Key interest of the lab is to understand key mechanisms that drive intestinal inflammation. Within the COLORS in IBD study project we investigate novel genetic defects in early onset intestinal inflammation.
Uhlig et al. Gastroenterology 2014 The diagnostic approach to monogenic very early onset inflammatory bowel disease.
Uhlig HH, Muise AM. Trends Genet. 2017 Clinical Genomics in Inflammatory Bowel Disease.
Uhlig HH Powrie F Ann Rev Immunol 2018 Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease.
Uhlig HH, et al. JPGN 2021 Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.
Autophagic Defects in Monogenic forms of IBD
Defective antibacterial autophagy in the NOD2-RIPK2-XIAP pathway is the cause of several rare Mendelian disorders that present with granulomatous intestinal inflammation. We study how dysfuntion of autophagy affects elimination of intracellular bacteria. We like to understand how incomplete bacterial clearance (immunodeficiency) can cause dysregulated cytokine responses.
In addition to study the pathophysiology of dysregulated antimicrobial activity we like to explore how pharmaceutical induction of autophagy can restore bacterial killing as a potential therapeutic strategy. Recently we identified in studies jointly performed with the Powrie lab the short chain fatty acid butyrate as a inducer of antimicrobial activity.
Schulthess J, Pandey S et al. Immunity 2019 The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages.
Projects that illustrate the broad interest of the lab in multiple Mendelian disorders are related to:
ROLE OF IL10 SIGNALLING FOR INTESTINAL
Niemann-Pick Type C1
We investigate how dysfunction of the endosomal-lysosomal protein NPC affect antimicrobial activity in human.
Cavounidis A, Uhlig HH. Dig Dis Sci. 2018. Crohn's Disease in Niemann-Pick Disease Type C1: Caught in the Cross-Fire of Host-Microbial Interactions.
We investigate defective anti-microbial pathways in patients with Hermansky-Pudlak Syndrome which can develop inflammatory bowel disease. In particular patients with genetic defects in HPS1 and HPS4 intestinal inflammation is a feature suggesting that the vesicle trafficing pathway is essential for colitogenic mechanisms.
As an example how single mutations in human genes affect mucosal immune regulation we study the immune response in patients with PTEN hamartoma tumor syndrome.
Due to heterozygous mutations in the PTEN gene patients develop a spectrum of symptoms including Bannayan Riley Ruvalcaba syndrome and Cowden's syndrome. PTEN deficiency in humans can lead to massive mucosal lymphoid hyperplasia and autoimmunity. We investigate the functional consequences of PTEN deficiency for the development of the mucosa-associated lymphoid tissue.
Heindl et al. Gastroenterology 2012 Autoimmunity, intestinal lymphoid hyperplasia, and defects in mucosal B-cell homeostasis in patients with PTEN hamartoma tumor syndrome.
Chen H, Handel H, et al., JACI 2016 Immune dysregulation in patients with PTEN hamartoma tumor syndrome – analysis of FOXP3 regulatory T cells.
Taylor, Laurence, Uhlig Cold Spring Harb Perspect Med. 2019 The Role of PTEN in Innate and Adaptive Immunity.
Taylor, Yerlioglu, Phen et al. Hum Mol Genet. 2021 mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in juvenile polyposis of infancy due to PTEN-BMPR1A deletion syndrome.
Deficiency of the PI3Kdelta kinase causes immunodeficiency, autoimmunity and intestinal inflammation.
Swan, Aschenbrenner et al. Haematologica 2019 Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ.
Immunodeficiency caused by Gp130 defects
GP130, encoded by IL6ST, is a key signalling receptor subunit for multiple cytokines of the IL-6 cytokine family including IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC and CNTF. We have an expanding spectrum of GP130-associated Mendelian diseases, where mutations in IL6ST cause distinct and extreme clinical phenotype including immunodeficiency and skeletal abnormalities. We have been able to use these Mendelian disorders to establish several genotype-phenotype associations and identify novel structural features that explains the pathogenicity of the variant and/or functional defects. These are 1) complete loss-of-function; 2) mono-allelic dominant-negative variants in the intracellular domain; 3) Recessive selective biallelic loss-of-function due to non-synonymous variants at domain interfaces; and 4) a selective IL-11 defect. These phenotypes inform on differential contribution of GP130-depedent cytokines and helps to understand GP130 as a potential drug target.
Schwerd et al. J Exp Med. 2017 A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis.
Shahin, Aschenbrenner et al. Haemaologica 2019 Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function.
Chen et al. J Exp Med 2020 Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome.
Beziat et al. J Exp Med 2020 Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.
Schwerd et al. Bone Res 2020 A variant in IL6ST with a selective IL-11 signaling defect in humans and mice.
Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice
Spleen Tyrosine Kinase (SYK) is a evolutionary conserved non-receptor tyrosine kinase and critical immune signaling molecule. SYK is primarily expressed in mononuclear phagocytes, B cells and, to a lesser extent, the intestinal epithelium. SYK mediates signal transduction downstream of the B cell receptor, C-type lectin receptors, Fc receptors, complement receptors, Toll-like receptors and integrins. We investigated monoallelic SYK variants in patients with immune deficiency, systemic disease such as colitis, arthritis and skin inflammation, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling indicating gain-of-function. Building on these studies that were done as part of the VEOIBD consortium and the 100K Genome project we are investigating SYK signalling pathway functions in inflammatory disease to define immunological mechanisms and inform personalized medicine approaches.
Wang, Aschenbrenner, Zeng et al. Nat Gen 2021 Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.
Immunodysregulation caused by DNASE2 defects
DNASe2 defects affect the cellular ability to digest double-stranded DNA. This is relevant for the handling of cell-intrinsic DNA during steady-state as well as during infection caused by some viruses. Macrophages are particularly affected by those genetic DNASE2. defects since those cells have a problem digesting DNA of phagocytosed apoptotic cells and bacteria.
Hong, Capitani et a. JACI 2019 Janus kinase inhibition for autoinflammation in patients with DNASE2 deficiency.
Defects in the Glucose 6 phosphate metabolism
Patients with defects in the glucose-6-phosphate metabolism present with congenital neutropenia. We investigate why some of the patients develop intestinal inflammation.
Environmental enteropathy (environmental enteric dysfunction) is a disorder of chronic intestinal inflammation presenting in children living in low-resource settings. The functional mechanisms of this disorder are poorly understood, but determining how environmental factors and immunological responses intersect may have important consequences for growth, vaccine responses and mortality.
We collaborate with the Childhood Acute Infection and Nutrition (CHAIN) Network and research groups from India, Kenya, the UK, and other countries to understand the immune responses of children with environmental enteropathy.
Immunological parameter that affect vaccine responses to oral poliovirus in infants in India.
Babji et al. NPJ Vaccines. 2020 Immune Predictors of Oral Poliovirus Vaccine Immunogenicity Among Infants in South India