Publications by authors named "Moshe Arditi"

139 Publications

HLA class I-associated expansion of TRBV11-2 T cells in Multisystem Inflammatory Syndrome in Children.

J Clin Invest 2021 Mar 11. Epub 2021 Mar 11.

Cedars-Sinai Medical Center, Los Angeles, United States of America.

Multisystem Inflammatory Syndrome in Children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vβ-chains results in Vβ-skewing, whereby T cells with specific Vβ-chains and diverse antigen specificity are overrepresented in the TCR repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR Βeta Variable gene (TRBV)11-2, with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and CDR3 length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion showed HLA class I allele restriction to HLA-I A02, C35 and C04, indicating a novel mechanism for CDR3-independent T cell expansion. In silico modelling indicated that polyacidic residues in the Vβ chain encoded by TRBV11-2 strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.
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http://dx.doi.org/10.1172/JCI146614DOI Listing
March 2021

Characterization of the T Cell Response to Cell Wall Extract in Children With Kawasaki Disease and Its Potential Role in Vascular Inflammation.

Front Pediatr 2021 19;9:633244. Epub 2021 Feb 19.

Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, La Jolla, CA, United States.

KD is an acute febrile illness and systemic vasculitis of unknown etiology among young children, which can cause coronary artery abnormalities and aneurysms (CAA) and is the leading cause of acquired heart disease among children in the US. cell wall extract (LCWE) induces in mice a vasculitis following intraperitoneal injection defined by the activation of macrophages, dendritic cells and CD8+ cytotoxic T cells leading to aortitis, coronary arteritis, aneurysms and myocarditis that strongly mimic the immunopathology and the cardiac lesions observed in children with Kawasaki disease (KD). To address a potential pathogenic role of LCWE-specific T cells in human vascular inflammation, we studied the activation of circulating CD4+ and CD8+ T cells in response to LCWE in 3 cohorts: (1) KD children 2-3 weeks after fever onset, (2) age-similar healthy children controls, (3) healthy adult controls. In all subjects studied, pro-inflammatory CD4+ and CD8+T cells responded to LCWE with no significant differences. Peripherally-induced regulatory T cells (iTreg) also responded to LCWE and potentially reverted to Th17, as suggested by the detection of IL-17 in culture supernatants. Central memory T cells were also detectable and were more abundant in adults. The potential homing to the vessels of LCWE-specific T cells was suggested by the expression of CCR6 and CD31. In conclusion, a non-pathogenic, LCWE-specific T cell repertoire could lead to KD depending upon priming conditions, genetic factors and immune activation by other antigens.
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http://dx.doi.org/10.3389/fped.2021.633244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933244PMC
February 2021

Seroprevalence of antibodies to SARS-CoV-2 in healthcare workers: a cross-sectional study.

BMJ Open 2021 02 12;11(2):e043584. Epub 2021 Feb 12.

Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California, USA

Objective: We sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers.

Design: Observational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires.

Settings: A multisite healthcare delivery system located in Los Angeles County.

Participants: A diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions.

Main Outcomes: Using Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection.

Results: We observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, p<0.001) in addition to fever (OR 2.02, p=0.002) and myalgias (OR 1.65, p=0.035). After adjusting for potential confounders, seroprevalence was also associated with Hispanic ethnicity (OR 1.98, p=0.001) and African-American race (OR 2.02, p=0.027) as well as contact with a COVID-19-diagnosed individual in the household (OR 5.73, p<0.001) or clinical work setting (OR 1.76, p=0.002). Importantly, African-American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal COVID-19 diagnosis status, suggesting the contribution of unmeasured structural or societal factors.

Conclusion And Relevance: The demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19.
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http://dx.doi.org/10.1136/bmjopen-2020-043584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883610PMC
February 2021

SARS-CoV-2 specific antibody and neutralization assays reveal the wide range of the humoral immune response to virus.

Commun Biol 2021 01 29;4(1):129. Epub 2021 Jan 29.

Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

Development of antibody protection during SARS-CoV-2 infection is a pressing question for public health and for vaccine development. We developed highly sensitive SARS-CoV-2-specific antibody and neutralization assays. SARS-CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n = 115) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. SARS-CoV-2 neutralization was determined in COVID-19 and convalescent plasma at up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which were also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Interestingly, some COVID-19 patients also possessed NAbs against SARS-CoV Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.
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http://dx.doi.org/10.1038/s42003-021-01649-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846565PMC
January 2021

Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation.

Proc Natl Acad Sci U S A 2021 Jan;118(1)

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)-deficient macrophages have reduced caspase-1 activity and diminished IL-1β release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b-dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1β production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α-CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.
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http://dx.doi.org/10.1073/pnas.2015632118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817159PMC
January 2021

A monoclonal antibody against staphylococcal enterotoxin B superantigen inhibits SARS-CoV-2 entry .

bioRxiv 2020 Nov 24. Epub 2020 Nov 24.

We recently discovered a superantigen-like motif, similar to Staphylococcal enterotoxin B (SEB), near the S1/S2 cleavage site of SARS-CoV-2 Spike protein, which might explain the multisystem-inflammatory syndrome (MIS-C) observed in children and cytokine storm in severe COVID-19 patients. We show here that an anti-SEB monoclonal antibody (mAb), 6D3, can bind this viral motif, and in particular its PRRA insert, to inhibit infection by blocking the access of host cell proteases, TMPRSS2 or furin, to the cleavage site. The high affinity of 6D3 for the furin-cleavage site originates from a poly-acidic segment at its heavy chain CDR2, a feature shared with SARS-CoV-2-neutralizing mAb 4A8. The affinity of 6D3 and 4A8 for this site points to their potential utility as therapeutics for treating COVID-19, MIS-C, or common cold caused by human coronaviruses (HCoVs) that possess a furin-like cleavage site.
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http://dx.doi.org/10.1101/2020.11.24.395079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709177PMC
November 2020

BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of health care workers.

J Clin Invest 2021 01;131(2)

Department of Pediatrics, Division of Infectious Diseases and Immunology, Infectious and Immunologic Diseases Research Center (IIDRC), and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.

BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 1 million deaths worldwide; thus, there is an urgent need to develop preventive and therapeutic strategies. The antituberculosis vaccine bacillus Calmette-Guérin (BCG) demonstrates nonspecific, protective innate immune-boosting effects. Here, we determined whether a history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a longitudinal, retrospective observational study of a diverse cohort of health care workers (HCWs).METHODSWe assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, which included information on BCG vaccination status and preexisting demographic and clinical characteristics, from an observational cohort of HCWs in a multisite Los Angeles health care organization. We used multivariate analysis to determine whether a history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion.RESULTSOf the 6201 HCWs, 29.6% reported a history of BCG vaccination, whereas 68.9% had not received BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as the incidence of self-reported clinical symptoms associated with coronavirus disease 2019 (COVID-19) were markedly decreased among HCWs with a history of BCG vaccination compared with those without BCG vaccination. After adjusting for age and sex, we found that a history of BCG vaccination, but not meningococcal, pneumococcal, or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion.CONCLUSIONSA history of BCG vaccination was associated with a decrease in the seroprevalence of anti-SARS-CoV-2 IgG and a lower number of participants who self-reported experiencing COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized, prospective clinical trials of BCG vaccination are urgently needed to confirm whether BCG vaccination can confer a protective effect against SARS-CoV-2 infection.
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http://dx.doi.org/10.1172/JCI145157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810479PMC
January 2021

Identification of a unique TCR repertoire, consistent with a superantigen selection process in Children with Multi-system Inflammatory Syndrome.

bioRxiv 2020 Nov 9. Epub 2020 Nov 9.

