Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children

Vagrecha, Anshul; Zhang, Mingce; Acharya, Suchitra S.; Lozinsky, Shannon; Singer, Aaron; Levine, Chana; Al-Ghafry, Maha; Levy, Carolyn Fein; Cron, Randy Q.

doi:10.3390/biology11030417

Cited by 25 publications

(63 citation statements)

References 39 publications

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“…Those genes include PRF1 , that we found mutated in 5 patients with MIS-C and previously in 20 patients with autoinflammatory diseases, all bearing the pathogenic Ala91Val mutation that seems to be peculiar to Southern Italy and NOD2 (mutated in two MIS-C patients - one of which compound heterozygous for two different mutations). Our results are in agreement with a recent report documenting HLH associated gene (including DOCK8 and PRF1 ) mutations identified in children with MIS-C ( 34 ). Of interest, one MIS-C patient was heterozygous for three mutations in the MEFV gene.…”

Section: Discussionsupporting

confidence: 94%

MIS-C: A COVID-19-as sociated condition between hypoimmunity and hyperimmunity

et al. 2022

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Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-β, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.

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Section: Discussionsupporting

confidence: 94%

MIS-C: A COVID-19-as sociated condition between hypoimmunity and hyperimmunity

et al. 2022

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“…The median age of children affected by MIS-C, clinical features and prevalence of comorbidities are in accordance with those of previously published cohorts (Ahmed et al 2020 ; Feldstein et al 2020 , Lee et al 2020 ; Chou et al 2021 ; Sancho-Shimizu et al 2021 ). However, similar to Vagrecha et al ( 2022 ), we found a clear male preponderance (68.7%) in our MIS-C cohort. The male sex bias is also evident for COVID-19 hospitalization and death, compared to females (The Sex, Gender and COVID-19 Project, 2022).…”

Section: Discussionsupporting

confidence: 92%

“…The STRING v.11.5 database was used to recover the Protein–Protein Interactions (PPIs) of each mutated gene, and Cytoscape software 3.7.1 (Shannon et al 2003 ) was applied to plot the network. Next, the retrieved genes were cross-referenced with those in a dataset of 19 genes, in which variants or abnormal mRNA expression were previously associated with MIS-C (Lee et al 2020 ; Chou et al 2021 ; Beckmann et al 2021 ; Abolhassani et al 2022 ; Vagrecha et al 2022 ) and 14 genes for which genome-wide studies found an association with Kawasaki disease (Sancho-Shimizu et al 2021 ) (Additional file 1 : Table S1). Direct interactions with a confidence score > 0.4 were considered for further enrichment analysis by the web server EnrichR ( https://maayanlab.cloud/Enrichr/ ).…”

Section: Methodsmentioning

confidence: 99%

Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children

Santos-Rebouças

Piergiorge

Ferreira

et al. 2022

Mol Med

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Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which manifests as a hyper inflammatory process with multiorgan involvement in predominantly healthy children in the weeks following mild or asymptomatic coronavirus disease 2019 (COVID-19). However, host monogenic predisposing factors to MIS-C remain elusive. Methods Herein, we used whole exome sequencing (WES) on 16 MIS-C Brazilian patients to identify single nucleotide/InDels variants as predisposition factors associated with MIS-C. Results We identified ten very rare variants in eight genes (FREM1, MPO, POLG, C6, C9, ABCA4, ABCC6, and BSCL2) as the most promising candidates to be related to a higher risk of MIS-C development. These variants may propitiate a less effective immune response to infection or trigger the inflammatory response or yet a delayed hyperimmune response to SARS-CoV-2. Protein–Protein Interactions (PPIs) among the products of the mutated genes revealed an integrated network, enriched for immune and inflammatory response mechanisms with some of the direct partners representing gene products previously associated with MIS-C and Kawasaki disease (KD). In addition, the PPIs direct partners are also enriched for COVID-19-related gene sets. HLA alleles prediction from WES data allowed the identification of at least one risk allele in 100% of the MIS-C patients. Conclusions This study is the first to explore host MIS-C-associated variants in a Latin American admixed population. Besides expanding the spectrum of MIS-C-associated variants, our findings highlight the relevance of using WES for characterising the genetic interindividual variability associated with COVID-19 complications and ratify the presence of overlapping/convergent mechanisms among MIS-C, KD and COVID-19, crucial for future therapeutic management.

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“…TLR3, IFNB1) were identified among a cohort of MIS-C children from the Middle East [29]. Previously, haploinsufficiency in SOCS1 (suppressor of cytokine signaling 1) was reported in children with MIS-C [30 ]. The same group of investigators also identified a boy with MIS-C possessing a missense mutation in the X-linked gene XIAP & ], a newly proposed HLH gene [18,34 ,35].…”

Section: Key Pointsmentioning

confidence: 99%

Biologic disease-modifying antirheumatic drugs to treat multisystem inflammatory syndrome in children

Cron

2022

Current Opinion in Rheumatology

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Purpose of reviewMultisystem inflammatory syndrome in children (MIS-C) is a postinfectious complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily affecting children. MIS-C shares features with Kawasaki disease (KD) and cytokine storm syndrome (CSS) frequently requiring intensive care support. Although intravenous immunoglobulin (IVIg) and glucocorticoids (GCs) are effective therapeutics for most, refractory MIS-C is treated with various biologic disease-modifying antirheumatic drugs (bDMARDs). Understanding the clinical features, inflammatory cytokines, and genetic associations provides rationale for bDMARD in treating severe MIS-C. Recent findingsChildren with MIS-C have clinical KD features and often present in hypovolemic and cardiogenic shock requiring volume repletion (gastrointestinaI losses) and cardiac pressor support (epinephrine). Investigation of MIS-C serum reveals elevated pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18, interferon gamma (IFNg), tumor necrosis factor (TNF)], but to a lesser extent than other established CSS. Gene sequencing of MIS-C children identifies heterozygous mutations in CSS associated genes. Treatment of refractory (IVIg and GC) MIS-C with bDMARDs to IL-1, IL-6, and TNF is efficacious for survival as well as resolving cardiac and coronary artery inflammation. Summary MIS-C is a postinfectious complication of SARS-CoV-2 resembling KD and CSS, both genetically and by pro-inflammatory cytokines. MIS-C that is refractory to IVIg and GC is routinely responsive to bDMARDs targeting IL-1, IL-6, and TNF.

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Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children

Cited by 25 publications

References 39 publications

MIS-C: A COVID-19-as sociated condition between hypoimmunity and hyperimmunity

MIS-C: A COVID-19-as sociated condition between hypoimmunity and hyperimmunity

Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children

Biologic disease-modifying antirheumatic drugs to treat multisystem inflammatory syndrome in children

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