The WHIMs of leukocytes

WHIM, a dominant immunodeficiency caused by mutations in the chemokine receptor CXCR4, leads to myeloid and lymphoid retention in tissues producing its cognate ligand, CXCL12 (SDF-1), by virtue of an exaggerated chemotactic and adhesion response to ligand.

Gulino and colleagues (page 444) have put pathophysiologic meaning to the dominant mutations in human CXCR4 leading to the rare combined immunodeficiency, WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. WHIM is characterized by human papilloma virus (HPV) infections; hypogammaglobulinemia; recurrent infections, especially of the respiratory tract; and leukopenia. One of the hallmarks of the disease is myelokathexis (derived from the Greek myelo-, meaning marrow, and kathexis, meaning retention). Leukopenia is present in the periphery, whereas bone marrow aspiration shows myeloid hypercellularity with increased numbers of granulocytes at all stages of differentiation. During episodes of infection, neutrophil counts typically increase over baseline. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) also mobilize mature neutrophils from the bone marrow and decrease the number of infections. Warts and hypogammaglobulinemia suggest an immunologic defect including T and B cells, as well as the myeloid series. Interestingly, normalization of immunoglobulin levels has been observed during G-CSF or GM-CSF treatment. These disparate features of WHIM syndrome were not especially unified by the identification of causative mutations in CXCR4,¹  a chemokine receptor better known as an HIV coreceptor. However, CXCR4 and its sole cognate ligand, CXCL12/stromal-derived factor-1 (SDF-1), have emerging and critical roles in HIV susceptibility, hematopoiesis, and leukocyte trafficking.²  Martin et al³  have shown that even activities on the distal end of the neutrophil life cycle, recirculation of senescing neutrophils back to the bone marrow, are CXCR4/CXCL12 dependent.³ FIG1 

In contrast to the genetic and in vitro studies that led to the identification of CXCR4's roles in HIV, Gulino and coworkers focused on the critical resource to help sort out the pathophysiology of CXCR4 mutations in WHIM: patients. Chemotaxis of WHIM T cells and neutrophils to CXCL12 was increased, as was adherence to CXCL12-treated endothelial cells, despite normal surface CXCR4 display, calcium flux, and internalization in response to CXCL12. Despite low total and memory (CD27⁺) B cells and hypogammaglobulinemia, patients had normal specific antibody production but poor long-term maintenance of titers. They also found reduced circulating naive T cells (CD45R0^-/CCR7⁺), increased proportions of effector memory (CCR7^-) cells, and oligoclonal expansion of T cells.

Therefore, the myelokathexis of WHIM appears to be caused by myeloid and lymphoid retention in the marrow or other CXCL12-producing tissues by virtue of exaggerated chemotactic and adhesion responses to ligand. This is an important observation, as it puts a clear pathophysiologic mechanism to some of an otherwise enigmatic assortment of phenotypes. These findings also help elucidate potential therapies, such as the SDF-1 antagonist AMD3100.⁴  Still, the precise mechanisms that cause HPV infection, restricted T-cell repertoire, or hypogammaglobulinemia remain unclear. The pursuit and study of rare diseases is sometimes regarded as a calling more fit for a Don Quixote (or perhaps a Sancho Panza). The yielding of the mechanisms of WHIM exemplifies the transition from enigmatic to paradigmatic.