Molecular Mechanisms Of The Autoimmune Lymphoproliferative Syndrome And Other Immunoregulatory Disorders

National Institute Of Allergy And Infectious Diseases

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Abstract

This project was originally based on our discovery that genetic mutations that affect programmed death, or apoptosis, of lymphocytes are responsible for the Autoimmune Lymphoproliferative Syndrome (ALPS). ALPS is a congenital disease causing loss of normal lymphocyte homeostasis manifested as swollen lymph glands and organs. This excess of lymphocytes leads to a pathological autoimmune attack on the patients own tissues. During the clinical investigations on ALPS, many patients have been referred to our program with other immunoregulatory and immunodeficiency syndromes for evaluation. Therefore we launched a clinical genomics program to identify the genetic causes of these diseases. In addition to NIH patients, we have also established clinical research centers in China, Turkey, and India, providing many patients to study at the cellular and genomic level. We have discovered a very interesting genetic disease affecting 10 patients, mostly coming from our center in Istanbul, Turkey, suffering from abdominal pain and diarrhea caused by early-onset protein-losing enteropathy (PLE) with lymphangiectasia, edema due to hypoproteinemia, malabsorption, and, less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease. Interestingly, this disease was very similar if not identical to a condition called Waldmann's disease, that was first reported in 1961 by Dr. Thomas A. Waldmann at the NIH clinical center. We identified autosomal recessive mutations leading to loss of protein expression in the gene encoding CD55/Decay accelerating factor. Patient T lymphocytes and CD55-deficient cell lines displayed abnormally increased deposition of complement factor C3d. Genetic reconstitution of CD55 prevented C3d deposition. Stimulation of anaphylatoxin receptors on patient T lymphocytes produced increased tumor necrosis factor alpha, which caused a decreased ratio of the anti-coagulatory protein thrombomodulin to the pro-coagulatory protein tissue factor. CD55 costimulation by CD97, and the contingent production of interleukin-10, was defective in patient T lymphocytes. Hence, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE (CHAPLE) disease is caused by abnormal complement activation due to autosomal recessive loss-of-function (LOF) mutations in the CD55 gene. Interestingly, Dr. Waldmann had originally attributed protein-losing enteropathy to primary intestinal lymphangiectasis and, some 50 years later, our findings provide a genetic etiology for this disease. Moreover, our in vitro results suggest that eculizumab (Soliris, Alexion), an FDA-approved, complement-inhibiting therapeutic may benefit these patients. We have now tested that hypothesis in over 30 patients that have been treated at Marmara hospital in Istanbul in which eculizumab has achieved dramatic treatment effects. We find that almost immediately after administration of the drug, the diarrhea and abdominal pain ceases. After 2 treatments over the course of 4 weeks, blood protein levels and other abnormalities were reversed. Thus, our results show how disorders of this specialized arm of innate immunity can lead to severe disease. Moreover, these results are an important demonstration of how precision medicine based on genetic insights can have a dramatic impact on a severe disease with a high rate of morbidity and mortality. Recently, we have uncovered a novel disease involving Clathrin-mediated endocytosis (CME) is the major endocytic pathway by which eukaryotic cells internalize cell-surface cargo proteins and extracellular molecules, thereby enabling a broad range of biological processes, including cell signaling, nutrient and growth factor uptake, and cell fate and differentiation. This system depends on the F-BAR domain only proteins 1 and 2 (FCHO1/FCHO2) that are involved in the maturation of clathrin-coated pits for endocytosis and can manage specific vesicular cargo in immune cells in ways that have important effects on immune function.