Michael J Lenardo

National Institute of Allergy and Infectious Diseases, 베서스다, Maryland, United States

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Publications (281)2928.21 Total impact

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    Full-text · Dataset · Feb 2016
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    ABSTRACT: Necroptosis as a molecular program, rather than simply incidental cell death, was established by elucidating the roles of receptor interacting protein (RIP) kinases 1 and 3, along with their downstream partner, mixed lineage kinase-like domain protein (MLKL). Previous studies suggested that phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein that associates with RIP1/RIP3/MLKL complex, promotes necroptosis. We have generated mice deficient in the pgam5 gene and surprisingly found PGAM5-deficiency exacerbated rather than reduced necroptosis in response to multiple in vitro and in vivo necroptotic stimuli, including ischemic reperfusion injury (I/R) in the heart and brain. Electron microscopy, biochemical, and confocal analysis revealed that PGAM5 is indispensable for the process of PINK1 dependent mitophagy which antagonizes necroptosis. The loss of PGAM5/PINK1 mediated mitophagy causes the accumulation of abnormal mitochondria, leading to the overproduction of reactive oxygen species (ROS) that worsen necroptosis. Our results revise the former proposal that PGAM5 acts downstream of RIP1/RIP3 to mediate necroptosis. Instead, PGAM5 protects cells from necroptosis by independently promoting mitophagy. PGAM5 promotion of mitophagy may represent a therapeutic target for stroke, myocardial infarction and other diseases caused by oxidative damage and necroptosis.
    Full-text · Article · Jan 2016 · PLoS ONE
  • Michael Lenardo · Bernice Lo · Carrie L Lucas
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    ABSTRACT: GenomicDNAsequencing technologies have been one of the great advances of the 21st century, having decreased in cost by seven orders of magnitude and opening up new fields of investigation throughout research and clinical medicine. Genomics coupled with biochemical investigation has allowed the molecular definition of a growing number of new genetic diseases that reveal new concepts of immune regulation. Also, defining the genetic pathogenesis of these diseases has led to improved diagnosis, prognosis, genetic counseling, and, most importantly, new therapies. We highlight the investigational journey from patient phenotype to treatment using the newly defined XMEN disease, caused by the genetic loss of the MAGT1 magnesium transporter, as an example. This disease illustrates how genomics yields new fundamental immunoregulatory insights as well as how research genomics is integrated into clinical immunology. At the end, we discuss two other recently described diseases, PASLI (PI3K dysregulation) and CHAI/LATAIE (CTLA-4 deficiency), as additional examples of the journey from unknown immunological diseases to new precision medicine treatments using genomics. Expected final online publication date for the Annual Review of Immunology Volume 34 is May 20, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    No preview · Article · Jan 2016 · Annual Review of Immunology
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    Full-text · Dataset · Nov 2015
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    ABSTRACT: Members of the miR-290 family are the most abundantly expressed microRNAs (miRNAs) in mouse embryonic stem cells (ESCs). They regulate aspects of differentiation, pluripotency, and proliferation of ESCs, but the molecular program that they control has not been fully delineated. In the absence of Dicer, ESCs fail to express mature miR-290 miRNAs and have selective aberrant overexpression of Hoxa, Hoxb, Hoxc, and Hoxd genes essential for body plan patterning during embryogenesis, but they do not undergo a full differentiation program. Introduction of mature miR-291 into DCR(-/-) ESCs restores Hox gene silencing. This was attributed to the unexpected regulation of Polycomb-mediated gene targeting by miR-291. We identified the methyltransferase Ash1l as a pivotal target of miR-291 mediating this effect. Collectively, our data shed light on the role of Dicer in ESC homeostasis by revealing a facet of molecular regulation by the miR-290 family.
    Preview · Article · Nov 2015 · Stem Cell Reports
  • Michael J. Lenardo · Louis M. Staudt

