Clara Abraham, MD
Professor of Medicine (Digestive Diseases)
Research & Publications
Biography
News
Research Summary
Homeostasis of the intestinal immune system. The development of inflammatory bowel disease appears to be related to the uncontrolled activation of immune cells within the specialized immune system of the intestine. We are addressing mechanisms regulating intestinal immune homeostasis and the dysregulation that occurs with intestinal inflammation through studies in mouse models of disease and through the use of primary cells from healthy individuals and patients with Crohn’s disease and ulcerative colitis. We seek to understand both innate and adaptive immune pathways that contribute to these diseases. Further, we utilize the genetic discoveries in inflammatory bowel disease to guide these studies, such that we focus on understanding the immunological consequences of genetic variants (e.g. NOD2, IL23/Th17 pathway, JAK/STAT pathway, TNFSF15, IRF5, RNF186, LACC1, RNF186, MTMR3, ICOS) implicated in either increasing or decreasing the likelihood of developing human inflammatory bowel disease.
Key Phrases: Regulation of the intestinal immune system; Genetics and immunobiology of inflammatory bowel disease; host:microbe interactions.
Research Interests
Colitis, Ulcerative; Crohn Disease; Genetics; Immune System; Immunity, Innate; Inflammation; Intestines; Molecular Biology; T-Lymphocytes; Inflammatory Bowel Diseases
Selected Publications
- The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomesRanjan K, Hedl M, Abraham C. The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2013500118. PMID: 34353900, PMCID: PMC8364215, DOI: 10.1073/pnas.2013500118.
- Myeloid Cell Expression of LACC1 Is Required for Bacterial Clearance and Control of Intestinal InflammationKang JW, Yan J, Ranjan K, Zhang X, Turner JR, Abraham C. Myeloid Cell Expression of LACC1 Is Required for Bacterial Clearance and Control of Intestinal Inflammation. Gastroenterology 2020, 159: 1051-1067. PMID: 32693188, PMCID: PMC8139320, DOI: 10.1053/j.gastro.2020.07.024.
- T Cell-Intrinsic IRF5 Regulates T Cell Signaling, Migration, and Differentiation and Promotes Intestinal InflammationYan J, Pandey SP, Barnes BJ, Turner JR, Abraham C. T Cell-Intrinsic IRF5 Regulates T Cell Signaling, Migration, and Differentiation and Promotes Intestinal Inflammation. Cell Reports 2020, 31: 107820. PMID: 32610123, PMCID: PMC7409536, DOI: 10.1016/j.celrep.2020.107820.
- LACC1 Required for NOD2-Induced, ER Stress-Mediated Innate Immune Outcomes in Human Macrophages and LACC1 Risk Variants Modulate These OutcomesHuang C, Hedl M, Ranjan K, Abraham C. LACC1 Required for NOD2-Induced, ER Stress-Mediated Innate Immune Outcomes in Human Macrophages and LACC1 Risk Variants Modulate These Outcomes. Cell Reports 2019, 29: 4525-4539.e4. PMID: 31875558, PMCID: PMC7372507, DOI: 10.1016/j.celrep.2019.11.105.
- IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomesSun R, Hedl M, Abraham C. IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes. Gut 2019, 69: 264. PMID: 31097538, PMCID: PMC6858485, DOI: 10.1136/gutjnl-2018-316830.
- Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomesLahiri A, Hedl M, Yan J, Abraham C. Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes. Nature Communications 2017, 8: 15614. PMID: 28593945, PMCID: PMC5472760, DOI: 10.1038/ncomms15614.
- An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomesYan J, Hedl M, Abraham C. An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes. Journal Of Clinical Investigation 2017, 127: 2192-2205. PMID: 28436939, PMCID: PMC5451247, DOI: 10.1172/jci86282.
- Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel DiseasesAbraham C, Dulai PS, Vermeire S, Sandborn WJ. Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases. Gastroenterology 2016, 152: 374-388.e4. PMID: 27780712, PMCID: PMC5287922, DOI: 10.1053/j.gastro.2016.10.018.
- IRF5 and IRF5 Disease-Risk Variants Increase Glycolysis and Human M1 Macrophage Polarization by Regulating Proximal Signaling and Akt2 ActivationHedl M, Yan J, Abraham C. IRF5 and IRF5 Disease-Risk Variants Increase Glycolysis and Human M1 Macrophage Polarization by Regulating Proximal Signaling and Akt2 Activation. Cell Reports 2016, 16: 2442-2455. PMID: 27545875, PMCID: PMC5165654, DOI: 10.1016/j.celrep.2016.07.060.
- MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activationLahiri A, Hedl M, Abraham C. MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 10461-10466. PMID: 26240347, PMCID: PMC4547281, DOI: 10.1073/pnas.1501752112.
- A TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretionHedl M, Abraham C. A TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion. Gut 2015, 65: 1799. PMID: 26215868, PMCID: PMC5106344, DOI: 10.1136/gutjnl-2014-308922.
- Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and ActivatorsZheng S, Hedl M, Abraham C. Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators. The Journal Of Immunology 2015, 195: 217-226. PMID: 26019273, PMCID: PMC4501480, DOI: 10.4049/jimmunol.1402808.
- T Cell–Extrinsic CD18 Attenuates Antigen-Dependent CD4+ T Cell Activation In VivoWu X, Lahiri A, Sarin R, Abraham C. T Cell–Extrinsic CD18 Attenuates Antigen-Dependent CD4+ T Cell Activation In Vivo. The Journal Of Immunology 2015, 194: 4122-4129. PMID: 25801431, PMCID: PMC4404034, DOI: 10.4049/jimmunol.1401328.
- A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1Hedl M, Abraham C. A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 13451-13456. PMID: 25197060, PMCID: PMC4169936, DOI: 10.1073/pnas.1404178111.
- Activation of Pattern Recognition Receptors Up-Regulates Metallothioneins, Thereby Increasing Intracellular Accumulation of Zinc, Autophagy, and Bacterial Clearance by MacrophagesLahiri A, Abraham C. Activation of Pattern Recognition Receptors Up-Regulates Metallothioneins, Thereby Increasing Intracellular Accumulation of Zinc, Autophagy, and Bacterial Clearance by Macrophages. Gastroenterology 2014, 147: 835-846. PMID: 24960189, PMCID: PMC4170054, DOI: 10.1053/j.gastro.2014.06.024.
- Pattern Recognition Receptor Signaling in Human Dendritic Cells is Enhanced by ICOS Ligand and Modulated by the Crohn’s Disease ICOSLG Risk AlleleHedl M, Lahiri A, Ning K, Cho JH, Abraham C. Pattern Recognition Receptor Signaling in Human Dendritic Cells is Enhanced by ICOS Ligand and Modulated by the Crohn’s Disease ICOSLG Risk Allele. Immunity 2014, 40: 734-746. PMID: 24837102, PMCID: PMC4157904, DOI: 10.1016/j.immuni.2014.04.011.
- NOD2 Regulates CXCR3-Dependent CD8+ T Cell Accumulation in Intestinal Tissues with Acute InjuryWu X, Lahiri A, Haines GK, Flavell RA, Abraham C. NOD2 Regulates CXCR3-Dependent CD8+ T Cell Accumulation in Intestinal Tissues with Acute Injury. The Journal Of Immunology 2014, 192: 3409-3418. PMID: 24591373, PMCID: PMC4064676, DOI: 10.4049/jimmunol.1302436.
- NF-κB1 Inhibits NOD2-Induced Cytokine Secretion through ATF3-Dependent MechanismsZheng S, Abraham C. NF-κB1 Inhibits NOD2-Induced Cytokine Secretion through ATF3-Dependent Mechanisms. Molecular And Cellular Biology 2013, 33: 4857-4871. PMID: 24100018, PMCID: PMC3889551, DOI: 10.1128/mcb.00797-13.
- Host–microbe interactions have shaped the genetic architecture of inflammatory bowel diseaseJostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Philip Schumm L, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D’Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, Silverberg M, Annese V, Hakonarson H, Brant S, Radford-Smith G, Mathew C, Rioux J, Schadt E, Daly M, Franke A, Parkes M, Vermeire S, Barrett J, Cho J. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012, 491: 119-124. PMID: 23128233, PMCID: PMC3491803, DOI: 10.1038/nature11582.
- IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestineHuber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L, Hu B, Hedl M, Zhang W, O’Connor W, Murphy AJ, Valenzuela DM, Yancopoulos GD, Booth CJ, Cho JH, Ouyang W, Abraham C, Flavell RA. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 2012, 491: 259-263. PMID: 23075849, PMCID: PMC3493690, DOI: 10.1038/nature11535.
- Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responsesSarin R, Wu X, Abraham C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 9560-9565. PMID: 21606346, PMCID: PMC3111257, DOI: 10.1073/pnas.1017854108.
- Inflammatory Bowel DiseaseAbraham C, Cho JH. Inflammatory Bowel Disease. New England Journal Of Medicine 2009, 361: 2066-2078. PMID: 19923578, PMCID: PMC3491806, DOI: 10.1056/nejmra0804647.