Major Areas of Research
- Defining the molecular mechanisms of new inherited human immunological diseases
- Understanding DOCK8 function in health and human disease
- Elucidating innate immunoregulatory mechanisms for control of respiratory virus infections in humans
The goals of the Human Immunological Diseases Section (HIDS) are to understand the molecular mechanisms regulating the human immune system and how their derangements cause disease, with the objective of improving diagnosis and treatment. We study patients with a spectrum of poorly characterized, inherited immunodeficiencies and autoimmune diseases, who lack molecular diagnoses. These patients display combinations of 1) lymphocyte accumulation leading to enlarged spleens, lymph nodes, or lymphocyte infiltration into other organs such as the lungs; 2) immunodeficiencies that reflect defective lymphocyte function, with increased susceptibility to viral, fungal, or bacterial infections; and/or 3) autoimmunity, including hemolytic anemia and idiopathic thrombocytopenic purpura; and 4) allergy. By combining clinical evaluations, assessments of immune function, biochemical and genetic analyses, and new technologies, we aim to define new clinical entities and discover novel or unappreciated roles of genes that regulate the human immune system.
We are particularly interested in combined immunodeficiencies that lead to susceptibility to virus infections and the new biological insights that studying these patients can provide. One example is our discovery of DOCK8 deficiency, which causes patients to have increased susceptibility to various infections, but especially viral skin infections, including herpes simplex virus, human papillomavirus, and molluscum contagiosum virus. For more information about this research, see DOCK8 Deficiency. These patients also often have severe allergic disease, as well as increased risk of developing skin cancers or lymphomas. Our studies in these patients revealed that DOCK8 is crucial for lymphocytes to maintain cell shape integrity when they move within skin that is distinct from other tissues in being characterized by having many highly confined spaces. When DOCK8 is lacking, the resident memory CD8+ T cells in the skin undergo a catastrophic cell breakage, which we term cytothripsis, and this cell death impairs local anti-viral T cell immunity within the skin. By applying similar experimental approaches to other patients having novel combined immunodeficiencies, we hope to gain insights into the molecular regulation of the human lymphocytes for antiviral immunity in both normal and diseased states.
We are also interested in new 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 who had 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. The extent to which MDA5 physiologically contributes in humans to protect against other respiratory viruses is being studied. For more information about this research, see NIAID Scientists Discover Rare Genetic Susceptibility to Common Cold. By applying similar experimental approaches to other patients having recurrent or severe infections with respiratory viruses including influenza virus and more recently COVID-19 (see https://www.covidhge.com), we hope to gain insights into the molecular regulation of the antiviral innate immunity.
To study these and other rare diseases, we have established close collaborations with several groups at the National Institutes of Health (NIH) including the Laboratory of Immune Systems Biology and the Laboratory of Infectious Diseases within NIAID, as well as others outside NIH including international collaborations. We also bring in patients to the NIH Clinical Center for detailed clinical and research investigations, where we follow their natural history of disease.
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.
Lamborn IT, Jing, H, Zhang Y, Drutman SB, Abbott JK, Munir S, Bade S, Murdock HM, Santos CP, Brock LG, Masutani E, Fordjour EY, McElwee JJ, Hughes JD, Nichols DP, Belkadi A, Oler AJ, Happel CS, Matthews HF, Abel L, Collins PL, Subbarao K, Gelfand EW, Ciancanelli MJ, Casanova JL, Su HC. Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. J Exp Med. 2017 Jul 3;214(7):1949-1972.
Abolhassani H, Edwards ES, Ikinciogullari A, Jing H, Borte S, Buggert M, Du L, Matsuda-Lennikov M, Romano R, Caridha R, Bade S, Shang Y, Frederiksen J, Fang M, Bal SK, Haskologlu S, Dogu F, Tacyildiz N, Matthews HF, McElwee JJ, Gostick E, Price DA, Palendira U, Aghamohammadi A, Boisson B, Rezaei N, Karlsson AC, Lenardo MJ, Casanova JL, Hammarstrom L, Tangye SG, Su HC, Pan-Hammarström Q. Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J Exp Med. 2017 Jan;214(1):91-106.
Happel CS, Stone KD, Freeman AF, Shah NN, Wang A, Lyons JJ, Guerrerio PA, Hickstein DD, Su HC. Food allergies can persist after myeloablative hematopoietic stem cell transplantation in dedicator of cytokinesis 8-deficient patients. J Allergy Clin Immunol. 2016 Jun;137(6):1895-1898.
Zhang Q, Dove CG, Hor JL, Murdock HM, Strauss-Albee DM, Garcia JA, Mandl JN, Grodick RA, Jing H, Chandler-Brown DB, Lenardo TE, Crawford G, Matthews HF, Freeman AF, Cornall RJ, Germain RN, Mueller SN, Su HC. DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity. J Exp Med. 2014 Dec 15;211(13):2549-2566.
Lu W, Zhang Y, McDonald DO, Jing H, Carroll B, Robertson N, Zhang Q, Griffin H, Sanderson S, Lakey JH, Morgan NV, Reynard LN, Zheng L, Murdock HM, Turvey SE, Hackett SJ, Prestidge T, Hall JM, Cant AJ, Matthews HF, Koref MF, Simon AK, Korolchuk VI, Lenardo MJ, Hambleton S, Su HC. Dual proteolytic pathways govern glycolysis and immune competence. Cell. 2014 Dec 18;159(7):1578-1590.
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 HIDS 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