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Research Projects

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The 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 HH. Gut 2013 Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease

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.

 

Autophagic Defects in Monogenic forms of IBD

GUT 2016 Schwerd Pandey

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 dysfunction of autophagy affects the 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 an 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:

Niemann-Pick Type C1

We investigate how dysfunction of the endosomal-lysosomal protein NPC affect antimicrobial activity in human. 

Schwerd T,  et al. Gut 2016 Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann–Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn’s disease

Hermansky-Pudlak Syndrome

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 trafficking pathway is essential for colitogenic mechanisms.

 

PTEN Deficiency

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.

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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.

 

PI3Kdelta deficiency

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 IL6 cytokine family including IL-6, IL-11, IL-27, OSM, and LIF. We investigate how defects in Gp130 can cause human disease including immunodeficiency and skeletal abnormalities. 

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 research 2020 A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

 

Immunodysregulation caused by DNASE2 defects

DNASe2 defects cause a problem of cells of the human body to digest double-stranded DNA. It is relevant for the cell-intrinsic DNA as well as during infection caused by some viruses.  Macrophages are particularly affected since they 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.

Bolton et al. JCC 2020 Remission of Inflammatory Bowel Disease in Glucose-6-Phosphatase 3 Deficiency by Allogeneic Haematopoietic Stem Cell Transplantation. 

 

Environmental enteropathy 

Environmental factors or 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 it has important consequences for growth, vaccine responses, and mortality. 

We do collaborate with research groups from India, Kenya, the UK, and other countries to understand the immune responses of children with environmental enteropathy.

Babji et al. NPJ Vaccines. 2020 Immune Predictors of Oral Poliovirus Vaccine Immunogenicity Among Infants in South India

Grassly et al. Lancet Infect Dis. 2016 The effect of azithromycin on the immunogenicity of oral poliovirus vaccine: a double-blind randomised placebo-controlled trial in seronegative Indian infants.