Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency

ABSTRACT

Introduction: WHIM syndrome is a rare combined primary immunodeficiency disorder caused by autosomal dominant gain-of-function mutations in the chemokine receptor CXCR4. It is the only Mendelian condition known to be caused by mutation of a chemokine or chemokine receptor. As such, it provides a scientific opportunity to understand chemokine-dependent immunoregulation in humans and a medical opportunity to develop mechanism-based treatment and cure strategies.

Areas covered: This review covers the clinical features, genetics, immunopathogenesis and clinical management of WHIM syndrome. Clinical trials of targeted therapeutic agents and potential cure strategies are also included.

Expert opinion: WHIM syndrome may be particularly amenable to mechanism-based therapeutics for three reasons: 1) CXCR4 has been validated as the molecular target in the disease by Mendelian genetics; 2) the biochemical abnormality is excessive CXCR4 signaling; and 3) antagonists selective for CXCR4 have been developed. Plerixafor is FDA-approved for hematopoietic stem cell (HSC) mobilization and has shown preliminary safety and efficacy in phase I clinical trials in WHIM syndrome. Gene editing may represent a viable cure strategy, since chromothriptic deletion of the disease allele in HSCs resulted in clinical cure of a patient and because CXCR4 haploinsufficiency enhances engraftment of transplanted HSCs in mice.

KEYWORDS:

• CXCR4
• G-CSF
• myelokathexis
• plerixafor/AMD3100
• WHIM syndrome
• X4P-001/AMD11070

Article highlights

• Autosomal dominant gain-of-function mutations in the C-tail of chemokine receptor CXCR4 cause 98% of reported cases of WHIM syndrome. Coincidentally, CXCR4 C-tail mutations are also commonly found in patients with Waldenstrom’s macroglobulinemia, suggesting a mutational hotspot, and are associated with poorer prognosis.

• The main clinical manifestations of WHIM syndrome are warts, hypogammaglobulinemia, recurrent bacterial oto-sino-pulmonary and skin infections, and myelokathexis. Myelokathexis is neutropenia due to impaired egress of functionally normal neutrophils from the bone marrow. However, many patients have panleukopenia.

• Despite combined immunodeficiency, invasive and life-threatening infection is uncommon in WHIM patients, due to the ability of neutrophils to be released from bone marrow during infection.

• The molecular pathogenesis of WHIM syndrome involves impaired CXCR4 downregulation and possibly other unknown mechanisms resulting in increased signaling strength. This results in exaggeration of the normal function of CXCR4 to promote neutrophil retention in the bone marrow. Patients may also have impaired vaccine responses possibly due to defects in lymphocyte development and trafficking as well as immune synapse formation.

• Targeted mechanism-based treatment strategies using CXCR4 antagonists are currently in clinical trials.

• A cure strategy involving gene editing of the mutant allele in HSCs that has a fortuitous side-effect of enhancing HSC engraftment potential has been conceived based on the case of the first patient ever described with WHIM syndrome. WHIM-09 acquired a second mutation through chromothripsis (chromosome shattering) that deleted the WHIM mutation in an HSC, which acquired a selective growth advantage and repopulated her myeloid lineage, resulting in clinical cure.

This box summarizes key points contained in the article.

Declaration of Interest

P.M.M., D.H.M., Q.L. and J-L.G. are listed as inventors on U.S. Patent Application No. 62/026,138, which describes a method of enhancing engraftment of hematopoietic stem cells by genetically inactivating one copy of CXCR4. The authors have no other 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 royalties.

Additional information

Funding

This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH.