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Journal of Clinical Immunology

, Volume 39, Issue 6, pp 532–556 | Cite as

WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure

  • Lauren E. Heusinkveld
  • Shamik Majumdar
  • Ji-Liang Gao
  • David H. McDermott
  • Philip M. MurphyEmail author
CME Review

Abstract

WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and β-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.

Keywords

Chemokine CXCL12 CXCR4 CXCR2 myelokathexis human papillomavirus plerixafor 

Notes

Acknowledgments

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

Compliance with Ethical Standards

Conflict of Interest

PMM is a member of the Scientific Advisory Board of X4-Pharma. PMM, J-LG, and DHM are listed as inventors on a patent application disclosing a method of enhancing hematopoietic stem cell engraftment by CXCR4 knockdown. There are no other stated conflicts of interest.

Supplementary material

10875_2019_665_MOESM1_ESM.docx (44 kb)
ESM 1 (DOCX 33 kb)
10875_2019_665_MOESM2_ESM.docx (120 kb)
ESM 2 (DOCX 89 kb)

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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaUSA
  2. 2.Cleveland ClinicCleveland Clinic Lerner College of MedicineClevelandUSA

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