Adaptive Immunodeficiency in WHIM Syndrome

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.

Spinal cord injury causes chronic bone marrow failure

“…Bone marrow failure diseases develop when the bone marrow is unable to produce appropriate numbers of healthy mature white and red blood cells. Normal aging 12,57 and various diseases including diabetes 58,59 , warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome [60][61][62] , glioblastoma 63 , and chemotherapy 64 and molecular cues orchestrated between HSPCs, CXCL12expressing perivascular stromal cells and the autonomic nervous system, particularly sympathetic noradrenergic nerve fibers, control HSPC proliferation, regeneration, and differentiation 8,10,11,65 . Specifically, post-ganglionic sympathetic neurons release norepinephrine into the bone marrow, causing bone marrow stromal cells to decrease their expression of CXCL12 which, in turn, untethers CXCR4 + HSPCs and mature leukocytes from the niche, facilitating their egress into the circulation 8,10,36 .…”

Arhgap25deficiency leads to decreased numbers of peripheral blood B cells and defective germinal center reactions

“…The WHIM mutation results in much greater hyperresponsiveness to CXCL12 than Arhgap25 deletion, so it is not surprising that the WHIM phenotype is much more extreme than the phenotype we report. In humans, WHIM is characterized by sequestration of neutrophils in the bone marrow (myelokathexis), as well as lymphopenia, variable hypogammaglobulinemia, and an inability to mount appropriate antibody responses (29). Mice bearing the WHIM mutation also have profound lymphopenia, impaired B and T cell development, disorganized secondary lymphoid architecture, and defects in plasma cell differentiation.…”

The G Protein-Coupled Receptor Kinases (GRKs) in Chemokine Receptor-Mediated Immune Cell Migration: From Molecular Cues to Physiopathology

“…Furthermore, upon chromothripsis, the WHIM-CXCR4 allele deleted from the myeloid lineage of a patient with WHIM was associated with a correction of neutropenia [ 148 ]. In addition, clinical studies based on the chronic use of AMD3100 (i.e., market name of plerixafor) show beneficial effects on the mobilization of neutrophils and most subtypes of leukocytes [ 60 ], because patients suffer from panleukopenia, including lymphopenia, consistent with important roles for CXCL12/CXCR4 signalling in regulating haematopoiesis and immunity, as observed in patients and a mouse model of WHIM syndrome [ 149 ]. Finally, the still-debated questions of the sources of neutrophils mobilized by AMD3100 together with neutrophil heterogeneity (spatial, phenotypic and functional) have prompted doubts about neutrophil sequestration in the BM as the sole mechanism to explain neutropenia driven by the WHIM-associated gain of CXCR4 function.…”