Multisystem Inflammatory Syndrome in Children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares many clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. The superantigen specificity for binding different Vβ-chains results in Vβ-skewing, whereby T cells with specific Vβ-chains and diverse antigen specificity are overrepresented in the TCR repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR Beta Variable gene (TRBV)11-2. Furthermore, TRBV11-2 skewing was remarkably correlated with MIS-C severity and serum cytokine levels. Further analysis of TRBJ gene usage and CDR3 length distribution of MIS-C expanding TRBV11-2 clones revealed extensive junctional diversity, indicating a superantigen-mediated selection process for TRBV expansion. modelling indicates that polyacidic residues in TCR Vβ11-2 engage in strong interactions with the superantigen-like motif of SARS-CoV-2 spike glycoprotein. Overall, our data indicate that the immune response in MIS-C is consistent with superantigenic activation.

Highlights: Multisystem Inflammatory Disease in Children (MIS-C) patients exhibit T cell receptor (TCR) repertoire skewing, with expansion of T cell Receptor Beta Variable gene (TRBV)11-2TRBV11-2 skewing correlates with MIS-C severity and cytokine stormJ gene/CDR3 diversity in MIS-C patients is compatible with a superantigen selection process modelling indicates TCR Vβ11-2 engages in CDR3-independent interactions with the polybasic insert P RRAR in the SAg-like motif of SARS-CoV-2 spike.
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http://dx.doi.org/10.1101/2020.11.09.372169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668738PMC
November 2020

Inositol-requiring enzyme-1 regulates phosphoinositide signaling lipids and macrophage growth.

EMBO Rep 2020 12 2;21(12):e51462. Epub 2020 Nov 2.

Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P ) 5-phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P levels in macrophages. The modulation of cellular PI(3,4,5)P /PIP ratio and anabolic mTOR signaling by the IRE1-induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.
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http://dx.doi.org/10.15252/embr.202051462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726810PMC
December 2020

Multisystem Inflammatory Syndrome in Children in the United States.

N Engl J Med 2020 10 21;383(18):1794. Epub 2020 Oct 21.

University of Pittsburgh School of Medicine, Pittsburgh, PA.

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http://dx.doi.org/10.1056/NEJMc2026136DOI Listing
October 2020

COVID-19-associated multisystem inflammatory syndrome in children (MIS-C): A novel disease that mimics toxic shock syndrome-the superantigen hypothesis.

J Allergy Clin Immunol 2021 01 16;147(1):57-59. Epub 2020 Oct 16.

Division of Pediatric Infectious Diseases and Immunology, Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, Calif; Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, Calif; Cedars-Sinai Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, Calif. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564502PMC
January 2021

Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model.

Front Immunol 2020 24;11:554725. Epub 2020 Sep 24.

Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2'-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. mice showed increased influx of Ly6C monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of mice had significantly higher expression of type I IFN genes (, and ). In keeping with loss of resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent expression was observed in BMDMs from mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced expression in monocytes associated with skin involvement in SLE patients and the expression of was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.
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http://dx.doi.org/10.3389/fimmu.2020.554725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541920PMC
September 2020

Superantigenic character of an insert unique to SARS-CoV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation.

Proc Natl Acad Sci U S A 2020 10 28;117(41):25254-25262. Epub 2020 Sep 28.

Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213;

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in children with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These children and adult patients with severe hyperinflammation present with a constellation of symptoms that strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to T cell receptors (TCRs) and/or major histocompatibility complex class II (MHCII) molecules. Here, using structure-based computational models, we demonstrate that the SARS-CoV-2 spike (S) glycoprotein exhibits a high-affinity motif for binding TCRs, and may form a ternary complex with MHCII. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in other SARS-related coronaviruses), which is highly similar in both sequence and structure to the bacterial superantigen staphylococcal enterotoxin B. This interaction between the virus and human T cells could be strengthened by a rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from an intercellular adhesion molecule (ICAM)-like motif shared between the SARS viruses from the 2003 and 2019 pandemics. A neurotoxin-like sequence motif on the receptor-binding domain also exhibits a high tendency to bind TCRs. Analysis of the TCR repertoire in adult COVID-19 patients demonstrates that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen activation. These data suggest that SARS-CoV-2 S may act as a superantigen to trigger the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.
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http://dx.doi.org/10.1073/pnas.2010722117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568239PMC
October 2020

Immune pathogenesis of COVID-19-related multisystem inflammatory syndrome in children.

