Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Understanding the WHIM syndrome and search for new therapies: molecular analysis of CXCR4 functions in leukocyte trafficking and activation

Project Coordinator

Instituto Clinico Humanitas, IRCCS - Humanitas Mirasole SpA Adaptive Immunity


Françoise Bachelerie Institut Pasteur Department of Virology Paris, France
Santos Manes Consejo Superior de Investigaciones Cientificas Immunology and Oncolgy Madrid, Spain

The syndrome of neutropenia, hypogammaglobulinemia, myelokathexis (WHIM; OMIM: #193670) is a rare primary immunodeficiency that transmits usually as autosomal dominant disease and manifests as recurrent bacterial infections and warts of hands, feet and genitalia. The genetic basis of the disease have been discovered by identifying heterozygous mutations in the cytoplasmic tail of the chemokines receptor CXCR4. CXCR4 signaling controls cell migration to CXCL12, a chemokine playing a crucial role in coordinating lymphoid tissue homeostasis. All the mutations of CXCR4 identified in WHIM patients confer increased cell responsiveness to CXCL12, and it has been proposed that sustained CXCR4 chemotactic activity accounts for the clinical manifestations of the WHIM syndrome. However, some of the typical manifestations of the disease, such as the hypogammaglobulinemia and the extreme susceptibility to HPV infections, remain unexplained. In addition, recent evidence indicates that the syndrome is genetically heterogeneous.
This collaborative research proposal is aimed to address key questions about the WHIM disease at molecular and cellular levels. On the one hand, we will analyze if and how CXCR4 mutations found in WHIM patients modify the capacity of the receptor to deliver signals controlling lymphocyte activation. We will perform a detailed analysis of the molecular mechanisms that underlie the immune cell dysfunctions observed in WHIM patients, focusing on CXCR4 signaling pathways that are still unexplored but potentially crucial for specific therapeutic strategies. On the other, using a WHIM mouse model, we will perform an in vivo analysis of the pathogenic mechanisms of the syndrome and monitor the impact of antagonist molecules on the CXCL12/CXCR4 pathways. Thus, this study will proceed in parallel in both human and mouse experimental systems, and the presence of researchers from molecular biology centers, biomedical institutes and clinical frameworks will guarantee the necessary synergies to attack the pathogenic processes intrinsic to WHIM immunodeficiency.


E-Rare 2012 - Created by Toussaint Biger