Targeted strategies directed at the molecular defect: Toward precision medicine for select primary immunodeficiency disorders

Abstract

Primary immunodeficiency disorders (PIDs) represent a range of genetically determined diseases that typically have increased susceptibility to infections and in many also have evidence of immune dysregulation that often presents as autoimmunity. Most recently, the concept of gain of function (GOF) mutations associated with PIDs has become well recognized and adds a new dimension to the understanding of this group of disorders moving beyond the more commonly seen loss of function mutations. The rapidly expanding genetic defects that have been identified in previously uncharacterized PIDs has opened up the potential for targeted therapy directed at the specific disease-causing abnormality. This has been driven by linking PID specific genetic defects to the associated unique abnormalities in cellular signaling pathways amenable to directed therapies. These include agents that either block over active or enhance under responsive cellular pathways. Selected primary immunodeficiences were chosen, whose genetic defects have been recently characterized and are amenable to targeted therapy, as a reflection of the power of precision medicine forward.

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

“…Despite the progress in the genetic characterization of PIDs, many patients still lack a molecular diagnosis. A better understanding of the genetic and immune defects of patients is critical to develop therapeutic strategies aimed at changing the clinical course of the disease and to guarantee an appropriate genetic counseling allowing the identification of PID patients before the onset of the disease (11)(12)(13). The application of Next Generation Sequencing (NGS) to PIDs has been a revolution and it has accelerated the discovery and identification of novel disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity (7,8,(14)(15)(16).…”

Compound Heterozygous Mutations of IL2-Inducible T cell Kinase in a Swedish Patient: the Importance of Early Genetic Diagnosis

“…Other factors may also contribute to the development of the disease, for instance, alterations in the epigenome, transcriptome, proteome or microbiome can influence the disease phenotype (127), and we will, therefore, consider using alternative strategies to look for other explanations for the disorders in our patients.…”

Immunodeficiency and disorders of immune dysregulation

“…Importantly, the disease is characterized by incomplete penetrance and variable expressivity . Initially, patients with CTLA4 haploinsufficiency were treated only with rapamycin to decrease T‐cell hyperactivity, but abatacept and belatacept have shown to be an effective targeted treatment to control the immune dysregulation . HSCT is the only definitive therapy in patients with CTLA4 haploinsufficiency …”

“…The onset of the disease is typically in childhood with sinopulmonary infections that are most commonly due to S pneumoniae and H influenza and often lead to bronchiectasis. Recurrent or persistent infections due to herpesviridae , such as EBV, cytomegalovirus, HSV, and VZV, are also frequent . Lymphoproliferation, manifesting as lymphadenopathy, splenomegaly, and/or hepatomegaly, is present in the majority of the patients, and autoimmunity, lymphoid hyperplasia of the airways and gut, developmental delay, and enteropathy are also common.…”

“…Lymphoproliferation, manifesting as lymphadenopathy, splenomegaly, and/or hepatomegaly, is present in the majority of the patients, and autoimmunity, lymphoid hyperplasia of the airways and gut, developmental delay, and enteropathy are also common. APDS patients are at higher risk of lymphomas (particularly EBV‐driven B‐cell lymphoma) . Growth retardation has been noticed in around half of APDS2, but not in APDS1 patients.…”