Molecular Mechanisms Of The Autoimmune Lymphoproliferative Syndrome And Other Immunoregulatory Disorders

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

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. The 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, India, and Turkey, providing many patients to study at the cellular and genomic level. Here we focus on three projects this reporting period. We have discovered a very interesting genetic disease causing severe abdominal pain and diarrhea due to early-onset protein-losing enteropathy (PLE) with lymphangiectasia, edema due to hypoproteinemia, malabsorption, and, less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease. We previously 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. We named this disease CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE (CHAPLE disease). To establish an effective treatment, we first studied the monoclonal antibody eculizumab, which targets complement Factor C5, to treat 16 CHAPLE cases with distinct CD55 gene mutations. We were interested to understand how pharmacological inhibition downstream of C5 will affect immune dysregulatory disease caused by CD55 loss by affecting upstream control at the C3 convertase. We demonstrated that eculizumab is broadly effective in patients with CHAPLE disease with different mutations. Recovery from complement damage to gut lymphatics was achieved rapidly in 100% of cases. The loss of immunoglobulins, infections, and long-standing functional GI abnormalities were substantially reversed. However, the effects of the drug were temporary. We saw an immediate flare-up of symptoms and serum albumin and immunoglobulin loss when the medication was withdrawn. This observation implies that complement and its innate immune and inflammatory effector mechanisms are constantly provoked, and that patients will require continuous treatment. Thus, eculizumab effectively treats, but does not cure, CHAPLE disease. Aside from the high cost, other drawbacks of eculizumab include a requirement for IV drug administration and adverse side effects. Currently, we are completing a clinical trial with collaborators Dr. Ivan Fuss in NIAID and scientists from Regeneron Pharmaceuticals, using the monoclonal antibody Pozelimab. This antibody is also directed against the terminal complement protein C5, blocking the formation of the membrane-attack complex that mediates cell lysis and preventing the formation of specific anaphylatoxins. Pozelimab can be given by intravenous or subcutaneous administration and binds to polymorphic variations in C5 that are not recognized by eculizumab. This trial offers a promising opportunity to treat CHAPLE disease patients for which there are no approved targeted therapies. We have recruited a patient with this rare disease to the NIH Clinical Center and he is currently undergoing therapy. Based upon the results of the clinical trial, the U.S. Food and Drug Administration approved Pozelimab for treatment of CHAPLE disease. Our second project focuses on a new inborn error of immunity with GIMAP5, a GTPase, which is thought to regulate the lifespan of lymphocytes. Our findings provide evidence of the link between ceramides (CERs) and T cell immunosenescence and establish a novel regulatory axis involving protein kinase CK2 (CK2), CERS2, and GIMAP5. GIMAP5 is the best-known member of the GIMAP gene family, but its deficiency causes severe immune pathology that is poorly understood. We found that GIMAP5 deficiency causes a new human genetic immunodeficiency disease with a T and NK cell lymphopenia phenotype and reveal its critical biochemical role in lipid homeostasis to ensure cell longevity and prevent senescence. We call this disease GIMAP5 deficiency with immunodysregulation, splenomegaly, enlarged lymph nodes, liver disease and lymphopenia or GISELL. We found that GIMAP5 governs CER levels by controlling CK2:CERS2 association in lymphocytes. The absence of GIMAP5 allows for their constitutive interaction causing CER accumulation and consequential cell senescence or death. The defects caused by GIMAP5 are rescued by CK2 inhibition drugs. These may be an effective treatment option for GISELL, which has a very high mortality.