Oligoclonality, impaired class switch and B-cell memory responses in WHIM syndrome

Abstract

Heterozygous truncating mutations in CXCR4 have been identified as a cause of WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency and myelokathexis). The receptor truncations have been proposed to lead to altered lymphocyte trafficking. The purpose of the described studies was to characterize the B-cell repertoire in WHIM subjects. We confirmed profound B-cell lymphopenia and demonstrated oligoclonality of the circulating B-cell pool by HCDR3 spectratyping. The response to immunization was studied in one subject utilizing a bacteriophage ΦX174 immunization protocol. Spectratyping showed oligoclonality at baseline with normalization of the HCDR3 length distribution by five months after immunization with ΦX174 with eventual return to the baseline state. Isotype switching from phage specific neutralizing antibody of the IgM class to IgG was markedly reduced. Overall, these data suggest that impaired CXCR4 signaling in WHIM syndrome results in defective B-cell function and abnormal isotype switching, possibly through effects on germinal center trafficking of lymphocytes.

A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor

“…30,31 Vaccination studies have identified effector memory T cells in mouse bone marrow that may serve as a reservoir, 32,33 and this may also be true in humans. 34 Thus, bone marrow is potentially a major source of all the major cell types mobilized to the blood by plerixafor.…”

Unexpected developments in immune organs in WHIM syndrome

“…As such, it has been proposed that the bone marrow microenvironment may be a target for new therapeutic agents in the treatment of myeloma. 6,7 Supporting this idea, Ghobrial and colleagues have previously demonstrated that targeting of CXCR4 with AMD3100-altered myeloma homing to the bone marrow, increased circulating myeloma cells, and increased sensitivity to cytotoxic agents. 8,9 These and other studies examining the CXCL12/CXCR4 axis have resulted in ongoing clinical trials.…”

“…In this regard, there are several reports of short-lived antibody responses to vaccines and vaccination failures in WHIM patients. 6 Importantly, the CXCR4 1013 knock-in mouse will now allow systematic modeling of primary and memory vaccine responses, germinal center formation, and the relative importance of lymphoid versus myeloid defects to infection susceptibility in WHIM syndrome.…”

How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome

“…Despite normal immunoglobulin levels or a mild reduction in the immunoglobulin levels, WHIM subjects display B-cell lymphopenia with a reduced number of switched memory (CD27 1 ) B cells and B-cell oligoclonality, likely contributing to infection. 5,35 Moreover, the inefficient plasma cell differentiation and maintenance that was shown in mice may account for the defective humoral immunity observed in WHIM patients. 36 Indications for the use of immunoglobulin therapy for WHIM Since the detection of hypogammaglobulinemia, WHIM patients have often been started with monthly intravenous (IVIG) or weekly subcutaneous immunoglobulin therapies, even though this symptomatic treatment is expensive, requires good patient adherence, and has an efficacy that has not been properly proved (Figure 3).…”

“…46 Overall, these observations and the evidence that complications of any kind have never been reported with live vaccines, such as the varicella vaccine and Bacillus Calmette-Guérin (BCG) vaccine, in patients diagnosed after vaccination, suggest that HPV vaccines may be routinely used as early prophylactic treatment of young WHIM patients. Meanwhile, it has to be considered that the long-term efficacy of vaccines is reduced in WHIM patients because of defective development or maintenance of memory B cells 35 and the early decline of an antibody response against vaccine antigens.…”