About

Clara Abraham, MD, is a Professor of Medicine in the Department of Digestive Diseases at Yale School of Medicine. Her research interests include inflammatory bowel diseases such as colitis, ulcerative colitis, and Crohn's disease, with a focus on genetics, immune system mechanisms, innate immunity, inflammation, and molecular biology related to the intestines. She explores the roles of T-lymphocytes, immune responses, and bacterial interactions in intestinal inflammation and immune-mediated diseases. Her work involves studying cellular and molecular pathways, including autophagy, bacterial infections, immune cell subsets, and the genetic factors influencing immune responses in gastrointestinal conditions. Dr. Abraham has contributed to understanding the immune environment in colitis and related disorders, with research published on topics such as autophagy, bacterial infections, T-cell subsets, and genetic variants affecting innate immune outcomes.

Research topics

• Biology
• Internal medicine
• Medicine
• Cell biology
• Gastroenterology
• Pathology
• Chemistry
• Immunology

Selected publications

• Autophagy and Bacterial infections

  Autophagy Reports · 2025-09-01 · 4 citations

  reviewOpen access

  Autophagy is an evolutionarily conserved cellular process that is prominent during bacterial infections. In this review article, we discuss how direct pathogen clearance via xenophagy and regulation of inflammatory products represent dual functions of autophagy that coordinate an effective antimicrobial response. We detail the molecular mechanisms of xenophagy, including signals that indicate the presence of an intracellular pathogen and autophagy receptor-mediated cargo targeting, while highlighting pathogen counterstrategies, such as bacterial effector proteins that inhibit autophagy initiation or exploit autophagic membranes for replication. Pathways that are related to autophagy, including LC3-associated phagocytosis (LAP) and conjugation of ATG8 to single membranes (CASM), are expanding the role of autophagy in antimicrobial defense beyond traditional double-membrane autophagosomes. Examination of Crohn disease-associated genes links impaired autophagy to inflammation and defective bacterial handling. We propose emerging concepts, such as effector-triggered immunity, where autophagy inhibition by pathogens triggers inflammatory defenses and discusses the therapeutic potential of modulating autophagy in infectious and inflammatory diseases.

  PublisherOA PDFDOI

• Roles of endothelial cells during infection

  Current Opinion in Immunology · 2025-08-29 · 3 citations

  reviewOpen access

  Endothelial cells (ECs) integrate immune and vascular functions to promote host defense against pathogens. While previously studied as forming passive flow conduits, ECs are now recognized as active contributors to maladaptive inflammation. During acute infection, ECs may promote tissue pathologies, including hypoxia, acidosis, electrolyte disturbances, and capillary barrier breakdown. These pathologies significantly contribute to organ dysfunction and septic shock. In chronic vascular infection, ECs may promote loss of vascular quiescence, contributing to vascular malformations and vaso-occlusive lesions. In this review, we discuss the interplay between the immune and vascular roles of blood ECs, an emerging area of interest with therapeutic implications. While previously overlooked, therapies targeting dysregulation of EC function(s) may show clinical benefit towards improving outcomes related to both acute and chronic forms of infection.

  PublisherDOI

• Interleukin-23 p19 and Interleukin-12 p40, Head-to-Head, against Gut Inflammation

  New England Journal of Medicine · 2024-07-17 · 1 citations

  editorial1st authorCorresponding
  PublisherDOI

• IL-12 and IL-23 pathway inhibition in inflammatory bowel disease

  Nature Reviews Gastroenterology & Hepatology · 2023 · 218 citations

  • Medicine
  • Gastroenterology
  • Internal medicine
  PublisherOA PDFDOI

• ScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis

  Journal for ImmunoTherapy of Cancer · 2023-08-01 · 10 citations

  articleOpen access

  Immune checkpoint inhibitors (ICIs) are increasingly being used to manage multiple tumor types. Unfortunately, immune-related adverse events affect up to 60% of recipients, often leading to treatment discontinuation in settings where few alternative cancer therapies may be available. Checkpoint inhibitor induced colitis (ICI-colitis) is a common toxicity for which the underlying mechanisms are poorly defined. To better understand the changing colon-specific and peripheral immune environments over the course of progression and treatment of colitis, we collected blood and colon tissue from a patient with Merkel cell carcinoma who developed colitis on treatment with pembrolizumab. We performed single-cell RNA sequencing and T-cell receptor sequencing on samples collected before, during and after pembrolizumab and after various interventions to mitigate toxicity. We report T-cells populations defined by cytotoxicity, memory, and proliferation markers at various stages of colitis. We show preferential depletion of CD8+ T cells with biologic therapy and nominate both circulating and colon-resident T-cell subsets as potential drivers of inflammation and response to immune suppression. Our findings highlight the need for further exploration of the colon immune environment and rationalize future studies evaluating biologics for ICI-colitis, including in the context of ICI re-challenge.

