Primary immunodeficiencies: a decade of shifting paradigms, the current status and the emergence of cutting-edge therapies and diagnostics

Abstract

A shift has occurred in the diagnostic and therapeutic modalities considered for patients with primary immunodeficiency diseases (PIDs). Early diagnosis remains the mainstay in appropriate management and remarkably influences the prognosis. More specific diagnostic tests as well as therapeutic modalities have been introduced in the last few decades. Nonetheless, the importance of a thorough history taking and physical examination should not be neglected. Novel diagnostic modalities including genetic sequencing have led to the recognition of previously unknown defects underlying PIDs. In addition, newborn screening is being advocated as an imperative diagnostic test. In terms of treatment, hematopoietic stem cell transplantation is considered the optimal treatment modality for many cases and has dramatically improved the outcome. Gene transfer into hematopoietic stem cells prior to transplantation has improved the efficacy of hematopoietic stem cell transplantation. In this article, the latest advances made in terms of diagnosis and treatment of PIDs are reviewed.

Keywords:

• diagnosis
• gene sequencing
• gene therapy
• hematopoietic stem cell transplantation
• immunoglobulin replacement therapy
• primary immunodeficiency diseases
• treatment

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• A thorough history taking and physical examination remain the initial steps in establishing the diagnosis of primary immunodeficiency diseases (PIDs).

• The introduction of Sanger DNA sequencing method formed a new era in modern molecular biology, leading to the identification of more than 230 well-defined molecular genetic causes of various PIDs.

• Despite advances made in terms of hematopoietic stem cell transplantation and gene therapy, immunoglobulin replacement therapy remains the only life-saving and life-long therapy in many patients, including those with common variable immunodeficiency as it tackles down their primary antibody failure.

• The most common cause of hematopoietic stem cell transplantation failure in severe combined immunodeficiency patients is inadequate T-cell immunity development.

• Gene transfer into the hematopoietic stem cell is an optimal treatment option for patients with PIDs who do not have access to an HLA-matched donor.

Notes

AD: Autosomal dominant; AR: Autosomal recessive; BLNK: B-cell linker; CASP: Caspase; CSR: class-switch recombination; DAF: Decay accelerating factor; DOCK: Dedicator of cytokinesis; FADD: Fas-Associated protein with Death Domain; FAS: First apoptosis signal; FASLG: FAS ligand; HIES: Hyper-immunoglobulin (Ig)E syndromes; ICF: Immunodeficiency-centromeric instability and facial abnormalities; ICOS: inducible costimulator; IRAK: Interleukin-1 receptor-associated kinase; LUBAC: Linear ubiquitin chain assembly complex; MCP: Monocyte chemoattractant protein; MTHFD: Methylenetetrahydrofolate dehydrogenase; PGM3: Phosphoglucomutase 3; PI3KD: Phosphoinositide-3 kinase delta; PKcs: Protein kinase catalytic subunit; PMS2: Postmeiotic segregation increased 2; RHOH: Ras homology, family member H; RIDDLE: Radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties; STIM: Stromal interaction molecule; TAP: Transporter associated with antigen presentation; TRAF: TNF receptor associated factor; TRIF: TIR-domain-containing adapter-inducing interferon-β; ZAP-70: Zeta-chain-associated protein 70 kD.