Human Immunological Diseases Section
Established in 2007
Helen C. Su, M.D., Ph.D.
Chief, Human Immunological Diseases Section
Director, NIAID Clinical Genomics Program
Acting Chief, Molecular Development of the Immune System Section
Contact: For contact information, search the NIH Enterprise Directory.
Specialty(s): Allergy and Immunology, Pediatrics Provides direct clinical care to patients at NIH Clinical Center
Higlight
Scientists Discover Genetic and Immunologic Underpinnings of Some Cases of Severe COVID-19
September 24, 2020
Findings explain why some people with COVID-19 develop severe disease and may provide the first molecular explanation for why more men than women die from COVID-19.
Major Areas of Research
- Defining the molecular mechanisms of new inherited human immunological diseases
- Elucidating innate immunoregulatory mechanisms for control of respiratory virus infections in humans
- Understanding DOCK8 function in health and human disease
Program Description
The Human Immunological Diseases Section (HIDS) carries out research to understand molecular mechanisms regulating the human immune system and how their derangements cause disease. We study patients with poorly characterized, inherited immunodeficiencies and autoimmune diseases, often lacking molecular diagnoses. These patients display combinations of 1) abnormal lymphocyte accumulation in spleens, lymph nodes, or other organs such as the lungs; 2) immunodeficiencies that reflect defective lymphocyte function, with increased problems fighting off virus and other infections; 3) autoimmunity, including hemolytic anemia and idiopathic thrombocytopenic purpura; and/or 4) exaggerated inflammatory responses. By carefully investigating these “experiments of nature” we can draw inferences about molecular functions based on patient phenotype. Through a broad program that brings together the patients’ clinical evaluations, assessments of their immune function, genetic and biochemical analyses, we gain insights into the molecular and cellular basis of immunity, especially against viruses, while also improving diagnosis and treatment.
We are particularly interested in combined immunodeficiencies that present with increased susceptibility to virus infections. One example is our discovery of DOCK8 deficiency, in which patients have difficulty fighting off herpes simplex virus and human papillomavirus infections of the skin. More recently, we discovered a combined immunodeficiency caused by mutations in GNAI2. Gαi2 (encoded by GNAI2) is part of a G-protein complex that is important in cells for delivering biochemical signals from hormones, neurotransmitters, chemokines, and other environmental cues. In humans, mutations that abnormally activate Gαi2 cause MAGIS syndrome (Midline malformations of the brain, Anterior hypopituitarism, Growth retardation, Immunodeficiency/immunodysregulation, Skeletal abnormalities). We found that the immune-system disease results from impaired migration of white blood cells to fight off infections, as well as T-cell hyperresponsiveness contributing to their autoimmunity that is caused by increased activation of a cAMP-independent Gαi2 > RASA2 > RAS intracellular pathway. We are collaborating with multiple groups at NIH and elsewhere to better understand these diseases and improve treatments for them.
We are also interested in inherited defects of innate immunity that can cause increased susceptibility to virus infections, especially those targeting the respiratory tract. One example is our discovery of human MDA5 deficiency in a patient having recurrent severe rhinovirus and other respiratory viruses. The patient’s loss of MDA5 demonstrated the physiological importance of this cytosolic viral nucleic acid sensor for immunity against the common cold virus, and studies are ongoing to determine how MDA5 physiologically contributes to protecting against other viruses in humans. More recently, we have applied similar experimental approaches to patient cohorts having recurrent or severe infections with respiratory viruses including influenza virus and COVID-19 (see Covid Human Genetic Effort). The latter led to discoveries of genetic defects and neutralizing anti-cytokine autoantibodies that highlight the importance of Type I IFN pathways for antiviral innate immunity against SARS-CoV-2 in humans.
For our studies, we bring patients to the NIH Clinical Center for detailed clinical and research investigations, where we follow their natural history of disease. We have established a broad network of international collaborations and co-lead the NIAID IRP COVID-19 Consortium and the COVID Human Genetic Effort Consortium.
Biography
Education
M.D., Ph.D., Brown University
Helen Su received M.D. and Ph.D. degrees from Brown University. She completed training in pediatrics at St. Louis Children’s Hospital, Washington University, and subspecialty training in allergy and immunology at NIAID. After postdoctoral training with Michael Lenardo, M.D., in the Laboratory of Immunology, she joined the Laboratory of Host Defenses in 2007 as a tenure-track clinical investigator and was tenured in 2016. She has received the Society for Pediatric Research E. Mead Johnson Award and the Gale and Ira Drukier Prize in Children’s Health Research. She was elected a member of the American Society for Clinical Investigation and the Association of American Physicians.
Clinical Studies
Information for Patients and Referring Physicians
A patient may be considered for our research studies through referral by his or her personal physician. To determine eligibility, we generally request a referral letter that contains a concise summary of the patient’s medical history and relevant laboratory tests. The NIH Clinical Center's Patient Recruitment Office can provide general information about clinical research protocols across all NIH institutes.
The Human Immunological Diseases Section participates in multiple clinical protocols, including the following, which are actively recruiting patients:
- Screening Protocol for Genetic Diseases of Lymphocyte Homeostasis and Programmed Cell Death. # 06-I-0015
- Screening and Baseline Assessments of Patients With Abnormalities of Immune Function. # 05-I-0213
- Establishing Fibroblast-Derived Cell Lines From Skin Biopsies of Patients With Immunodeficiency or Immunodysregulation Disorders. #09-I-0133 (NCT00895271)
- Send-In Sample Collection for Comprehensive Analyses of Innate and Adaptive Immune Responses During Acute COVID-19 and Convalescence. #000044 (NCT04582903)
Selected Publications
Ham H, Jing H, Lamborn IT, Kober MM, Koval A, Berchiche YA, Anderson DE, Druey KM, Mandl JN, Isidor B, Ferreira CR, Freeman AF, Ganesan S, Karsak M, Mustillo PJ, Teo J, Zolkipli-Cunningham Z, Chatron N, Lecoquierre F, Oler AJ, Schmid JP, Kuhns DB, Xu X, Hauck F, Al-Herz W, Wagner M, Terhal PA, Muurinen M, Barlogis V, Cruz P, Danielson J, Stewart H, Loid P, Rading S, Keren B, Pfundt R, Zarember KA, Vill K, Potocki L, Olivier KN, Lesca G, Faivre L, Wong M, Puel A, Chou J, Tusseau M, Moutsopoulos NM, Matthews HF, Simons C, Taft RJ, Soldatos A, Masle-Farquhar E, Pittaluga S, Brink R, Fink DL, Kong HH, Kabat J, Kim WS, Bierhals T, Meguro K, Hsu AP, Gu J, Stoddard J, Banos-Pinero B, Slack M, Trivellin G, Mazel B, Soomann M, Li S, Watts VJ, Stratakis CA, Rodriguez-Quevedo MF, Bruel AL, Lipsanen-Nyman M, Saultier P, Jain R, Lehalle D, Torres D, Sullivan KE, Barbarot S, Neu A, Duffourd Y, Similuk M, McWalter K, Blanc P, Bézieau S, Jin T, Geha RS, Casanova JL, Makitie OM, Kubisch C, Edery P, Christodoulou J, Germain RN, Goodnow CC, Sakmar TP, Billadeau DD, Küry S, Katanaev VL, Zhang Y, Lenardo MJ, Su HC. Germline mutations in a G protein identify signaling cross-talk in T cells. Science. 2024 Sep 20;385(6715):eadd8947.
See here for free access reprints of this research article from the American Association for the Advancement of Science.
Su HC, Jing H, Zhang Y, Casanova JL. Interfering with Interferons: A Critical Mechanism for Critical COVID-19 Pneumonia. Annu Rev Immunol. 2023 Apr 26;41:561-585.
Shaw ER, Rosen LB, Cheng A, Dobbs K, Delmonte OM, Ferré EMN, Schmitt MM, Imberti L, Quaresima V, Lionakis MS, Notarangelo LD, Holland SM, Su HC. Temporal Dynamics of Anti-Type 1 Interferon Autoantibodies in COVID-19 Patients. Clin Infect Dis. 2021 Dec 7:ciab1002.
Cananzi M, Wohler E, Marzollo A, Colavito D, You J, Jing H, Bresolin S, Gaio P, Martin R, Mescoli C, Bade S, Posey JE, Dalle Carbonare M, Tung W, Jhangiani SN, Bosa L, Zhang Y, Filho JS, Gabelli M, Kellermayer R, Kader HA, Oliva-Hemker M, Perilongo G, Lupski JR, Biffi A, Valle D, Leon A, de Macena Sobreira NL, Su HC, Guerrerio AL. IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease. Hum Genet. 2021 Sep;140(9):1299-1312.
Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, Ogishi M, Sabli IKD, Hodeib S, Korol C, Rosain J, Bilguvar K, Ye J, Bolze A, Bigio B, Yang R, Arias AA, Zhou Q, Zhang Y, Onodi F, Korniotis S, Karpf L, Philippot Q, Chbihi M, Bonnet-Madin L, Dorgham K, Smith N, Schneider WM, Razooky BS, Hoffmann HH, Michailidis E, Moens L, Han JE, Lorenzo L, Bizien L, Meade P, Neehus AL, Ugurbil AC, Corneau A, Kerner G, Zhang P, Rapaport F, Seeleuthner Y, Manry J, Masson C, Schmitt Y, Schlüter A, Le Voyer T, Khan T, Li J, Fellay J, Roussel L, Shahrooei M, Alosaimi MF, Mansouri D, Al-Saud H, Al-Mulla F, Almourfi F, Al-Muhsen SZ, Alsohime F, Al Turki S, Hasanato R, van de Beek D, Biondi A, Bettini LR, D'Angio' M, Bonfanti P, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Oler AJ, Tompkins MF, Alba C, Vandernoot I, Goffard JC, Smits G, Migeotte I, Haerynck F, Soler-Palacin P, Martin-Nalda A, Colobran R, Morange PE, Keles S, Çölkesen F, Ozcelik T, Yasar KK, Senoglu S, Karabela ŞN, Rodríguez-Gallego C, Novelli G, Hraiech S, Tandjaoui-Lambiotte Y, Duval X, Laouénan C; COVID-STORM Clinicians; COVID Clinicians; Imagine COVID Group; French COVID Cohort Study Group; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; NIAID-USUHS/TAGC COVID Immunity Group, Snow AL, Dalgard CL, Milner JD, Vinh DC, Mogensen TH, Marr N, Spaan AN, Boisson B, Boisson-Dupuis S, Bustamante J, Puel A, Ciancanelli MJ, Meyts I, Maniatis T, Soumelis V, Amara A, Nussenzweig M, García-Sastre A, Krammer F, Pujol A, Duffy D, Lifton RP, Zhang SY, Gorochov G, Béziat V, Jouanguy E, Sancho-Shimizu V, Rice CM, Abel L, Notarangelo LD, Cobat A, Su HC, Casanova JL. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4570.
Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann HH, Zhang Y, Dorgham K, Philippot Q, Rosain J, Béziat V, Manry J, Shaw E, Haljasmägi L, Peterson P, Lorenzo L, Bizien L, Trouillet-Assant S, Dobbs K, de Jesus AA, Belot A, Kallaste A, Catherinot E, Tandjaoui-Lambiotte Y, Le Pen J, Kerner G, Bigio B, Seeleuthner Y, Yang R, Bolze A, Spaan AN, Delmonte OM, Abers MS, Aiuti A, Casari G, Lampasona V, Piemonti L, Ciceri F, Bilguvar K, Lifton RP, Vasse M, Smadja DM, Migaud M, Hadjadj J, Terrier B, Duffy D, Quintana-Murci L, van de Beek D, Roussel L, Vinh DC, Tangye SG, Haerynck F, Dalmau D, Martinez-Picado J, Brodin P, Nussenzweig MC, Boisson-Dupuis S, Rodríguez-Gallego C, Vogt G, Mogensen TH, Oler AJ, Gu J, Burbelo PD, Cohen JI, Biondi A, Bettini LR, D'Angio M, Bonfanti P, Rossignol P, Mayaux J, Rieux-Laucat F, Husebye ES, Fusco F, Ursini MV, Imberti L, Sottini A, Paghera S, Quiros-Roldan E, Rossi C, Castagnoli R, Montagna D, Licari A, Marseglia GL, Duval X, Ghosn J; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort, Tsang JS, Goldbach-Mansky R, Kisand K, Lionakis MS, Puel A, Zhang SY, Holland SM, Gorochov G, Jouanguy E, Rice CM, Cobat A, Notarangelo LD, Abel L, Su HC, Casanova JL. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4585.
Research Networks
NIAID IRP COVID-19 Consortium (see https://www.niaid.nih.gov/research/immune-response-covid-19 ), COVID Human Genetic Effort Consortium, University of Pennsylvania Immunology Graduate Group.
Training Program
NIAID Allergy and Immunology Fellowship Program
Featured Research
Research Group
To carry out the Human Immunological Diseases Section (HIDS) research, our team of dedicated scientific and clinical staff studies patients using our combined expertise in genetics/genomics, immunology, molecular and cellular biology, biochemistry, and virology.