  PublisherOA PDFDOI

• HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

  Gastroenterology · 2023-07-14 · 16 citations

  articleOpen access

  Background & AimsUlcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.MethodsHLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.ResultsThese studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.ConclusionsWe identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC. Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC.

  PublisherOA PDFDOI

• Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting

  Gut Microbes · 2023-10-16 · 4 citations

  articleOpen access

  The present report summarizes the United States Department of Veterans Affairs (VA) field-based meeting titled "Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans." Our Veteran patient population experiences a high incidence of service-related chronic physical and mental health problems, such as infection, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), various forms of hematological and non-hematological malignancies, neurologic conditions, end-stage organ failure, requiring transplantation, and posttraumatic stress disorder (PTSD). We report the views of a group of scientists who focus on the current state of scientific knowledge elucidating the mechanisms underlying the aforementioned disorders, novel therapeutic targets, and development of new approaches for clinical intervention. In conclusion, we dovetailed on four research areas of interest: 1) microbiome interaction with immune cells after hematopoietic cell and/or solid organ transplantation, graft-versus-host disease (GVHD) and graft rejection, 2) intestinal inflammation and its modification in IBD and cancer, 3) microbiome-neuron-immunity interplay in mental and physical health, and 4) microbiome-micronutrient-immune interactions during homeostasis and infectious diseases. At this VA field-based meeting, we proposed to explore a multi-disciplinary, multi-institutional, collaborative strategy to initiate a roadmap, specifically focusing on host microbiome-immune interactions among those with service-related chronic diseases to potentially identify novel and translatable therapeutic targets.

  PublisherDOI

• Pattern Recognition Receptor Signaling and Cytokine Networks in Microbial Defenses and Regulation of Intestinal Barriers: Implications for Inflammatory Bowel Disease

  Gastroenterology · 2022 · 115 citations

  1st authorCorresponding
  • Immunology
  • Biology
  • Medicine
  PublisherOA PDFDOI

• The Tight Junction Protein ZO-1 Is Dispensable for Barrier Function but Critical for Effective Mucosal Repair

  Gastroenterology · 2021 · 498 citations

  • Cell biology
  • Chemistry
  • Biology
  PublisherOA PDFDOI

• Ubiquitination of ATF6 by disease-associated RNF186 promotes the innate receptor-induced unfolded protein response

  Journal of Clinical Investigation · 2021-08-31 · 37 citations

  articleOpen accessSenior authorCorresponding

  Properly balancing microbial responses by the innate immune system through pattern recognition receptors (PRRs) is critical for intestinal immune homeostasis. Ring finger protein 186 (RNF186) genetic variants are associated with inflammatory bowel disease (IBD). However, functions for the E3 ubiquitin ligase RNF186 are incompletely defined. We found that upon stimulation of the PRR nucleotide-binding oligomerization domain containing 2 (NOD2) in human macrophages, RNF186 localized to the ER, formed a complex with ER stress sensors, ubiquitinated the ER stress sensor activating transcription factor 6 (ATF6), and promoted the unfolded protein response (UPR). These events, in turn, led to downstream signaling, cytokine secretion, and antimicrobial pathway induction. Importantly, RNF186-mediated ubiquitination of K152 on ATF6 was required for these outcomes, highlighting a key role for ATF6 ubiquitination in PRR-initiated functions. Human macrophages transfected with the rare RNF186-A64T IBD risk variant and macrophages from common rs6426833 RNF186 IBD risk carriers demonstrated reduced NOD2-induced outcomes, which were restored by rescuing UPR signaling. Mice deficient in RNF186 or ATF6 demonstrated a reduced UPR in colonic tissues, increased weight loss, and less effective clearance of bacteria with dextran sodium sulfate-induced injury and upon oral challenge with Salmonella Typhimurium. Therefore, we identified that RNF186 was required for PRR-induced, UPR-associated signaling leading to key macrophage functions; defined that RNF186-mediated ubiquitination of ATF6 was essential for these functions; and elucidated how RNF186 IBD risk variants modulated these outcomes.

  PublisherOA PDFDOI

Recent grants

• Mechanisms Regulating Innate Immune Responses

  NIH · $2.0M · 2016–2022

• NIH Grant K08DK002905

  NIH · $546k · 2006

• NIH Grant R01DK077905

  NIH · $1.7M · 2013

• Functional outcomes of inflammatory bowel disease associated variants

  NIH · $6.2M · 2013–2028

• NIH Grant R56AI120369

  NIH · $416k · 2016

Frequent coauthors

• Judy H. Cho

  Icahn School of Medicine at Mount Sinai

  62 shared

• Mark S. Silverberg

  University of Toronto

  52 shared

• Mark J. Daly

  Massachusetts General Hospital

  50 shared

• Steven R. Brant

  Rutgers, The State University of New Jersey

  49 shared

• L. Philip Schumm

  University of Chicago

  46 shared

• Richard H. Duerr

  45 shared

• John D. Rioux

  Université de Montréal

  44 shared

• Alain Bitton

  McGill University Health Centre

  43 shared