Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies

Transient Decrease of Circulating and Tissular Dendritic Cells in Patients With Mycobacterial Disease and With Partial Dominant IFNγR1 Deficiency

“…In patients with Interferon Regulator Factor (IRF) eight mutations the AR variant causes a complete lack of circulating monocytes and DCs, while the AD variant associates with a selective depletion of CD11c+CD1c+ circulating dendritic cells ( 18 , 19 ), as reported also in patients with the recently described SPPL2A (signal peptide peptidase-like 2A) deficiency, where a defective IL-12 and IL-23 production by mDCs may disrupt the priming of T lymphocytes ( 19 , 20 ). Other disorders may display pancytopenia with monocyte and DCs deficiencies, from the WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome ( 21 ), to defects in genes related to DCs development and functions, such as the CD40/CD40L deficiency, the MCH class II deficiency, the Wiskott-Aldrich syndrome, the Pitt-Hopkins Syndrome, or the IRF7 deficiency ( 22 ). The activation of DCs depends upon a crosstalk with CD4+ T lymphocytes, enabling the same DCs to prime cytotoxic T lymphocytes, polarize a Th1 T cells response, and regulate the immunity against intracellular pathogens ( 23 – 25 ).…”

WHIM Syndrome

“…In humans, the chemokine receptor CXCR4 is expressed on most leukocyte subsets and functions to promote hematopoietic stem cell (HSC) and neutrophil homing to and retention in bone marrow. In contrast to the lack of Cxcr4 expression in the many murine models, in human patients the WHIM mutations alter the CXCR4 carboxyl terminus such that it enhances and prolongs receptor signaling (Kawai and Malech 2009;Dotta et al 2019).…”

“…As a result, egress of normally produced and functional neutrophils from the bone marrow to the blood is impaired causing neutropenia in the circulation but an expansion of the pool of (over)differentiated neutrophils that do not have the typical multilobulated nuclear morphology of three to four lobes but increased to five or even six lobes (Kawai and Malech 2009;Dotta et al 2019).…”

“…WHIM syndrome is a rare combined immunohematologic disorder characterized by chronic panleukopenia, including circulating neutrophils and B and T lymphocytes (Kawai and Malech 2009;Dotta et al 2019). Despite this, patients show limited susceptibility to pathogens, with the notable exception of human papillomavirus and respiratory encapsulated bacteria (Kawai and Malech 2009).…”

Acute myeloid leukemia arising after Hodgkin lymphoma in a patient with WHIM syndrome

“…WHIM syndrome has characteristics of a PID that predispose to malignancies and hematological disorders . Lymphomas have been the only hematologic malignancies reported so far in WHIM syndrome (Table ). We report a female with WHIM syndrome who developed Hodgkin lymphoma (HL) and acute myeloid leukemia (AML) ensuing in less than 2 years.…”