Recent advances in primary immunodeficiency: from molecular diagnosis to treatment

Abstract

The technological advances in diagnostics and therapy of primary immunodeficiency are progressing at a fast pace. This review examines recent developments in the field of inborn errors of immunity, from their definition to their treatment. We will summarize the challenges posed by the growth of next-generation sequencing in the clinical setting, touch briefly on the expansion of the concept of inborn errors of immunity beyond the classic immune system realm, and finally review current developments in targeted therapies, stem cell transplantation, and gene therapy.

An appraisal of the Wilson & Jungner criteria in the context of genomic-based newborn screening for inborn errors of immunity

“…A greater understanding of immunologic mechanisms in health and disease, coupled with new drug development, has led to further options for the provision of targeted therapy for specific forms of IEI. 33 These newer agents, including enzyme replacement therapy, biologic therapies, and small-molecule drugs (including cytokines, cytokine inhibitors, and agents inhibiting signal transduction molecules) target specific immunologic pathways and ameliorate defective immune responses at the molecular level. This contrasts with traditional agents such as corticosteroids and other immunosuppressants, which are nonspecific, have several off-target effects, and potentially more significant adverse effects.…”

“…Jakinibs are small molecules that inhibit the Janus-activating kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway, and include ruxolitinib, baracitinib (predominant JAK1/JAK2 blockade), and tofacitinib (predominant JAK1/JAK3 blockade). 33 They have been demonstrated to be safe and efficacious in treating disease complications arising due to gain-of-function mutations in STAT1 43,44 and STAT3 43,45,46 by abrogating abnormal pathway activation.…”

“…In addition to mammalian target of rapamycin inhibition for activated phosphoinositide 3-kinase d syndrome, 2 selective inhibitors of PI3K have been developed and are currently under evaluation: leniolisib (oral inhibitor of the p110d subunit of PI3Kd) and nemiralisib (inhaled inhibitor of PI3Kd). 33 Cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion proteins. The cytotoxic T-lymphocyte-associated protein 4-immunoglobulin fusion protein abatacept has been used for the management of cytotoxic T-lymphocyte-associated protein 4 haploinsufficiency and LPSresponsive and beige-like anchor protein deficiency.…”

“…Anti-CD20 agents (such as rituximab) are used to manage autoimmune and lymphoproliferative complications in several forms of IEI. 33 Plerixafor.…”

Multicenter Outcome of Hematopoietic Stem Cell Transplantation for Primary Immune Deficiency Disorders in India

“…This is the first report of a multicenter data on HSCT for PID in India. All children with PID now have access to molecular diagnosis and treatment ( 32 , 33 ). Although only a third of the children have a matched family donor and unrelated registries like DATRI have a donor database of over 600,000 volunteers in the country, and this has made MUD transplants a reality ( 34 ).…”