Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency

Abstract

2.1 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. 2.2 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. 2.3 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.

Regulator of G protein signaling 5 restricts neutrophil chemotaxis and trafficking

“…Although chemotactic responses to both CXCL1/2 and CXCL12 were increased in neutrophils from Rgs5 Ϫ/Ϫ mice relative to WT, we detected neither increased retention of neutrophils in bone marrow nor impaired neutrophil mobilization to tissues following an inflammatory stimulus. Of interest, this phenotype somewhat resembles warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome in humans, a disorder that is due to a gain-of-function mutation in CXCR4 (39). WHIM patients have peripheral blood neutropenia due to increased bone marrow retention but are nonetheless able to mobilize neutrophils to sites of inflammation.…”

WHIM syndrome: Immunopathogenesis, treatment and cure strategies

“…The disease incidence is unknown but is estimated to be about one in 4.3 million live births . To date less than 100 cases have been reported in the medical literature . Diagnosis can be difficult due to six main factors: (a) the disease is very rare so that few practitioners have ever seen a case, (b) the phenotypes are incompletely penetrant or variable in severity, (c) about one‐third of the cases arise de novo (parents test negative), (d) warts typically do not appear until the second decade of life, (e) acute infection typically increases the neutrophil count, so that neutropenia may be absent when patients are most likely to seek medical attention, and (f) myelokathexis can only be diagnosed by direct bone marrow examination .…”

“…19 All but one truncate the receptor 20 and remove an inhibitory region where serine and threonine residues are normally phosphorylated by G protein-coupled receptor kinase (GRK) proteins after activation by the CXCR4 agonist CXCL12, previously known as SDF-1 (stromal cell-derived factor 1). 21,22 β-arrestin normally binds to the phosphorylated domain to facilitate receptor internalization and degradation. 23 Thus, truncating mutations of the CXCR4 C-terminus act to delay internalization and prolong CXCR4 signaling (gain-of-function, Figure 3).…”

“…21,22 Diagnosis can be difficult due to six main factors: (a) the disease is very rare so that few practitioners have ever seen a case, (b) the phenotypes are incompletely penetrant or variable in severity, (c) about one-third of the cases arise de novo (parents test negative), (d) warts typically do not appear until the second decade of life, (e) acute infection typically increases the neutrophil count, so that neutropenia may be absent when patients are most likely to seek medical attention, and (f) myelokathexis can only be diagnosed by direct bone marrow examination. 21,22 Thus, it has been suggested that the diagnosis is best made genetically by testing for relevant mutations in CXCR4 by traditional Sanger DNA sequencing or the increasingly utilized technique of whole exome sequencing which allows automated analysis and discovery of multiple mutations that affect coding regions of known genes. 25 Rarely (<2% of cases) individuals may present with WHIM syndrome but lack a CXCR4 mutation implying that there is genetic heterogeneity.…”

Low-level Cxcr4-haploinsufficient HSC engraftment is sufficient to correct leukopenia in WHIM syndrome mice

“…Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, combined primary immunodeficiency disease caused in almost all cases by autosomal dominant, gain-of-function mutations in the gene encoding chemokine receptor CXCR4 (1,2). In response to its principal agonist CXCL12, CXCR4 signaling normally mediates homing, retention, and multilineage differentiation of hematopoietic stem and progenitor cells in BM niches by regulating their migration, survival, and quiescence (3)(4)(5)(6).…”