted cytokine interaction network, given in vitro data on the effects of the blockage of single cytokine receptors on the secretion rate of other cytokines. Existing biological network inference methods typically consider the correlation structure of the underlying dataset, but this can make them poorly suited for highly connected, non-linear cytokine interaction data. Our method uses ordinary differential equation systems to represent cytokine interactions, and efficiently computes the configuration with the lowest Akaike information criterion value for all possible network configurations. It enables us to study indirect cytokine interactions and quantify inhibition effects. The extracted network can also be used to predict the combined effects of inhibiting various cytokines simultaneously. The model equations can easily be adjusted to incorporate more complicated dynamics and accommodate temporal data. We validate our method using synthetic datasets and apply our method to an experimental dataset on the regulation of IL23, a cytokine with therapeutic relevance in psoriasis and IBD. We validate several model predictions against experimental data that were not used for model fitting. In summary, we present a novel method specifically designed to efficiently infer cytokine interaction networks from cytokine perturbation data in the context of IMIDs.


Subject(s)
Inflammatory Bowel Diseases , Psoriasis , Cytokines , Humans , Inflammation , Psoriasis/drug therapy , Receptors, Cytokine
18.
Immunity ; 38(4): 630-2, 2013 Apr 18.
Article in English | MEDLINE | ID: mdl-23601681

ABSTRACT

It has been unclear whether an innate lymphoid cell (ILC) counterpart to the T helper 1 cell type exists. New studies, including Fuchs et al. (2013) in this issue of Immunity, identify T-bet(+)IFN-γ(+) ILC1 that accumulate in the inflamed intestine of IBD patients.

19.
Brain ; 144(12): 3597-3610, 2021 12 31.
Article in English | MEDLINE | ID: mdl-34415310

ABSTRACT

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.


Subject(s)
Hereditary Central Nervous System Demyelinating Diseases/genetics , Intestinal Atresia/genetics , Minor Histocompatibility Antigens/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , Primary Immunodeficiency Diseases/genetics , Female , Humans , Male , Pedigree , Polymorphism, Single Nucleotide
20.
J Allergy Clin Immunol ; 148(2): 585-598, 2021 08.
Article in English | MEDLINE | ID: mdl-33771552

ABSTRACT

BACKGROUND: Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling. OBJECTIVE: Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. METHODS: We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed. RESULTS: We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome. CONCLUSION: Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.


Subject(s)
Cytokine Receptor gp130 , Job Syndrome , Molecular Dynamics Simulation , Mutation, Missense , Child , Cytokine Receptor gp130/chemistry , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/immunology , Cytokines/genetics , Cytokines/immunology , Genes, Recessive , Humans , Job Syndrome/genetics , Job Syndrome/immunology , Male , RNA-Seq , Signal Transduction/genetics , Signal Transduction/immunology , Exome Sequencing
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