ORCID Profile
0000-0001-5746-0153
Current Organisation
Massachusetts General Hospital
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Publisher: Cold Spring Harbor Laboratory
Date: 30-03-2022
DOI: 10.1101/2022.03.29.486273
Abstract: Inflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Epigenetics facilitate integration of environmental cues for transcriptional output. However, evidence of epigenetic dysregulation directly causing host-commensal dysbiosis and IBD is lacking. Speckled Protein 140 (SP140) is an immune-restricted chromatin ‘reader’ with homology to Autoimmune Regulator (AIRE). SP140 mutations associate with three immune diseases: Crohn’s disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL), but disease-causing mechanisms remain undefined. Here we identify a critical immune-intrinsic role for SP140 in preventing expansion of inflammatory Proteobacteria, including Helicobacter in mice and Enterobacteriaceae in humans. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis which was transmissible upon co-housing and ameliorated with antibiotics. SP140 was critical for calibration of macrophage microbicidal responses required for normal host-commensal crosstalk and elimination of invasive pathogens. Mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by the microbiome, such as IBD and MS.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2010
DOI: 10.1038/NATURE09589
Publisher: American Association for the Advancement of Science (AAAS)
Date: 31-03-2017
DOI: 10.1126/SCIIMMUNOL.AAG3160
Abstract: The epigenetic reader SP140, which is polymorphic in Crohn’s disease patients, regulates transcriptional programs in macrophages.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-10-2019
Abstract: Tissue-resident memory T (T RM ) cells constitute a subpopulation of memory cells that reside in tissues instead of recirculating. CD8 + epithelial TRM (eT RM ) cells, which occupy the epithelium of sites like the skin, require transforming growth factor–β (TGF-β) for their development. Mani et al. found that α V integrin–expressing dendritic cells, which activate and present TGF-β, are key (see the Perspective by Farber). Surprisingly, this interplay did not occur in the skin or draining lymph nodes during T cell priming. Rather, resting naïve CD8 + T cells interacted with α V integrin–expressing migratory dendritic cells during immune homeostasis, reversibly preconditioning them to become eT RM cells upon activation. A potent cytokine is thus controlled in a context-dependent manner and preimmune T cell repertoires may be less uniform than previously presumed. Science , this issue p. eaav5728 see also p. 188
Publisher: Elsevier BV
Date: 10-2010
Publisher: Elsevier BV
Date: 08-2022
Publisher: Springer Science and Business Media LLC
Date: 11-2019
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
Publisher: Springer Science and Business Media LLC
Date: 08-12-2020
Publisher: Rockefeller University Press
Date: 21-09-2022
DOI: 10.1084/JEM.20220081
Abstract: A sleepless night may feel awful in its aftermath, but sleep’s revitalizing powers are substantial, perpetuating the idea that convalescent sleep is a consequence-free physiological reset. Although recent studies have shown that catch-up sleep insufficiently neutralizes the negative effects of sleep debt, the mechanisms that control prolonged effects of sleep disruption are not understood. Here, we show that sleep interruption restructures the epigenome of hematopoietic stem and progenitor cells (HSPCs) and increases their proliferation, thus reducing hematopoietic clonal ersity through accelerated genetic drift. Sleep fragmentation exerts a lasting influence on the HSPC epigenome, skewing commitment toward a myeloid fate and priming cells for exaggerated inflammatory bursts. Combining hematopoietic clonal tracking with mathematical modeling, we infer that sleep preserves clonal ersity by limiting neutral drift. In humans, sleep restriction alters the HSPC epigenome and activates hematopoiesis. These findings show that sleep slows decay of the hematopoietic system by calibrating the hematopoietic epigenome, constraining inflammatory output, and maintaining clonal ersity.