J Clin Invest 2020 Nov;130(11):5619-5621

Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, and.

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http://dx.doi.org/10.1172/JCI143840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598032PMC
November 2020

C9orf72 in myeloid cells suppresses STING-induced inflammation.

Nature 2020 09 19;585(7823):96-101. Epub 2020 Aug 19.

Center for Neural Science and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells. Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72 mice show marked early activation of the type I interferon response, and C9orf72 myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72 myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72 immune cells as well as splenomegaly and inflammation in C9orf72 mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.
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http://dx.doi.org/10.1038/s41586-020-2625-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484469PMC
September 2020

Phase II Open Label Study of Anakinra in Intravenous Immunoglobulin-Resistant Kawasaki Disease.

Arthritis Rheumatol 2021 01 17;73(1):151-161. Epub 2020 Nov 17.

AP-HP, University of Paris Saclay, Bicêtre Hospital, Paris, France.

Objective: Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous immunoglobulin (IVIG)- and steroid-resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin-1 in patients with IVIG-resistant KD.

Methods: Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient's body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C-reactive protein (CRP) levels.

Results: Seventy-five percent of patients in the intention-to-treat group and 87.5% in the per-protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval [95% CI] 68.1-99.8%) of physician evaluations and on 100% (95% CI 73.5-100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. At day 45, 5 of 10 patients (50% [95% CI 18.7-81.3%]) and 6 of 12 patients (50% [95% CI 21.1-78.9%]) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred.

Conclusion: Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG-refractory KD.
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http://dx.doi.org/10.1002/art.41481DOI Listing
January 2021

Novel SARS-CoV-2 specific antibody and neutralization assays reveal wide range of humoral immune response during COVID-19.

medRxiv 2020 Jul 8. Epub 2020 Jul 8.

Development of antibody protection during SARS-CoV-2 (CoV-2) infection is a pressing question for public health and for vaccine development. We developed highly sensitive CoV-2-specific antibody and neutralization assays. CoV-2 Spike protein or Nucleocapsid protein specific IgG antibodies at titers more than 1:100,000 were detectable in all PCR+ subjects (n=87) and were absent in the negative controls. Other isotype antibodies (IgA, IgG1-4) were also detected. CoV-2 neutralization was determined in COVID-19 and convalescent plasma up to 10,000-fold dilution, using Spike protein pseudotyped lentiviruses, which was also blocked by neutralizing antibodies (NAbs). Hospitalized patients had up to 3000-fold higher antibody and neutralization titers compared to outpatients or convalescent plasma donors. Further, subjects who donated plasma further out from the diagnosis of COVID-19 appeared to have lower titers. Interestingly, some COVID-19 patients also contained NAbs against SARS Spike protein pseudovirus. Together these results demonstrate the high specificity and sensitivity of our assays, which may impact understanding the quality or duration of the antibody response during COVID-19 and in determining the effectiveness of potential vaccines.
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http://dx.doi.org/10.1101/2020.07.07.20148106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359542PMC
July 2020

Sex-Specific Effects of the Nlrp3 Inflammasome on Atherogenesis in LDL Receptor-Deficient Mice.

JACC Basic Transl Sci 2020 Jun 20;5(6):582-598. Epub 2020 May 20.

Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, California.

