Publications by authors named "Meghan Acres"

10 Publications

  • Page 1 of 1

Blood and immune development in human fetal bone marrow and Down syndrome.

Nature 2021 10 29;598(7880):327-331. Epub 2021 Sep 29.

Wellcome Sanger Institute, Hinxton, UK.

Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception, yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21).
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http://dx.doi.org/10.1038/s41586-021-03929-xDOI Listing
October 2021

Regulation and Role of αE Integrin and Gut Homing Integrins in Migration and Retention of Intestinal Lymphocytes during Inflammatory Bowel Disease.

J Immunol 2021 11 24;207(9):2245-2254. Epub 2021 Sep 24.

Translational and Clinical Research Institute, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom;

Targeting interactions between α4β7 integrin and endothelial adhesion molecule MAdCAM-1 to inhibit lymphocyte migration to the gastrointestinal tract is an effective therapy in inflammatory bowel disease (IBD). Following lymphocyte entry into the mucosa, a subset of these cells expresses αEβ7 integrin, which is expressed on proinflammatory lymphocytes, to increase cell retention. The factors governing lymphocyte migration into the intestinal mucosa and αE integrin expression in healthy subjects and IBD patients remain incompletely understood. We evaluated changes in factors involved in lymphocyte migration and differentiation within tissues. Both ileal and colonic tissue from active IBD patients showed upregulation of ICAM-1, VCAM-1, and MAdCAM-1 at the gene and protein levels compared with healthy subjects and/or inactive IBD patients. β1 and β7 integrin expression on circulating lymphocytes was similar across groups. TGF-β1 treatment induced expression of αE on both β7 and β7 T cells, suggesting that cells entering the mucosa independently of MAdCAM-1/α4β7 can become αEβ7 ITGAE gene polymorphisms did not alter protein induction following TGF-β1 stimulation. Increased phospho-SMAD3, which is directly downstream of TGF-β, and increased TGF-β-responsive gene expression were observed in the colonic mucosa of IBD patients. Finally, in vitro stimulation experiments showed that baseline β7 expression had little effect on cytokine, chemokine, transcription factor, and effector molecule gene expression in αE and αE T cells. These findings suggest cell migration to the gut mucosa may be altered in IBD and α4β7, and α4β7 T cells may upregulate αEβ7 in response to TGF-β once within the gut mucosa.
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http://dx.doi.org/10.4049/jimmunol.2100220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525869PMC
November 2021

Germline TET2 loss of function causes childhood immunodeficiency and lymphoma.

Blood 2020 08;136(9):1055-1066

Primary Immunodeficiency Group, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom.

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.
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http://dx.doi.org/10.1182/blood.2020005844DOI Listing
August 2020

Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in .

Sci Immunol 2019 12;4(42)

Department of Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in , a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2 in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2 to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
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http://dx.doi.org/10.1126/sciimmunol.aav7501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115903PMC
December 2019

Decoding human fetal liver haematopoiesis.

Nature 2019 10 9;574(7778):365-371. Epub 2019 Oct 9.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.
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http://dx.doi.org/10.1038/s41586-019-1652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861135PMC
October 2019

Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance.

J Exp Med 2019 06 30;216(6):1311-1327. Epub 2019 Apr 30.

Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain () gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.
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http://dx.doi.org/10.1084/jem.20182304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547869PMC
June 2019

Signal transducer and activator of transcription 5B deficiency due to a novel missense mutation in the coiled-coil domain.

J Allergy Clin Immunol 2019 01 8;143(1):413-416.e4. Epub 2018 Sep 8.

Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320259PMC
January 2019

The pathogenesis of retinal and subdural haemorrhage in non-accidental head injury in infancy: assessment using Bradford Hill criteria.

Med Hypotheses 2014 Jan 16;82(1):1-5. Epub 2013 Sep 16.

University Hospitals of Morecambe Bay NHS Foundation Trust, Royal Lancaster Infirmary, Lancaster LA1 4RP, United Kingdom. Electronic address:

Fatal non-accidental head injury (NAHI) in infancy is characterised by severe bilateral retinal haemorrhage (sbRH), thin film diffuse bilateral subdural haemorrhage (dbSDH) and severe fatal hypoxic ischaemic encephalopathy (sfHIE). The Geddes hypothesis is that sfHIE is the direct cause of sbRH and dbSDH. The conventional hypothesis (post-Geddes) is that trauma precipitates hypoxia to cause sfHIE and independently tears veins to cause sbRH and dbSDH. These hypotheses are assessed using Bradford Hill criteria of causation. The triad (sbRH, dbSDH and sfHIE) is a strong, specific and consistent association which suggests a causative link. Furthermore sbRH and dbSDH are positively correlated with severity of HIE but negatively correlated with objective evidence of trauma. The conventional hypothesis (post-Geddes) fails the test of biological plausibility because trauma causes asymmetrical and focal bleeding not diffuse bilateral capillary and venular oozing. The conventional hypothesis lacks coherence since it was shown that the encephalopathy of the triad is not traumatic. Arguments by analogy also support the Geddes hypothesis. There is a paucity of experimental evidence for either hypothesis but this is likely to be rectified as molecular methods (genomics and proteomics) are used in the infant autopsy.
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http://dx.doi.org/10.1016/j.mehy.2013.09.017DOI Listing
January 2014

Anorexia nervosa, autoimmunity and the hygiene hypothesis.

Med Hypotheses 2012 Jun 31;78(6):772-5. Epub 2012 Mar 31.

Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YW, United Kingdom.

The hypothesis proposed is that anorexia nervosa (AN) is an autoimmune disease caused by delayed exposure to common micro-organisms in which auto-antibodies to regulatory peptides and hypothalamic neurons, which cross react with microbial antigens, disturb appetite and lead to decreased intake of food. IgG, IgA and IgM auto-antibodies to a range of regulatory peptides concerned with appetite and mood are found in patients with AN. The regulatory peptides show sequence homology with common micro-organisms of the microbial flora. Auto-antibodies to α melanocyte stimulating hormone (αMSH) are positively correlated with AN psychopathology. But patients with bulimia nervosa (BN) and normal healthy controls also have a similar range of auto-antibodies at comparable levels. The incidence of AN is rising in developed countries, the disease is more common in females than in males, the peak incidence is in the teenage years, there is seasonal variation in the month of birth and the disease is more common in higher socio-economic groups. These are all features which are consistent with the hygiene hypothesis. But there is no evidence that the disease is more common in first born than in later born children. There is a paucity of data on early life events such as attendance at nursery and exposure to pets. Genetic factors are important but the data on major histocompatibility complex (MHC) gene polymorphisms are contradictory. The epidemiological and serological data are consistent with the hypothesis under investigation but key questions in relation to the hygiene hypothesis have not been posed. A large case control study of AN epidemiology is indicated. MHC gene polymorphisms should be assessed. There is, however, sufficient evidence to justify a trial of pooled immunoglobulin therapy in patients with life threatening AN.
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http://dx.doi.org/10.1016/j.mehy.2012.03.002DOI Listing
June 2012
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