Michael Lenardo, M.D.

Molecular Development of the Immune System Section

NIH Main Campus, Bethesda, MD

Michael Lenardo, M.D.

Chief, Molecular Development of the Immune System Section
Co-Director, NIAID Clinical Genomics Program

Contact: For contact information, search the NIH Enterprise Directory.

Michael Lenardo, M.D.

Major Areas of Research

  • Genetic diseases of immune homeostasis and autoimmunity
  • Non-apoptotic mechanisms of cell death
  • Development of novel immunodiagnostics and immunotherapeutics

Program Description

The focus of the laboratory since its inception has been to understand crucial regulatory pathways in the lifespan of T lymphocytes at the most fundamental level. Our investigations continue to address issues of T cell homeostasis and apoptosis in autoimmune diseases. This has led to the identification of new unexpected genes contributing to human immune diseases such as autoimmune lymphoproliferative syndrome (ALPS), in which the failure of normal homeostatic mechanisms leads to autoimmunity and lymphoma. Our discovery of X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease raised the question of how the MagT1 protein controls T cell signaling for activation and apoptosis. Finding a gain-of-function mutation in phosphatidylinositol 3-kinase gene explained why PASLI disease individuals were unable to appropriately activate T cell responses to recurrent viral infections and simultaneously suffer from lymphoproliferation. Videos highlighting how our research helps patients with XMEN or PASLI disease can be viewed below. 

Due to the success of ALPS, XMEN, and PASLI disease discoveries, the lab began employing genetic approaches to understand autoimmune diseases. Our current Mendelian approach has enabled us to find disease alleles that are highly deleterious and fully penetrant. Using a two-prong method of genomics coupled with biochemical investigation has allowed us insight on the molecular definition of a growing number of new genetic diseases which reveal new concepts of immune regulation and disease pathogenesis. We learned that there are multiple benefits to defining the genetic pathobiology of these autoimmune diseases: improved diagnosis, prognosis, genetic counseling, and, most importantly, new therapies. 

The latest discovery from the lab is a loss-of-function mutation affecting the gene encoding CD55. CD55 is a cell surface inhibitor of complement factor C3 that prevents complement damage to healthy cells. The cardinal feature is severe protein-losing enteropathy due to primary intestinal lymphangiectasia associated with diarrhea, vomiting, abdominal pain, edema, recurrent infections due to hypogammaglobulinemia, and severe, often fatal, thromboembolic complications. This disorder is called complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy or CHAPLE disease. Unfortunately, the disease is brutal, and patients typically live to only late childhood/early adulthood. Current treatments do little to improve quality of life and have adverse side effects. The lab is currently involved in an international clinical trial for use of a promising therapeutic agent to treat CHAPLE disease. 

Recently, in collaboration with the NIAID Clinical Genomics Program and the National Institute for Neurological Disorders and Stroke, our newest project will focus on causative genetic variants for central nervous system autoimmune demyelinating diseases and assessment of their role in immune and inflammatory responses. Over 14,000 human specimens will be sequenced, making it the largest database of multiple sclerosis patients and family members in the research community. 




M.D., Washington University in St. Louis, St. Louis, MO

B.A., Johns Hopkins University, Baltimore, MD

Michael Lenardo received a Bachelor of Arts in Natural Sciences from Johns Hopkins University and obtained his Doctor of Medicine (M.D.) from Washington University in St. Louis. He performed clinical work in internal medicine and research at the University of Iowa. He received postdoctoral training at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology under the mentorship of Nobel laureates David Baltimore and Philip Sharp. He established an independent research unit at NIAID in 1989 and became a Senior Investigator and Section Chief in 1994. He is an Adjunct Professor of Pathology at the University of Pennsylvania School of Medicine, and a Visiting Fellow at Cambridge University. He has founded or co-founded several joint research programs including the NIH-Oxford-Cambridge Biomedical Research Scholars, the NIH-University of Pennsylvania Immunology Program, the NIH-Marshall Scholars, the NIH-Rhodes Scholars, the National M.D./Ph.D. partnership program, and the NIH-Institut Pasteur Infectious Disease and Immunology Program.


2006: Officer of the Most Excellent Order of the British Empire (O.B.E.) conferred by Queen Elizabeth II

2009: Fellow, American Association for the Advancement of Science

2014: Irish Society of Immunology Award

2019: Member, National Academy of Sciences

2019: Member, National Academy of Medicine

2019: NIH Distinguished Investigator (top 2-3% section chiefs at NIH)

2020: American Association of Immunologists Steinman Award for Human Immunology Research

2020: Fellow, Academy of Medical Sciences of Great Britain

Clinical Studies

Open-Label Efficacy and Safety Study of Pozelimab in Patients With CD55-Deficient Protein-Losing Enteropathy (CHAPLE Disease), NCT04209634; Key words: CD55-deficient Protein-losing Enteropathy, CHAPLE, PLE, pozelimab, eculizumab 

