Specifc aims:
Our proposal aims at identifying which molecules can be targeted to enhance NK cell functions in WHIM
patients, with particular interest dedicated to those that are involved in the clearance of human papillomavirus (HPV) infected cells. Thus, we will:
1) analyze the phenotypic and functional characteristics of NK subsets in WHIM disease. To assess the mechanisms underlying NK cell phenotype, attention will be dedicated to the analysis of the crosstalk with other immune (neutrophils), or non-immune (stromal cells) components of the NK cell differentiation niche in BM.
2) assess the influence of WHIM mutation on the anti-viral activity mediated by NK cells during HPV
infection.
3) establish approaches to increase NK cell accumulation in skin virus lesions.
Background/rationale
WHIM syndrome is a rare congenital disorder characterized by warts, hypogammaglobulinemia, recurrent bacterial infections, and myelokathexis. Genetic defects leading to persistent activation of the chemokine receptor CXCR4 are at the basis of the syndrome and result in marked leucopenia due to immune cell retention in generative organs. The associated immune defect underlies the marked susceptibility to bacterial and HPV infection.
Research design and methods for achieving the stated objectives
Our research goals will be pursued by performing an intensive characterization of peripheral blood (PB)
NK cell subsets by flow cytometry. NK cell characteristics will be related to the level of disease signs and to the functional status of other immune and non-immune cells expressing the mutated CXCR4. Moreover, NK cell role against HPV will be established by analyzing their migration and function in skin lesions.
Anticipated output
Through NK cell characterization, we foresee to obtain unknown information on the role of those cells in
the HPV clearance in the WHIM syndrome and to generate important therapeutic tools
