Disease mechanism in two novel primary immunodeficiencies characterized by increased viral susceptibility and immune dysregulation

Abstract

Primary Immunodeficiency Diseases (PIDs) are a heterogeneous group of genetic disorders characterised by malfunctioning of the immune system that predisposes to different patterns of infections, allergy, autoimmunity and cancer. To date, more than 300 gene defects have been identified to cause PIDs. PIDs are considered to be ‘experiments of nature’ as they provide in vivo assessment of the functional consequences when specific genes are defective and help our understanding of the basic cellular pathways and mechanisms of host defence in the human immune system. For this reason, many clinical and molecular studies have focused on the forward genetic potential of PIDs. In my study, I identified two novel PIDs characterised by increased viral susceptibility and immune dysregulation. Firstly, I investigated a patient who developed fatal illness after routine immunization with live attenuated vaccine measles, mumps and rubella (MMR) vaccine. By investigating type I interferon (IFN) signalling and performing targeted sequencing, I identified a homozygous mutation in the IFNα receptor 2 (IFNAR2) as the causative variant in the patient as well as in a newborn sibling. This phenotype emphasises the important role played by type I IFN signalling in antiviral immunity. Secondly, I investigated two siblings from a consanguineous marriage who presented with immune dysregulation characterised by lymphoproliferative disease (chronic lymphadenopathy, hepatosplenomegaly progressing to lymphoma) and susceptibility to herpesviruses. In addition, both patients developed autoimmunity. A clinical diagnosis of autoimmune lymphoproliferative syndrome (ALPS) was made, supported by laboratory findings that showed impaired FAS-mediated apoptosis and increased double negative (DN) T cells. By using the approach of combined whole exome sequencing and homozygosity mapping, I identified a homozygous missense mutation of Ten Eleven Translocation 2 (TET2) as the disease causing variant. TET2 is involved in epigenetic regulation of gene expression by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in the DNA demethylation process, amongst other mechanisms. ii The identification of these two novel gene defects in the two different PIDs provides new understanding and broadens our knowledge about physiological and pathophysiological pathways in the human immune system. Furthermore, knowledge of these genetic defects can help in providing better care and treatment to future patients.