In the mouse model of atherosclerosis, female bone marrow chimera and mice developed significantly smaller lesions in the aortic sinus and decreased lipid content in aorta en face, but a similar protection was not observed in males. Ovariectomized female mice lost protection from atherosclerosis in the setting of NLRP3 deficiency, whereas atherosclerosis showed a greater dependency on NLRP3 in castrated males. Thus, castration increased the dependency of atherosclerosis on the NLRP3 inflammasome, suggesting that testosterone may block inflammation in atherogenesis. Conversely, ovariectomy reduced the dependency on NLRP3 inflammasome components for atherogenesis, suggesting that estrogen may promote inflammasome-mediated atherosclerosis.
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http://dx.doi.org/10.1016/j.jacbts.2020.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315187PMC
June 2020

An insertion unique to SARS-CoV-2 exhibits superantigenic character strengthened by recent mutations.

bioRxiv 2020 May 21. Epub 2020 May 21.

Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with Coronavirus Disease 2019 (COVID-19) is a newly recognized condition in which children with recent SARS-CoV-2 infection present with a constellation of symptoms including hypotension, multiorgan involvement, and elevated inflammatory markers. These symptoms and the associated laboratory values strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to MHCII molecules and T cell receptors (TCRs). Here, we used structure-based computational models to demonstrate that the SARS-CoV-2 spike (S) exhibits a high-affinity motif for binding TCR, interacting closely with both the α- and β-chains variable domains' complementarity-determining regions. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in any other SARS coronavirus), which is highly similar in both sequence and structure to bacterial superantigens. Further examination revealed that this interaction between the virus and human T cells is strengthened in the context of a recently reported rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from a motif shared between the SARS viruses from the 2003 and 2019 pandemics, which has intracellular adhesion molecule (ICAM)-like character. These data suggest that the SARS-CoV-2 S may act as a superantigen to drive the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.
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http://dx.doi.org/10.1101/2020.05.21.109272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263503PMC
May 2020

Kawasaki disease: pathophysiology and insights from mouse models.

Nat Rev Rheumatol 2020 07 26;16(7):391-405. Epub 2020 May 26.

Departments of Pediatrics, Division of Infectious Diseases and Immunology, and Infectious and Immunologic Diseases Research Center (IIDRC), Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Kawasaki disease is an acute febrile illness and systemic vasculitis of unknown aetiology that predominantly afflicts young children, causes coronary artery aneurysms and can result in long-term cardiovascular sequelae. Kawasaki disease is the leading cause of acquired heart disease among children in the USA. Coronary artery aneurysms develop in some untreated children with Kawasaki disease, leading to ischaemic heart disease and myocardial infarction. Although intravenous immunoglobulin (IVIG) treatment reduces the risk of development of coronary artery aneurysms, some children have IVIG-resistant Kawasaki disease and are at increased risk of developing coronary artery damage. In addition, the lack of specific diagnostic tests and biomarkers for Kawasaki disease make early diagnosis and treatment challenging. The use of experimental mouse models of Kawasaki disease vasculitis has considerably improved our understanding of the pathology of the disease and helped characterize the cellular and molecular immune mechanisms contributing to cardiovascular complications, in turn leading to the development of innovative therapeutic approaches. Here, we outline the pathophysiology of Kawasaki disease and summarize and discuss the progress gained from experimental mouse models and their potential therapeutic translation to human disease.
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http://dx.doi.org/10.1038/s41584-020-0426-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250272PMC
July 2020

Platelets Fuel the Inflammasome Activation of Innate Immune Cells.

Cell Rep 2020 05;31(6):107615

Institute of Innate Immunity, Medical Faculty, University of Bonn, 53127 Bonn, NRW, Germany. Electronic address:

The inflammasomes control the bioactivity of pro-inflammatory cytokines of the interleukin (IL)-1 family. The inflammasome assembled by NLRP3 has been predominantly studied in homogeneous cell populations in vitro, neglecting the influence of cellular interactions that occur in vivo. Here, we show that platelets boost the inflammasome capacity of human macrophages and neutrophils and are critical for IL-1 production by monocytes. Platelets license NLRP3 transcription, thereby enhancing ASC oligomerization, caspase-1 activity, and IL-1β secretion. Platelets influence IL-1β production in vivo, and blood platelet counts correlate with plasmatic IL-1β levels in malaria. Furthermore, we reveal an enriched platelet gene signature among the highest-expressed transcripts in IL-1β-driven autoinflammatory diseases. The platelet effect is independent of cell-to-cell contact, platelet-derived lipid mediators, purines, nucleic acids, and a host of platelet cytokines, and it involves the triggering of calcium-sensing receptors on macrophages. Hence, platelets provide an additional layer of regulation of inflammasomes and IL-1-driven inflammation.
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http://dx.doi.org/10.1016/j.celrep.2020.107615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225754PMC
May 2020

Loss of testosterone impairs anti-tumor neutrophil function.

Nat Commun 2020 03 31;11(1):1613. Epub 2020 Mar 31.

Department of Pediatrics, Division of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.
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http://dx.doi.org/10.1038/s41467-020-15397-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109066PMC
March 2020

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury.

Front Immunol 2020 14;11:207. Epub 2020 Feb 14.

Division of Infectious Diseases and Immunology, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Targeting inflammasome activation to modulate interleukin (IL)-1β is a promising treatment strategy against acute respiratory distress syndrome and ventilator-induced lung injury (VILI). Autophagy is a key regulator of inflammasome activation in macrophages. Here, we investigated the role of autophagy in the development of acute lung injury (ALI) induced by lipopolysaccharide (LPS) and mechanical ventilation (MV). Two hours before starting MV, 0.2 mg/kg LPS was administered to mice intratracheally. Mice were then placed on high-volume MV (30 ml/kg with 3 cmHO positive end-expiratory pressure for 2.5 h without additional oxygen application). Mice with myeloid-specific deletion of the autophagic protein ATG16L1 () suffered severe hypoxemia (adjusted < 0.05) and increased lung permeability ( < 0.05, albumin level in bronchoalveolar lavage fluid) with significantly higher IL-1β release into alveolar space ( < 0.05). Induction of autophagy by fasting-induced starvation led to improved arterial oxygenation (adjusted < 0.0001) and lung permeability ( < 0.05), as well as significantly suppressed IL-1β production ( < 0.01). Intratracheal treatment with anti-mouse IL-1β monoclonal antibody (mAb; 2.5 mg/kg) significantly improved arterial oxygenation (adjusted < 0.01) as well as lung permeability ( < 0.05). On the other hand, deletion of IL-1α gene or use of anti-mouse IL-1α mAb (2.5 mg/kg) provided no significant protection, suggesting that the LPS and MV-induced ALI is primarily dependent on IL-1β, but independent of IL-1α. These observations suggest that autophagy has a protective role in controlling inflammasome activation and production of IL-1β, which plays a critical role in developing hypoxemia and increased lung permeability in LPS plus MV-induced acute lung injury.
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http://dx.doi.org/10.3389/fimmu.2020.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033480PMC
March 2021

A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis.

Curr Rheumatol Rep 2020 02 5;22(2). Epub 2020 Feb 5.

Division of Pediatric Infectious Diseases and Immunology; Burns and Allen Research Institute, Cedars-Sinai Medical Center and David Geffen School of Medicine at UCLA, Los Angeles, CA, 90048, USA.

Purpose Of The Review: Kawasaki disease (KD) is a childhood systemic vasculitis of unknown etiology that causes coronary artery aneurysms (CAA), and if left undiagnosed can result in long-term cardiovascular complications and adult cardiac disease. Up to 20% of KD children fail to respond to IVIG, the mainstay of therapy, highlighting the need for novel therapeutic strategies. Here we review the latest findings in the field regarding specific etiology, genetic associations, and advancements in treatment strategies to prevent coronary aneurysms.

