Michael J Lenardo

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

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Publications (249)2868.41 Total impact

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  • Michael J. Lenardo · Louis M. Staudt ·

    Proceedings of the National Academy of Sciences 11/2015; 112(46):201519815. DOI:10.1073/pnas.1519815112 · 9.67 Impact Factor
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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.
    Journal of Thrombosis and Haemostasis 11/2015; DOI:10.1111/jth.13202 · 5.72 Impact Factor
  • 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.
    Current opinion in immunology 10/2015; 37:28-33. DOI:10.1016/j.coi.2015.09.001 · 7.48 Impact Factor
  • Yu Zhang · Helen C Su · Michael J Lenardo ·

    Nature Immunology 09/2015; 16(10):1001-4. DOI:10.1038/ni.3275 · 20.00 Impact Factor
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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.
    Science 07/2015; 349(6246):436-40. DOI:10.1126/science.aaa1663 · 33.61 Impact Factor
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    Journal of Allergy and Clinical Immunology 06/2015; DOI:10.1016/j.jaci.2015.05.013 · 11.48 Impact Factor
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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.
    Blood 02/2015; 125(18). DOI:10.1182/blood-2014-11-567917 · 10.45 Impact Factor
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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.
    Cell 12/2014; 159(7):1578-1590. DOI:10.1016/j.cell.2014.12.001 · 32.24 Impact Factor
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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.
    Journal of Experimental Medicine 12/2014; 211(13). DOI:10.1084/jem.20141759 · 12.52 Impact Factor
  • 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.
    Clinical Immunology 12/2014; 156(2). DOI:10.1016/j.clim.2014.11.007 · 3.67 Impact Factor
  • 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.
    Current Opinion in Pediatrics 10/2014; 26(6). DOI:10.1097/MOP.0000000000000156 · 2.53 Impact Factor
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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.
    Nature Communications 09/2014; 5:4930. DOI:10.1038/ncomms5930 · 11.47 Impact Factor
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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.
    Science 09/2014; 345(6204). DOI:10.1126/science.1255904 · 33.61 Impact Factor
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    ABSTRACT: The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.
    European journal of human genetics: EJHG 09/2014; 23(6). DOI:10.1038/ejhg.2014.179 · 4.35 Impact Factor
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    Benjamin Chaigne-Delalande · Michael J Lenardo ·
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    ABSTRACT: Divalent cations of two alkaline earth metals Ca(2+) and Mg(2+) and the transition metal Zn(2+) play vital roles in the immune system, and several immune disorders are associated with disturbances of their function. Until recently only Ca(2+) was considered to serve as a second messenger. However, signaling roles for Mg(2+) and Zn(2+) have been recently described, leading to a reevaluation of their role as potential second messengers. We review here the roles of these cations as second messengers in light of recent advances in Ca(2+), Mg(2+), and Zn(2+) signaling in the immune system. Developing a better understanding of these signaling cations may lead to new therapeutic strategies for immune disorders.
    Trends in Immunology 06/2014; 35(7). DOI:10.1016/j.it.2014.05.001 · 10.40 Impact Factor
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    ABSTRACT: Epstein Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and persists in 95% of adults worldwide and has the potential to cause fatal disease, especially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malignancies have provided novel insights into the molecular mechanisms of immune defense against EBV. We have recently characterized a novel PID now named "X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia" (XMEN) disease characterized by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1), chronic high level EBV with increased EBV-infected B cells, and heightened susceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in immune functions and led to novel diagnostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mechanisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease.
    Blood 02/2014; 123(14). DOI:10.1182/blood-2013-11-538686 · 10.45 Impact Factor
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    ABSTRACT: The Autoimmune Lymphoproliferative Syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or "double negative" TCRαβ(+) T (DNT) lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last two decades. Our principal findings are that FAS mutations have a clinical penetrance of less than 60%, elevated serum vitamin B12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortality in these patients are the overwhelming post-splenectomy sepsis (OPSI) and development of lymphoma. With longer follow up, we observed a significantly greater relative risk of lymphoma than previously reported. Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients. This trial has been registered at www.clinicaltrials.gov (identifier: NCT00001350).
    Blood 01/2014; 123(13). DOI:10.1182/blood-2013-10-535393 · 10.45 Impact Factor
  • Carrie L Lucas · Michael J. Lenardo ·
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    ABSTRACT: Overview of Peripheral T Cell Homeostasis: The lymphocyte is a major class of white blood cell that defends the body from attack by infectious agents and confers long-term protection through immunological memory. Lymphocytes are also involved in pathological immune reactions including graft rejection, allergies, and autoimmune disorders. Their remarkable capacity to proliferate up to 5,000-fold in response to antigen must be counterbalanced by a controlled process of removing cells. This is achieved through molecular pathways of programmed cell death, which maintain selective and specific homeostasis of the numbers of lymphocytes and other immune cells. We focus principally on cell death mechanisms in T lymphocytes that control the number of T cells of a given antigen specificity represented in the finite T cell niche. Here, we discuss the central role of caspases in the regulation of the general pathways of cell-extrinsic and cell-intrinsic T cell apoptosis and programmed necrosis with an overview of their importance for human health. © 2014 Springer Science+Business Media New York. All rights are reserved.
    Cell Death: Mechanism and Disease, Edited by Hao Wu, 01/2014: pages 41-59; Springer New York., ISBN: 978-1-4614-9302-0
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    ABSTRACT: The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p110δ). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells. In vitro, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely 'rescued' the in vitro T cell defects and improved the clinical course.
    Nature Immunology 10/2013; 15(1). DOI:10.1038/ni.2771 · 20.00 Impact Factor

Publication Stats

29k Citations
2,868.41 Total Impact Points


  • 1990-2015
    • National Institute of Allergy and Infectious Diseases
      • • Laboratory of Immunoregulation
      • • Laboratory of Parasitic Diseases (LPD)
      베서스다, Maryland, United States
  • 1992-2012
    • National Institutes of Health
      • • Section of Inflammation Immunobiology
      • • Laboratory of Immunology
      • • Laboratory of Clinical Infectious Diseases
      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
  • 1999
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 1998
    • National Human Genome Research Institute
      Maryland, United States
    • The Rockefeller University
      New York, New York, United States
  • 1997
    • University of Toronto
      • Department of Immunology
      Toronto, Ontario, Canada
  • 1989
    • National Institute of Child Health and Human Development
      베서스다, Maryland, United States
  • 1987-1989
    • Whitehead Institute for Biomedical Research
      Cambridge, Massachusetts, United States