Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with combined immunodeficiency, common variable immunodeficiency (CVID), variants of hyper-IgE syndrome or autoimmune lymphoproliferative syndrome (ALPS), Evans syndrome, caspase-8-deficiency state (CEDS), X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), and PASLI (p110 delta activation mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) disease. Our evaluation includes functional screening and gene sequencing, and a subset of patients is also being intensively studied using biochemical analyses, gene expression microarrays, flow cytometric analyses, in vitro functional tests, and other technologies. These experiments have provided leads for sequencing of new candidate genes not previously associated with disease. Additionally, we are using comparative genomic hybridization (CGH) arrays, whole exome sequencing, whole genome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. In FY2015, using these approaches, we identified from our hyperimmunoglobulinemia E cohort a new combined immunodeficiency disease. TRIANGLE disease is characterized by recurrent sinopulmonary infections, persistent cytomegalovirus viremia and problems with other viruses, and severe autoimmunity including cytopenias and systemic lupus erythematosis. Patients also have developmental delay. We found that the disease is caused by autosomal recessive mutations in the tripeptidyl peptidase II (TPP2) gene. Loss of TPPII perturbs intracellular amino acid homeostasis, leading to compensatory lysosomal expansion with lysosomal degradation of a key glycolytic enzyme called hexokinase-2. The impaired glycolysis in turn causes defective immune effector functions. In FY2015, we also participated in several collaborative studies that involved the identification of two new multi-organ autoimmune diseases with lymphoproliferation and immunodeficiency (CTLA4 haploinsufficiency with autoimmune infiltration (CHAI) disease, and STAT3 gain-of-function disease) and one combined immunodeficiency with lymphoproliferation (PASLI disease caused by PIK3R1 loss-of-function mutations). Additionally, we also participated in a collaborative study that elucidated the mechanism of LRBA deficiency as interfering with CTLA4 intracellular trafficking and thus why this disease is responsive to CTLA4-targed therapy. Collectively, these discoveries now provide molecular diagnoses for some forms of complicated CVID. They have provided new insights into regulation of the human immune system, and our elucidating their pathogenic mechanisms has also led to new medical therapies tailored to each molecular diagnosis.

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2015
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Sapp, Julie C; Johnston, Jennifer J; Driscoll, Kate et al. (2018) Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot. Am J Hum Genet 103:358-366
Giannelou, Angeliki; Wang, Hongying; Zhou, Qing et al. (2018) Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors. Ann Rheum Dis 77:612-619
Comrie, William A; Faruqi, Aiman J; Price, Susan et al. (2018) RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol 141:1507-1510.e8
Hernandez, Nicholas; Melki, Isabelle; Jing, Huie et al. (2018) Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J Exp Med 215:2567-2585
Forbes, Lisa R; Vogel, Tiphanie P; Cooper, Megan A et al. (2018) Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations. J Allergy Clin Immunol :
Arjunaraja, Swadhinya; Angelus, Pamela; Su, Helen C et al. (2018) Impaired Control of Epstein-Barr Virus Infection in B-Cell Expansion with NF-?B and T-Cell Anergy Disease. Front Immunol 9:198
Randolph, Adrienne G; Yip, Wai-Ki; Allen, Emma Kaitlynn et al. (2017) Evaluation of IFITM3 rs12252 Association With Severe Pediatric Influenza Infection. J Infect Dis 216:14-21
Lamborn, Ian T; Jing, Huie; Zhang, Yu et al. (2017) Recurrent rhinovirus infections in a child with inherited MDA5 deficiency. J Exp Med 214:1949-1972
Su, Helen (2017) Studying human immunodeficiencies in humans: advances in fundamental concepts and therapeutic interventions. F1000Res 6:318
Ozen, Ahmet; Comrie, William A; Ardy, Rico C et al. (2017) CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 377:52-61

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