miércoles, 22 de julio de 2015

Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome (WHIMS)

WHIM syndrome is a rare immune disorder named after its symptoms. People with WHIM syndrome have low levels of infection-fighting white blood cells, especially neutrophils, in their bloodstream. This deficiency predisposes them to frequent infections and persistent warts.

Causes

WHIM syndrome is caused by mutations in the CXC chemokine receptor 4 (CXCR4) gene. One of the many functions of CXCR4 is to tether white blood cells to the bone marrow, where the cells originate. WHIM syndrome mutations result in excessive CXCR4 activity, which traps the cells inside the bone marrow and prevents their movement into the bloodstream and the rest of the body.

WHIM syndrome bone marrow sample (left) and blood sample (right). Pink cells are red blood cells, and blue cells are other blood cells including white blood cells (WBCs). WHIM syndrome is caused by mutations that trap WBCs in the bone marrow.
Credit: NIAID

Signs and Symptoms

People with WHIM syndrome experience the following symptoms:

Warts of the skin, mouth, and genitals caused by human papillomavirus (HPV)
Hypogammaglobulinemia, a deficiency in specific infection-fighting antibodies in the blood
Infections that recur frequently
Myelokathexis, the failure of neutrophils, a type of white blood cell, to move from the bone marrow into the bloodstream

WHIM syndrome patients also have trouble distributing most other types of immune cells to the blood. Such defects in the immune system predispose WHIM syndrome patients to frequent infections and an increased risk of developing cancer caused by HPV.

Diagnosis

WHIM syndrome is defined by the clinical manifestations in the acronym WHIM. Almost all WHIM syndrome patients have mutations in the CXCR4 gene.

Treatment and Research

Standard therapy for WHIM syndrome, which is aimed at restoring deficient components of the blood, includes intravenous immunoglobulin, a blood product containing antibodies, or granulocyte colony-stimulating factor (G-CSF), an immune-cell-growth molecule. However, these treatments do not specifically target the CXCR4 genetic defect and evidence of their efficacy from direct tests in clinical trials is lacking.

In 2011, NIAID investigators tested the drug plerixafor (Genzyme/Sanofi) in WHIM syndrome patients over the course of 1 week to investigate safety and to establish the minimally effective dose for raising the neutrophil count to a level at which infections would be unlikely to occur. Plerixafor, which blocks the activity of CXCR4, is approved by the Food and Drug Administration (FDA) to mobilize blood-forming stem cells from the bone marrow for collection and eventual transplantation after cancer therapy. Because it can mobilize immune cells to the blood in healthy people and targets CXCR4 specifically, it was considered an ideal drug candidate for treating patients with WHIM syndrome. In this study, the drug was safe and could elevate neutrophils to a safe level using approximately 5 percent of the FDA-approved dose for stem cell mobilization.

In 2014, a study by NIAID researchers revealed that low-dose plerixafor, designed to reduce but not eliminate CXCR4 activity, was safe and effective at raising the neutrophil count in the blood over the course of 6 months. The study also provided preliminary evidence of efficacy at reducing wart burden and the incidence of infection. Currently, NIAID scientists are comparing the safety and efficacy of plerixafor to that of G-CSF, a standard treatment, in clinical trials for the treatment of WHIM syndrome.

Interestingly in 2015, NIAID researchers reported the spontaneous cure of a person with WHIM syndrome that likely was the result of a genetic phenomenon called chromothripsis, or “chromosome shattering,” which caused a random and fortuitous deletion of the mutant CXCR4 gene. Presumably, a stem cell lacking mutant CXCR4 survived and repopulated all of the person’s neutrophils. The NIAID team is exploring how to apply the study findings to improve bone marrow transplantation, which relies on the ability of donor stem cells to repopulate in a recipient.