Abstract
Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The “M” in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.
Highlights
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (OMIM 193670) is an extremely rare, combined primary immunodeficiency disorder found worldwide, that is estimated to have an incidence of 0.23 cases per million births [1]
All but a few cases of WHIM syndrome are caused by autosomal dominant gain-of-function mutations in the G protein-coupled, cysteine-X-cysteine chemokine receptor CXCR4 [8], and these are the only chemokine or chemokine receptor mutations responsible for a Mendelian condition
One cellular consequence of this is that cells expressing the WHIM variant of CXCR4 demonstrate greater chemotaxis in vitro towards CXCL12 [10]
Summary
Hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (OMIM 193670) is an extremely rare, combined primary immunodeficiency disorder found worldwide, that is estimated to have an incidence of 0.23 cases per million births [1]. Heterozygous nonsense or frameshift mutations result in truncations of the cytoplasmic tail domain of the receptor, which is rich in serine and threonine residues Upon receptor activation, this domain normally becomes phosphorylated by G protein–coupled receptor kinases and binds β-arrestin which mediates receptor internalization/downregulation. Myelokathexis is key to the clinical diagnosis of WHIM syndrome. Congenital cardiovascular defects, including tetralogy of Fallot, have been observed in some patients with WHIM syndrome [1,4,17,20,25]. Together, these phenotypes have cautioned clinical trials of CXCR4-targeted therapy. WHIM syndrome is characterized by myelokathexis, most patients have panleukopenia, including lymphopenia, associated with hypogammaglobulinemia. Unlike other reviews of WHIM syndrome, the remainder of this review will focus on CXCR4 and WHIM mutations in adaptive immunity in patients and in the mouse model of WHIM syndrome [26]
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