Abstract
The Wiskott–Aldrich syndrome (WAS) is due to mutations of the WAS gene encoding for the cytoskeletal WAS protein, leading to abnormal downstream signaling from the T cell and B cell antigen receptors (TCR and BCR). We hypothesized that the impaired signaling through the TCR and BCR in WAS would subsequently lead to aberrations in the immune repertoire of WAS patients. Using next generation sequencing (NGS), the T cell receptor β and B cell immunoglobulin heavy chain (IGH) repertoires of eight patients with WAS and six controls were sequenced. Clonal expansions were identified within memory CD4+ cells as well as in total, naïve and memory CD8+ cells from WAS patients. In the B cell compartment, WAS patient IGH repertoires were also clonally expanded and showed skewed usage of IGHV and IGHJ genes, and increased usage of IGHG constant genes, compared with controls. To our knowledge, this is the first study that demonstrates significant abnormalities of the immune repertoire in WAS patients using NGS.
Highlights
The Wiskott–Aldrich syndrome (WAS) is an X-linked disease characterized by the triad of eczema, microthrombocytopenia, and immunodeficiency [1, 2]
Immunological abnormalities detected in patients included a variable degree of T cell lymphopenia, accumulation of effector memory and of CD8+ TEMRA cells, a low number of unswitched memory B cells, and an increased proportion of CD19+ CD21low CD38low B cells (Table 1)
We have reported for the first time on the use of next generation sequencing (NGS) to analyze the T and B cell repertoire in patients with WAS
Summary
The Wiskott–Aldrich syndrome (WAS) is an X-linked disease characterized by the triad of eczema, microthrombocytopenia, and immunodeficiency [1, 2]. The WAS gene encodes for the WAS protein (WASp) [5], which is expressed solely in hematopoietic cells, and is recruited to the inner cell membrane in response to activating signals, including engagement of the T and B cell antigen receptors (TCR and BCR) [6, 7]. WASp recruits the Arp2/3 complex, triggering actin polymerization [8]. Deficiency of WASp is associated with significant immune abnormalities that affect all leukocytes [9]. WAS patients manifest progressive T cell lymphopenia [10] and impaired formation of the immune synapse, defective IL-2 secretion, and reduced proliferation in response to TCR ligation [11, 12]. The B cell compartment is affected in WAS
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