    No preview · Article · Nov 2015 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Background: The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII, i.e. cross-reacting material (CRM), have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. Objectives: We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. Methods: Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. Results: All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. Conclusions: We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice making it valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a defined genetic background. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Journal of Thrombosis and Haemostasis
  • Carrie L Lucas · Michael J Lenardo
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    ABSTRACT: Common autoimmune diseases are relatively heterogeneous with both genetic and environmental factors influencing disease susceptibility and progression. As the populations in developed countries age, these chronic diseases will become an increasing burden in human suffering and health care costs. By contrast, rare immune diseases that are severe and develop early in childhood are frequently monogenic and fully penetrant, often with a Mendelian inheritance pattern. Although these may be incompatible with survival or cured by hematopoietic stem cell transplantation, we will argue that they constitute a rich source of genetic insights into immunological diseases. Here, we discuss five examples of well-studied Mendelian disease-causing genes and their known or predicted roles in conferring susceptibility to common, polygenic diseases of autoimmunity. Mendelian disease mutations, as experiments of nature, reveal human loci that are indispensable for immune regulation and, therefore, most promising as therapeutic targets.
    No preview · Article · Oct 2015 · Current opinion in immunology
  • Yu Zhang · Helen C Su · Michael J Lenardo
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    ABSTRACT: Advances in human genomics, when validated functionally, can lead to new insights into how the immune system works. Notably, previously unknown mechanisms revealed by genomics can lead to the development of precision medicine unanticipated on the basis of phenotype alone.
    No preview · Article · Sep 2015 · Nature Immunology
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    ABSTRACT: Mutations in the LRBA gene (encoding the lipopolysaccharide-responsive and beige-like anchor protein) cause a syndrome of autoimmunity, lymphoproliferation, and humoral immune deficiency. The biological role of LRBA in immunologic disease is unknown. We found that patients with LRBA deficiency manifested a dramatic and sustained improvement in response to abatacept, a CTLA4 (cytotoxic T lymphocyte antigen-4)–immunoglobulin fusion drug. Clinical responses and homology of LRBA to proteins controlling intracellular trafficking led us to hypothesize that it regulates CTLA4, a potent inhibitory immune receptor. We found that LRBA colocalized with CTLA4 in endosomal vesicles and that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in reduced levels of CTLA4 protein in FoxP3+ regulatory and activated conventional T cells. In LRBA-deficient cells, inhibition of lysosome degradation with chloroquine prevented CTLA4 loss. These findings elucidate a mechanism for CTLA4 trafficking and control of immune responses and suggest therapies for diseases involving the CTLA4 pathway.
    Full-text · Article · Jul 2015 · Science
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    Full-text · Article · Jun 2015 · Journal of Allergy and Clinical Immunology

