Population-based RNA profiling in Add Health finds social disparities in inflammatory and antiviral gene regulation to emerge by young adulthood

Cole, Steven W.; Shanahan, Michael J.; Gaydosh, Lauren; Harris, Kathleen Mullan

doi:10.1073/pnas.1821367117

Cited by 63 publications

(72 citation statements)

References 72 publications

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“…This cohort study of normal young adults demonstrated increased upregulation of interferon gene expression in Blacks and Asians relative to non-Hispanic whites. 39 We observed upregulation of interferon-responsive complement genes at onset of TA-TMA that returned to baseline after resolution of TA-TMA. These novel findings are in agreement with the highly inflammatory clinical phenotype of children presenting with severe TA-TMA, and may explain, at least in part, incomplete response to complement blocking therapy in some patients, especially after allogeneic transplant, despite achievement of therapeutic drug concentration in the blood.…”

Section: Discussionmentioning

confidence: 67%

Interferon-complement loop in transplant-associated thrombotic microangiopathy

et al. 2020

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Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

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Section: Discussionmentioning

confidence: 67%

Interferon-complement loop in transplant-associated thrombotic microangiopathy

et al. 2020

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“…Major immunological mechanisms in COVID-19 include: 19,20 This observation goes hand in hand with prevalence of lupus in these ethnicities, a predominantly type 1 IFN-driven disease.…”

Section: Ba S Ic Immune Inj Urie S In Covid -19 -A De Ja V U Of Lupmentioning

confidence: 99%

“…Body mass index (BMI) and smoking also increases type I IFN expression and inflammatory cytokines. 20 These 2 risk factors tend to adversely affect outcome of COVID-19 disease as well as lupus and other systemic autoimmune diseases. [21][22][23] These reports suggest that gender, ethnicity, BMI and smoking affect type I IFN secretion.…”

Section: F I G U R E 1 Comparison Of Demographic and Clinical Charactmentioning

confidence: 99%

Understanding immunopathological fallout of human coronavirus infections including COVID‐19: Will they cross the path of rheumatologists?

Kabeerdoss

Danda

2020

Int J of Rheum Dis

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19) is the biggest pandemic of our lifetime to date. No effective treatment is yet in sight for this catastrophic illness. Several antiviral agents and vaccines are in clinical trials, and drug repurposings as immediate and alternative choices are also under consideration. Immunomodulatory agents like hydroxychloroquine (HCQ) as well as biological disease-modifying anti-rheumatic drugs (bDMARDs) such as tocilizumab and anakinra received worldwide attention for treatment of critical patients with COVID-19. This is of interest to rheumatologists, who are well versed with rational use of these agents. This brief review addresses the understandings of some of the common immunopathogenetic mechanisms in the context of autoimmune rheumatic diseases like systemic lupus erythematosus (SLE) and COVID-19. Apart from demographic comparisons, the role of type I interferons (IFN), presence of antiphospholipid antibodies and finally mechanism of action of HCQ in both the scenarios are discussed here. High risks for fatal disease in COVID-19 include older age, metabolic syndrome, male gender, and individuals who develop delayed type I IFN response. HCQ acts by different mechanisms including prevention of cellular entry of SARS-CoV-2 and inhibition of type I IFN signaling. Recent controversies regarding efficacy of HCQ in management of COVID-19 warrant more studies in that direction. Autoantibodies were also reported in severe acute respiratory syndrome (SARS) as well as in COVID-19. Rheumatologists need to wait and see whether SARS-CoV-2 infection triggers development of autoimmunity in patients with COVID-19 infection in the long run.

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“…The CRTA is a stress response pathway mediated by the sympathetic nervous system and beta-adrenergic signaling to induce transcriptional activation of inflammatory genes in the immune system [31,34]. In a recent study of over 1,000 diverse and young adults, family poverty status was associated with transcription of interferon-response factors and immune cell activation of dendritic cells and may contribute to lifespan-related predisposition to inflammatory diseases and conditions [35].…”

Section: Introductionmentioning

confidence: 99%

The association between poverty and gene expression within peripheral blood mononuclear cells in a diverse Baltimore City cohort

et al. 2020

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Socioeconomic status (SES), living in poverty, and other social determinants of health contribute to health disparities in the United States. African American (AA) men living below poverty in Baltimore City have a higher incidence of mortality when compared to either white males or AA females living below poverty. Previous studies in our laboratory and elsewhere suggest that environmental conditions are associated with differential gene expression (DGE) patterns in peripheral blood mononuclear cells (PBMCs). DGE have also been associated with hypertension and cardiovascular disease (CVD) and correlate with race and sex. However, no studies have investigated how poverty status associates with DGE between male and female AAs and whites living in Baltimore City. We examined DGE in 52 AA and white participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) cohort, who were living above or below 125% of the 2004 federal poverty line at time of sample collection. We performed a microarray to assess DGE patterns in PBMCs from these participants. AA males and females living in poverty had the most genes differentially-expressed compared with above poverty controls. Gene ontology (GO) analysis identified unique and overlapping pathways related to the endosome, single-stranded RNA binding, long-chain fatty-acyl-CoA biosynthesis, toll-like receptor signaling, and others within AA males and females living in poverty and compared with their above poverty controls. We performed RT-qPCR to validate top differentially-expressed genes in AA males. We found that KLF6, DUSP2, RBM34, and CD19 are expressed at significantly lower levels in AA males in poverty and KCTD12 is higher compared to above poverty controls. This study serves as an additional link to better understand the gene expression response in peripheral blood mononuclear cells in those living in poverty.

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Population-based RNA profiling in Add Health finds social disparities in inflammatory and antiviral gene regulation to emerge by young adulthood

Cited by 63 publications

References 72 publications

Interferon-complement loop in transplant-associated thrombotic microangiopathy

Interferon-complement loop in transplant-associated thrombotic microangiopathy

Understanding immunopathological fallout of human coronavirus infections including COVID‐19: Will they cross the path of rheumatologists?

The association between poverty and gene expression within peripheral blood mononuclear cells in a diverse Baltimore City cohort

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