Helen C. Su, M.D., Ph.D.

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. 

Videos