Publisher: Cold Spring Harbor Laboratory
Date: 15-10-2021
DOI: 10.1101/2021.10.14.464404
Abstract: Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found virus like particles (VLPs) enriched from normal human colon resections, containing eukaryotic viruses and bacteriophages (collectively, the virome), actively elicited atypical anti-inflammatory innate immune programs. Conversely, IBD patient VLPs provoked inflammation, which was successfully d ened by healthy VLPs. The IBD colon tissue virome was perturbed, including enriched Picornovirus Enterovirus B, not previously observed in fecal virome studies. Mice with humanized healthy colon tissue viromes had attenuated intestinal inflammation while those with IBD-derived viromes exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD-associated MDA5 loss-of-function on patient intestinal epithelial cells exposed to healthy or IBD viromes. Our results demonstrate that innate recognition of either healthy or IBD human viromes autonomously influences disease phenotypes in IBD. Harnessing the virome may offer therapeutic and biomarker potential. Human viromes ergently shape host immunity and disease
Publisher: Springer Science and Business Media LLC
Date: 30-07-2020
DOI: 10.1186/S13073-020-00766-X
Abstract: Although the microbiome is established as an important regulator of health and disease, the role of viruses that inhabit asymptomatic humans (collectively, the virome) is less defined. While we are still characterizing what constitutes a healthy or diseased virome, an exciting next step is to move beyond correlations and toward identification of specific viruses and their precise mechanisms of beneficial or harmful immunomodulation. Illuminating this will represent a first step toward developing virome-focused therapies.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-04-2022
DOI: 10.1126/SCIIMMUNOL.ABN6660
Abstract: Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses and bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn’s disease colon resection viromes provoked inflammation, which was successfully d ened by non-IBD viromes. The IBD colon tissue virome was perturbed, including an increase in the enterovirus B species of eukaryotic picornaviruses, not previously detected in fecal virome studies. Mice humanized with non-IBD colon tissue viromes were protected from intestinal inflammation, whereas IBD virome mice exhibited exacerbated inflammation in a nucleic acid sensing–dependent fashion. Furthermore, there were detrimental consequences for IBD patient–derived intestinal epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed to viromes. Our results demonstrate that innate recognition of IBD or non-IBD human viromes autonomously influences intestinal homeostasis and disease phenotypes. Thus, perturbations in the intestinal virome, or an altered ability to sense the virome due to genetic variation, contribute to the induction of IBD. Harnessing the virome may offer therapeutic and biomarker potential.
Publisher: Springer Science and Business Media LLC
Date: 24-11-2013
DOI: 10.1038/NI.2766
Publisher: Elsevier BV
Date: 02-2020
Publisher: American Thoracic Society
Date: 06-2002
Abstract: Protease-activated receptor-2 (PAR2) acts as a receptor for trypsin and trypsin-like enzymes. The role of this receptor in airway inflammation is uncertain. In this study we assessed the effect of activation of PAR2 following intranasal administration of the peptide activator of PAR2, SLIGRL, over 72 h in mice. The extent of immune cell infiltration into the airways and activities of matrix metalloprotease-2 (MMP-2) and MMP-9 were assessed in bronchoalveolar lavage (BAL) by differential cell counts and gelatin zymography, respectively. SLIGRL did not cause a change in the number or types of cells retrieved in BAL at any time point and did not alter the levels of MMP-2 and MMP-9 present in BAL. In contrast, similar intranasal administration of bacterial lipopolysaccharide (LPS) caused a large influx of neutrophilic polymorphonuclear leukocytes, which was associated with increased MMP-2 at 3 h only and MMP-9 activity from 3-72 h. Simultaneous administration of SLIGRL and LPS transiently potentiated increased MMP-9 activity at 3 h but markedly inhibited neutrophil influx and elevated MMP-2 activity at 3 h. These findings suggest that PAR2 agonists may be useful therapeutic molecules in pulmonary inflammatory diseases.
Publisher: Springer Science and Business Media LLC
Date: 03-2012
DOI: 10.1038/NATURE10892
Publisher: Proceedings of the National Academy of Sciences
Date: 10-08-2010
Abstract: Canonical animal microRNAs (miRNAs) are generated by sequential cleavage of precursor substrates by the Drosha and Dicer RNase III enzymes. Several variant pathways exploit other RNA metabolic activities to generate functional miRNAs. However, all of these pathways culminate in Dicer cleavage, suggesting that this is a unifying feature of miRNA biogenesis. Here, we show that maturation of miR-451, a functional miRNA that is perfectly conserved among vertebrates, is independent of Dicer. Instead, structure-function and knockdown studies indicate that Drosha generates a short pre-mir-451 hairpin that is directly cleaved by Ago2 and followed by resection of its 3′ terminus. We provide stringent evidence for this model by showing that Dicer knockout cells can generate mature miR-451 but not other miRNAs, whereas Ago2 knockout cells reconstituted with wild-type Ago2, but not Slicer-deficient Ago2, can process miR-451. Finally, we show that the mir-451 backbone is amenable to reprogramming, permitting vector-driven expression of erse functional miRNAs in the absence of Dicer. Beyond the demonstration of an alternative strategy to direct gene silencing, these observations open the way for transgenic rescue of Dicer conditional knockouts.
Publisher: Wiley
Date: 06-01-2015
DOI: 10.1038/ICB.2014.101
Publisher: Elsevier BV
Date: 04-2022
Publisher: Frontiers Media SA
Date: 20-02-2017
Publisher: Elsevier BV
Date: 08-2020
Publisher: Springer Science and Business Media LLC
Date: 20-05-2021
No related grants have been discovered for Kate Jeffrey.