Recent Findings: Recent discoveries using the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model have accelerated the study of KD pathophysiology and have advanced treatment strategies including clinical trials for IL-1R antagonist, Anakinra. KD remains an elusive pediatric vasculitis syndrome and is the leading cause of acquired heart disease among children in the USA and developed countries. Advancements in combination treatment for refractory KD with further understanding of novel genetic risk factors serve as a solid foundation for future research endeavors in the field.
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http://dx.doi.org/10.1007/s11926-020-0882-1DOI Listing
February 2020

Interleukin-1 Beta-Mediated Sex Differences in Kawasaki Disease Vasculitis Development and Response to Treatment.

Arterioscler Thromb Vasc Biol 2020 03 30;40(3):802-818. Epub 2020 Jan 30.

From the Division of Infectious Diseases and Immunology, Department of Pediatrics (R.A.P., J.L.M., D.M., B.K., S.C., Y.L., M.N.R., M.A.), Cedars-Sinai Medical Center, Los Angeles, CA.

Objective: Kawasaki disease (KD) is the leading cause of acute vasculitis and acquired heart disease in children in developed countries. Notably, KD is more prevalent in males than females. We previously established a key role for IL (interleukin)-1 signaling in KD pathogenesis, but whether this pathway underlies the sex-based difference in susceptibility is unknown. Approach and Results: The role of IL-1 signaling was investigated in the cell wall extract-induced experimental mouse model of KD vasculitis. Five-week-old male and female mice were injected intraperitoneally with PBS, cell wall extract, or a combination of cell wall extract and the IL-1 receptor antagonist Anakinra. Aortitis, coronary arteritis inflammation score and abdominal aorta dilatation, and aneurysm development were assessed. mRNA-seq (messenger RNA sequencing) analysis was performed on abdominal aorta tissue. Publicly available human transcriptomics data from patients with KD was analyzed to identify sex differences and disease-associated genes. Male mice displayed enhanced aortitis and coronary arteritis as well as increased incidence and severity of abdominal aorta dilatation and aneurysm, recapitulating the increased incidence in males that is observed in human KD. Gene expression data from patients with KD and abdominal aorta tissue of cell wall extract-injected mice showed enhanced expression and IL-1 signaling genes in males. Although the more severe IL-1β-mediated disease phenotype observed in male mice was ameliorated by Anakinra treatment, the milder disease phenotype in female mice failed to respond.

Conclusions: IL-1β may play a central role in mediating sex-based differences in KD, with important implications for the use of anti-IL-1β therapies to treat male and female patients with KD.
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http://dx.doi.org/10.1161/ATVBAHA.119.313863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047651PMC
March 2020

Intestinal Permeability and IgA Provoke Immune Vasculitis Linked to Cardiovascular Inflammation.

Immunity 2019 09 27;51(3):508-521.e6. Epub 2019 Aug 27.

Division of Pediatric Infectious Diseases and Immunology, Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center (IIDRC), Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address:

Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1β (IL-1β) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1β signaling, we demonstrate that IL-1β lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1β pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.
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http://dx.doi.org/10.1016/j.immuni.2019.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751009PMC
September 2019

Autophagy Limits Inflammasome During Infection.

Front Immunol 2019 12;10:754. Epub 2019 Apr 12.

Division of Pediatric Infectious Diseases and Immunology, Department of Pediatrics, and Infectious and Immunological Diseases Research Center, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.

Autophagy can either antagonize or promote intracellular bacterial growth, depending on the pathogen. Here, we investigated the role of autophagy during a pulmonary infection with the obligate intracellular pathogen, (CP). In mouse embryonic fibroblasts (MEFs) or macrophages, deficiency of autophagy pathway components led to enhanced CP replication, suggesting that autophagy exerts a bactericidal role. However, , mice with myeloid-specific deletion of the autophagic protein ATG16L1 suffered increased mortality during CP infection, neutrophilia, and increased inflammasome activation despite no change in bacterial burden. Induction of autophagy led to reduced CP replication , but impaired survival in CP-infected mice, associated with an initial reduction in IL-1β production, followed by enhanced neutrophil recruitment, defective CP clearance, and later inflammasome activation and IL-1β production, which drove the resulting mortality. Taken together, our data suggest that a delicate interplay exists between autophagy and inflammasome activation in determining the outcome of CP infection, perturbation of which can result in inflammatory pathology or unrestricted bacterial growth.
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http://dx.doi.org/10.3389/fimmu.2019.00754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473188PMC
August 2020

Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis.

