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1.
Sci Immunol ; 7(68): eabf2846, 2022 02 11.
Article in English | MEDLINE | ID: covidwho-1685480

ABSTRACT

Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.


Subject(s)
Inflammation/immunology , Macrophage Activation/immunology , Signaling Lymphocytic Activation Molecule Family/immunology , Transcriptome/immunology , Acute Disease , Adult , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/metabolism , COVID-19/genetics , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , Chronic Disease , Crohn Disease/genetics , Crohn Disease/immunology , Crohn Disease/metabolism , Female , Humans , Inflammation/genetics , Inflammation/metabolism , Macrophage Activation/genetics , RNA-Seq/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Signaling Lymphocytic Activation Molecule Family/genetics , Signaling Lymphocytic Activation Molecule Family/metabolism , Single-Cell Analysis/methods , Synovial Membrane/immunology , Synovial Membrane/metabolism , Synovial Membrane/pathology , Transcriptome/genetics
2.
Gastroenterology ; 160(3): 925-928.e4, 2021 02.
Article in English | MEDLINE | ID: covidwho-1575253
3.
Elife ; 102021 10 12.
Article in English | MEDLINE | ID: covidwho-1478420

ABSTRACT

Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. Here we predict, based on the liability threshold model, the expected reduction in complex disease risk following polygenic embryo screening for a single disease. A strong determinant of the potential utility of such screening is the selection strategy, a factor that has not been previously studied. When only embryos with a very high PRS are excluded, the achieved risk reduction is minimal. In contrast, selecting the embryo with the lowest PRS can lead to substantial relative risk reductions, given a sufficient number of viable embryos. We systematically examine the impact of several factors on the utility of screening, including: variance explained by the PRS, number of embryos, disease prevalence, parental PRSs, and parental disease status. We consider both relative and absolute risk reductions, as well as population-averaged and per-couple risk reductions, and also examine the risk of pleiotropic effects. Finally, we confirm our theoretical predictions by simulating 'virtual' couples and offspring based on real genomes from schizophrenia and Crohn's disease case-control studies. We discuss the assumptions and limitations of our model, as well as the potential emerging ethical concerns.


Subject(s)
Crohn Disease/genetics , Fertilization in Vitro , Genetic Testing , Models, Genetic , Multifactorial Inheritance , Preimplantation Diagnosis , Schizophrenia/genetics , Computer Simulation , Female , Genetic Predisposition to Disease , Humans , Male , Predictive Value of Tests , Pregnancy , Risk Assessment , Risk Factors
4.
Genome Med ; 13(1): 64, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1195928

ABSTRACT

BACKGROUND: Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. METHODS: To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-ß) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. RESULTS: We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. CONCLUSIONS: Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.


Subject(s)
COVID-19/immunology , Cytokines/immunology , Macrophages/immunology , SARS-CoV-2 , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , COVID-19/genetics , Colitis, Ulcerative/genetics , Colitis, Ulcerative/immunology , Colon/immunology , Crohn Disease/genetics , Crohn Disease/immunology , Humans , Inflammation/genetics , Inflammation/immunology , Lung/immunology , Lung Diseases, Interstitial/genetics , Lung Diseases, Interstitial/immunology , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , Phenotype , RNA-Seq
5.
Gastroenterology ; 160(3): 809-822.e7, 2021 02.
Article in English | MEDLINE | ID: covidwho-990009

ABSTRACT

BACKGROUND AND AIMS: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls. METHODS: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti-tumor necrosis factor and anti-interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted. RESULTS: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-tumor necrosis factor rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders. CONCLUSIONS: Reduced SB but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease, but normalized after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Anti-Inflammatory Agents/therapeutic use , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Intestines/drug effects , Tumor Necrosis Factor Inhibitors/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Anti-Inflammatory Agents/adverse effects , COVID-19/enzymology , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Child , Child, Preschool , Colitis, Ulcerative/enzymology , Colitis, Ulcerative/genetics , Colitis, Ulcerative/immunology , Crohn Disease/enzymology , Crohn Disease/genetics , Crohn Disease/immunology , Databases, Genetic , Female , Gene Expression Regulation, Enzymologic , Host-Pathogen Interactions , Humans , Intestines/enzymology , Intestines/immunology , Male , Middle Aged , North America , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/enzymology , SARS-CoV-2/immunology , Severity of Illness Index , Treatment Outcome , Tumor Necrosis Factor Inhibitors/adverse effects , Tumor Necrosis Factor-alpha/metabolism , Young Adult
6.
Gastroenterology ; 160(3): 925-928.e4, 2021 02.
Article in English | MEDLINE | ID: covidwho-977281
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