  • No preview · Article · Jun 2015 · Pediatric Blood & Cancer
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    ABSTRACT: Ras-associated leukoproliferative disorder (RALD) is a chronic, nonmalignant condition, presenting with persistent monocytosis often associated with leukocytosis, lymphoproliferation, and autoimmune phenomena. RALD has clinical and laboratory features overlapping with juvenile and chronic myelomonocytic leukemia (JMML, CMML) including identical somatic mutations in KRAS or NRAS genes noted in peripheral blood mononuclear cells. Long-term follow-up of these patients suggests that RALD has an indolent clinical course whereas JMML is fatal if left untreated. Immunophenotyping peripheral blood from RALD patients shows characteristic circulating activated monocytes and polyclonal CD10+ B-cells. Distinguishing RALD from JMML/CMML has implications for clinical care and prognosis. Copyright © 2015 American Society of Hematology.
    Full-text · Article · Feb 2015 · Blood
  • Helen C. Su · Michael J. Lenardo
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    ABSTRACT: Combined immune deficiencies (CIDs) form a group of inherited immune disorders in which lymphocyte numbers may be diminished and lymphocyte functions are impaired. These disorders affect primarily T cells, typically disturbing their ability to provide assistance for antibody production and therefore causing decreased immunoglobulins. The disorders may also directly affect B cells and/or natural killer (NK) cells. The defects can occur during ontogeny and may be caused by genes that are known to cause severe combined immunodeficiency (SCID). In the case of CID, peripheral T cells are produced in greater numbers than in SCID due to less severe - i.e., hypomorphic - mutations that permit partial or full mature T cell egress from the thymus. Alternatively, defects in T cell function can occur at various stages of T cell receptor (TCR) signaling or cytokine responsiveness of mature T cells. Because B cells and NK cells have evolved similar signaling pathways, defects in these response mechanisms can impair B and/or NK cell functions.
    No preview · Article · Dec 2014
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    ABSTRACT: Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines, including IFN-γ and IL-1β. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health. Copyright © 2014 Elsevier Inc. All rights reserved.
    No preview · Article · Dec 2014 · Cell
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    ABSTRACT: Class IA phosphatidylinositol 3-kinases (PI3K), which generate PIP3 as a signal for cell growth and proliferation, exist as an intracellular complex of a catalytic subunit bound to a regulatory subunit. We and others have previously reported that heterozygous mutations in PIK3CD encoding the p110δ catalytic PI3K subunit cause a unique disorder termed p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease. We report four patients from three families with a similar disease who harbor a recently reported heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits. These patients suffer from recurrent sinopulmonary infections and lymphoproliferation, exhibit hyperactive PI3K signaling, and have prominent expansion and skewing of peripheral blood CD8(+) T cells toward terminally differentiated senescent effector cells with short telomeres. The PIK3R1 splice site mutation causes skipping of an exon, corresponding to loss of amino acid residues 434-475 in the inter-SH2 domain. The mutant p85α protein is expressed at low levels in patient cells and activates PI3K signaling when overexpressed in T cells from healthy subjects due to qualitative and quantitative binding changes in the p85α-p110δ complex and failure of the C-terminal region to properly inhibit p110δ catalytic activity.
    Full-text · Article · Dec 2014 · Journal of Experimental Medicine
  • Juha Grönholm · Michael J Lenardo
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    ABSTRACT: Type 1 diabetes is a progressive autoimmune disease with no curative treatment, making prevention critical. At the time of diagnosis, a majority of the insulin secreting β-cells has already been destroyed. Insulitis, lymphocytic infiltration to the pancreatic islets, is believed to begin months to years before the clinical symptoms of insulin deficiency appear. Insulitis should be treated as its own disease, for it is a known precursor to autoimmune diabetes. Because it is difficult to detect insulitic cellular infiltrates noninvasively, considerable interest has been focused on the levels of islet autoantibodies in blood as measurable diagnostic markers for islet autoimmunity. The traditional islet autoantibody detection assays have many limitations. New electrochemiluminescence-based autoantibody detection assays have the potential to overcome these challenges and they offer promising, cost-effective screening tools in identifying high-risk individuals for trials of preventive interventions. Here, we outline diagnostic and therapeutic strategies to overcome pancreatic β-cell destroying insulitis. Copyright © 2014. Published by Elsevier Inc.
    No preview · Article · Dec 2014 · Clinical Immunology
  • Juan Ravell · Benjamin Chaigne-Delalande · Michael Lenardo
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    ABSTRACT: Purpose of review: To describe the role of the magnesium transporter 1 (MAGT1) in the pathogenesis of 'X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia' (XMEN) disease and its clinical implications. Recent findings: The magnesium transporter protein MAGT1 participates in the intracellular magnesium ion (Mg) homeostasis and facilitates a transient Mg influx induced by the activation of the T-cell receptor. Loss-of-function mutations in MAGT1 cause an immunodeficiency named 'XMEN syndrome', characterized by CD4 lymphopenia, chronic EBV infection, and EBV-related lymphoproliferative disorders. Patients with XMEN disease have impaired T-cell activation and decreased cytolytic function of natural killer (NK) and CD8 T cells because of decreased expression of the NK stimulatory receptor 'natural-killer group 2, member D' (NKG2D). Patients may have defective specific antibody responses secondary to T cell dysfunction, but B cells have not been shown to be directly affected by mutations in MAGT1. Summary: XMEN disease has revealed a novel role for free intracellular magnesium in the immune system. Further understanding of the MAGT1 signaling pathway may lead to new diagnostic and therapeutic approaches.
    No preview · Article · Oct 2014 · Current Opinion in Pediatrics
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    ABSTRACT: Mitophagy is a specialized form of autophagy that selectively disposes of dysfunctional mitochondria. Delineating the molecular regulation of mitophagy is of great importance because defects in this process lead to a variety of mitochondrial diseases. Here we report that mice deficient for the mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5), displayed a Parkinson's-like movement phenotype. We determined biochemically that PGAM5 is required for the stabilization of the mitophagy-inducing protein PINK1 on damaged mitochondria. Loss of PGAM5 disables PINK1-mediated mitophagy in vitro and leads to dopaminergic neurodegeneration and mild dopamine loss in vivo. Our data indicate that PGAM5 is a regulator of mitophagy essential for mitochondrial turnover and serves a cytoprotective function in dopaminergic neurons in vivo. Moreover, PGAM5 may provide a molecular link to study mitochondrial homeostasis and the pathogenesis of a movement disorder similar to Parkinson's disease.
    Full-text · Article · Sep 2014 · Nature Communications
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    ABSTRACT: Cytotoxic T lymphocyte antigen–4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3+ regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21lo B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.
    Full-text · Article · Sep 2014 · Science

Publication Stats

30k Citations
2,928.21 Total Impact Points

Institutions

  • 1990-2016
    • National Institute of Allergy and Infectious Diseases
      • • Laboratory of Immunoregulation
      • • Laboratory of Parasitic Diseases (LPD)
      베서스다, Maryland, United States
  • 1989-2012
    • National Institutes of Health
      • • Section of Inflammation Immunobiology
      • • Laboratory of Immunology
      • • Cell Biology and Metabolism Program
      Maryland, United States
  • 1996-2011
    • National Institute of Allergy and Infectious Disease
      베서스다, Maryland, United States
  • 2010
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2009
    • Benaroya Research Institute
      Seattle, Washington, United States
  • 2006-2009
    • University of Oxford
      Oxford, England, United Kingdom
  • 2005
    • CRG Centre for Genomic Regulation
      Barcino, Catalonia, Spain
  • 2002
    • George Washington University
      • Department of Pathology
      Washington, Washington, D.C., United States
  • 1998-2001
    • National Human Genome Research Institute
      베서스다, Maryland, United States
    • The Rockefeller University
      New York, New York, United States
    • University of Texas Health Science Center at San Antonio
      • Department of Pediatrics
      San Antonio, Texas, United States
  • 1999
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 1997
    • University of Toronto
      • Department of Immunology
      Toronto, Ontario, Canada
  • 1987-1989
    • Whitehead Institute for Biomedical Research
      Cambridge, Massachusetts, United States