Selected Publications

Yao Y, Kim G, Shafer S, Chen Z, Kubo S, Ji Y, Luo J, Yang W, Perner SP, Kanellopoulou C, Park AY, Jiang P, Li J, Baris S, Aydiner EK, Ertem D, Mulder DJ, Warner N, Griffiths AM, Topf-Olivestone C, Kori M, Werner L, Ouahed J, Field M, Liu C, Schwarz B, Bosio CM, Ganesan S, Song J, Urlaub H, Oellerich T, Malaker SA, Zheng L, Bertozzi CR, Zhang Y, Matthews H, Montgomery W, Shih HY, Jiang J, Jones M, Baras A, Shuldiner A, Gonzaga-Jauregui C, Snapper SB, Muise AM, Shouval DS, Ozen A, Pan KT, Wu C, Lenardo MJ. Mucus sialylation determines intestinal host-commensal homeostasis. Cell. 2022 Mar 31;185(7):1172-1188.e28.  

Kubo S, Fritz JM, Raquer-McKay HM, Kataria R, Vujkovic-Cvijin I, Al-Shaibi A, Yao Y, Zheng L, Zou J, Waldman AD, Jing X, Farley TK, Park AY, Oler AJ, Charles AK, Makhlouf M, AbouMoussa EH, Hasnah R, Saraiva LR, Ganesan S, Al-Subaiey AA, Matthews H, Flano E, Lee HH, Freeman AF, Sefer AP, Sayar E, Çakır E, Karakoc-Aydiner E, Baris S, Belkaid Y, Ozen A, Lo B, Lenardo MJ. Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease. Nat Immunol. 2022 Jan;23(1):75-85.  

Cook SA, Comrie WA, Poli MC, Similuk M, Oler AJ, Faruqi AJ, Kuhns DB, Yang S, Vargas-Hernández A, Carisey AF, Fournier B, Anderson DE, Price S, Smelkinson M, Abou Chahla W, Forbes LR, Mace EM, Cao TN, Coban-Akdemir ZH, Jhangiani SN, Muzny DM, Gibbs RA, Lupski JR, Orange JS, Cuvelier GDE, Al Hassani M, Al Kaabi N, Al Yafei Z, Jyonouchi S, Raje N, Caldwell JW, Huang Y, Burkhardt JK, Latour S, Chen B, ElGhazali G, Rao VK, Chinn IK, Lenardo MJ. HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease. Science. 2020 Jul 10;369(6500):202-207.  

Ozen A, Comrie WA, Ardy RC, Domínguez Conde C, Dalgic B, Beser ÖF, Morawski AR, Karakoc-Aydiner E, Tutar E, Baris S, Ozcay F, Serwas NK, Zhang Y, Matthews HF, Pittaluga S, Folio LR, Unlusoy Aksu A, McElwee JJ, Krolo A, Kiykim A, Baris Z, Gulsan M, Ogulur I, Snapper SB, Houwen RHJ, Leavis HL, Ertem D, Kain R, Sari S, Erkan T, Su HC, Boztug K, Lenardo MJ. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med. 2017 Jul 6;377(1):52-61. 

Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, Zhang Y, Liu Z, Fritz JM, Marsh R, Husami A, Kissell D, Nortman S, Chaturvedi V, Haines H, Young LR, Mo J, Filipovich AH, Bleesing JJ, Mustillo P, Stephens M, Rueda CM, Chougnet CA, Hoebe K, McElwee J, Hughes JD, Karakoc-Aydiner E, Matthews HF, Price S, Su HC, Rao VK, Lenardo MJ, Jordan MB. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015 Jul 24;349(6246):436-40.  

Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014 Jan;15(1):88-97.  

Visit PubMed for a complete publication listing.

Training Programs

NIH Oxford-Cambridge Scholars Program 

NIH-Penn Immunology Graduate Partnership Program 


Baehrecke EH, Alva A, Lenardo MJ, Li Y, inventors; University of Maryland College Park, National Institutes of Health, assignees. Function of autophagy genes in cell death. United States patent US 7,838,645. 2010 Nov 23.

Lenardo MJ, Chan FKM, Siegel RM, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Identification of a novel domain in the tumor necrosis factor receptor family that mediates pre-ligand receptor assembly and function. United States patent US 7,148,061. 2006 Dec 12.

Nye SH, Lenardo MJ, McFarland HF, Matis LA, Mueller EE, Mueller JP, Pelfrey CM, Squinto SP, Wilkins JA. Modified myelin basic protein molecules. United States patent US 7,041,503. 2006 May 9.

Tools and Resources

NIAID Clinical Genomics Program 

Research Group

To carry out the research performed in the Molecular Development of the Immune System Section (MDISS), our team of dedicated scientific and clinical staff study patients using our combined expertise in genetics/genomics, molecular and cellular biology, biochemistry, and immunology.

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