Defining New Human Immunodeficiency and Immunodysregulation Disorders

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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.