Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome

Waugh, Katherine A.; Araya, Paula; Pandey, Ahwan; Jordan, Kimberly R.; Smith, Keith P; Granrath, Ross E; Khanal, Santosh; Butcher, Eric T.; Estrada, Belinda Enriquez; Rachubinski, Angela L.; McWilliams, Jennifer A.; Minter, Ross; Dimasi, Tiana; Colvin, Kelley L.; Baturin, Dmitry; Pham, Andrew T.; Galbraith, Matthew D.; Bartsch, Kyle W; Yeager, Michael E.; Porter, Christopher C.; Sullivan, Kelly D.; Hsieh, Elena W.Y.; Espinosa, Joaquín M.

doi:10.1016/j.celrep.2019.10.038

Cited by 104 publications

(164 citation statements)

References 81 publications

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“…Also in this issue, Kong et al elegantly show that the cluster of genes encoding type I IFN receptor, one subunit of type II IFN receptor, and one subunit of type III IFN receptor contribute to mild hyperactivity of the respective pathways [6], which is in line with the previous reports [7,8]. Interestingly, Kong et al note that only 12% of individuals with DS have detectably increased levels of circulating type I IFN cytokine, but most have increased levels of ISGs in peripheral blood.…”

supporting

confidence: 82%

Bourgeoning Scientific Research in Down Syndrome

Bogunovic

2020

J Clin Immunol

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supporting

confidence: 82%

Bourgeoning Scientific Research in Down Syndrome

Bogunovic

2020

J Clin Immunol

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“…Over-activation and hypersensitivity to interferon (IFN) signaling, resulting from increased expression of IFN-related genes located on Hsa21 (including IFNAR1, IFNAR2, IFNGR2 and IL10RB) outside of the DSCR region, has been observed in multiple cell types in individuals with DS [110]. During adulthood, individuals with DS display a perturbed immune system, consistent with a state of chronic inflammation [111,112]. IFN and inflammatory response transcriptional signatures have been recently observed in murine and human trisomic hematopoietic progenitors, as well as in DS-ALL samples [81] (Laurent A. and Malinge S., unpublished observations), and may be partly mediated by the microenvironment.…”

Section: Signaling Effectorsmentioning

confidence: 99%

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

2020

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Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor constitutive trisomy 21, highlight the link between gain of chromosome 21 and leukemogenesis, with an increased risk of developing acute leukemia compared with other children. Clinical outcomes for DS-associated leukemia have improved over the years through the development of uniform treatment protocols facilitated by international cooperative groups. The genetic landscape has also recently been characterized, providing an insight into the molecular pathogenesis underlying DS-associated leukemia. These studies emphasize the key role of trisomy 21 in priming a developmental stage and cellular context susceptible to transformation, and have unveiled its cooperative function with additional genetic events that occur during leukemia progression. Here, using DS-leukemia as a paradigm, we aim to integrate our current understanding of the role of trisomy 21, of critical dosage-sensitive chromosome 21 genes, and of associated mechanisms underlying the development of hematological malignancies. This review will pave the way for future investigations on the broad impact of gain of chromosome 21 in hematological cancer, with a view to discovering new vulnerabilities and develop novel targeted therapies to improve long term outcomes for DS and non-DS patients.

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“…The average age of death in individuals with DS has been estimated around 60 years of age (Covelli, Raggi, Meucci, Paganelli, & Leonardi, 2016). interferon-driven upregulation of IL-10, an immunosuppressive cytokine known to weaken the antibacterial defenses in the lung (Waugh et al, 2019) and bacterial pneumonia is a leading cause of death in this population (Uppal et al, 2015). Moreover, at a systemic level, they also present an increased immune response to lipopolysaccharide (LPS) that may contribute to more severe outcomes, leading to up to 30% greater sepsis mortality among individuals with DS than the general population (Huggard et al, 2018 values, or both.…”

Section: Other Characteristics Of Individuals With Ds Deceased Withmentioning

confidence: 99%

Clinical characteristics of individuals with Down syndrome deceased with CoVID‐19 in Italy—A case series

Villani

Carfì

Paola

et al. 2020

American J of Med Genetics Pt A

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BACKGROUND: Persons with Down syndrome (DS) are presumed to be at high risk of severe CoVID-19, due to immune dysregulation and often compromised cardiopulmonary function. Aim of the present study is to assess epidemiological and clinical characteristics of individuals with DS deceased in Italian hospitals with CoVID-19. METHODS: We used a nationwide database of 3,438 patients deceased with RT-PCR-confirmed SARS-CoV-2 infection in Italy (10.4% of all deaths with CoVID-19 in the country at the time of analysis). Data on demographics, pre-existing comorbidities and in-hospital complications leading to death were extracted from medical charts obtained from hospitals. Data on individuals with DS deceased with CoVID-19 were obtained from this sample. RESULTS: Sixteen cases of death in individuals with DS (0.5% of all charts analyzed) were identified. Acute respiratory distress syndrome occurred in all 16 cases. Compared with individuals without DS, those with DS deceased with CoVID-19 were younger (52.3 ± 7.3 vs. 78.1 ± 10.6 years, p < .001) and presented a higher incidence of superinfections (31.2 vs. 13.0%, p = .029). Autoimmune diseases (43.8 vs. 4%, p < .001), obesity (37.5 vs. 11%, p = .009), and dementia (37.5 vs. 16.3%, p = .012

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Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome

Cited by 104 publications

References 81 publications

Bourgeoning Scientific Research in Down Syndrome

Bourgeoning Scientific Research in Down Syndrome

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

Clinical characteristics of individuals with Down syndrome deceased with CoVID‐19 in Italy—A case series

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