J Am Coll Cardiol 2019 03;73(10):1149-1169

Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey; National Nanotechnology Center, Bilkent University, Ankara, Turkey; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California; Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Background: Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma.

Objectives: Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis.

Methods: The authors investigated ISR's role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes.

Results: The results show lipid-activated eIF2α signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1β secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis.

Conclusions: These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2α-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1β secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles' responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis.
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http://dx.doi.org/10.1016/j.jacc.2018.12.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424590PMC
March 2019

The Kawasaki Disease Comparative Effectiveness (KIDCARE) trial: A phase III, randomized trial of second intravenous immunoglobulin versus infliximab for resistant Kawasaki disease.

Contemp Clin Trials 2019 04 3;79:98-103. Epub 2019 Mar 3.

Harbor-UCLA Medical Center, 1124 W. Carson St., Torrance, CA, 90509, United States.

Background: Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease (KD), the most common cause of acquired heart disease in children, 10-20% of patients are IVIG-resistant and require additional therapy. This group has an increased risk of coronary artery aneurysms (CAA) and there has been no adequately powered, randomized clinical trial in a multi-ethnic population to determine the optimal therapy for IVIG-resistant patients.

Objectives: The primary outcome is duration of fever in IVIG-resistant patients randomized to treatment with either infliximab or a second IVIG infusion. Secondary outcomes include comparison of inflammatory markers, duration of hospitalization, and coronary artery outcome. An exploratory aim records parent-reported outcomes including signs, symptoms and treatment experience.

Methods: The KIDCARE trial is a 30-site randomized Phase III comparative effectiveness trial in KD patients with fever ≥36 h after the completion of their first IVIG treatment. Eligible patients will be randomized to receive either a second dose of IVIG (2 g/kg) or infliximab (10 mg/kg). Subjects with persistent or recrudescent fever at 24 h following completion of the first study treatment will cross-over to the other treatment arm. Subjects will exit the study after their first outpatient visit (5-18 days following last study treatment). The parent-reported outcomes, collected daily during hospitalization and at home, will be compared by study arm.

Conclusion: This trial will contribute to the management of IVIG-resistant patients by establishing the relative efficacy of a second dose of IVIG compared to infliximab and will provide data regarding the patient/parent experience of these treatments.
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http://dx.doi.org/10.1016/j.cct.2019.02.008DOI Listing
April 2019

Young bone marrow transplantation preserves learning and memory in old mice.

Commun Biol 2019 20;2:73. Epub 2019 Feb 20.

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA.

Restoration of cognitive function in old mice by transfer of blood or plasma from young mice has been attributed to reduced C-C motif chemokine ligand 11 (CCL11) and β2-microglobulin, which are thought to suppress neurogenesis in the aging brain. However, the specific role of the hematopoietic system in this rejuvenation has not been defined and the importance of neurogenesis in old mice is unclear. Here we report that transplantation of young bone marrow to rejuvenate the hematopoietic system preserved cognitive function in old recipient mice, despite irradiation-induced suppression of neurogenesis, and without reducing β2-microglobulin. Instead, young bone marrow transplantation preserved synaptic connections and reduced microglial activation in the hippocampus. Circulating CCL11 levels were lower in young bone marrow recipients, and CCL11 administration in young mice had the opposite effect, reducing synapses and increasing microglial activation. In conclusion, young blood or bone marrow may represent a future therapeutic strategy for neurodegenerative disease.
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http://dx.doi.org/10.1038/s42003-019-0298-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382867PMC
April 2020