""""""""Studies were performed to examine the human immune response in normal individuals and in patients with congenital and acquired immunodeficiency states associated with a high frequency of cancer. Interleukin-2 (IL-2) and the IL-2 receptor (IL-2R) play pivotal roles in the immune response. Previously we discovered a soluble form of the IL-2R alpha subunit (sIL-2Ra) and demonstrated abnormal levels of sIL-2Ra in patients with several disorders of immune function including cancer and AIDS. A recently discovered lymphokine, IL-15, shares many functional similarities with IL-2. We have shown that IL-15 stimulates the release of sIL-2Ra from both resting and activated cells in vitro and in vivo; suggesting the possibility that in certain disorders IL-15 may contribute to abnormalities of immune function and elevated sIL-2Ra levels in vivo. We continued studies on the primary immunodeficiency disorders. Two forms of X-linked agammaglobulinemia have been described: Bruton's agammaglobulinemia (XLA) due to defects in Bruton's tyrosine kinase (Btk) and agammaglobulinemia associated with growth hormone deficiency (XLA/GHD). Examination of Btk in patients with XLA/GHD revealed a normal abundance of normal sized BTK transcripts, normal BTK cDNA sequences, normal amounts of expressed Btk protein and normal Btk enzymatic activity. These studies establish XLA/GHD as a disease distinct from XLA and suggest additional X-chromosome genes critical for B-cell development. The function of the protein product of the gene responsible for the Wiskott-Aldrich syndrome (WASP) has not been defined. We have produced monoclonal antibodies to WASP and have studied its expression and function in normal and Wiskott-Aldrich syndrome patients. This cytoplasmic protein is expressed in platelets, monocytes, T-cells and B-cells. Some patients with the Wiskott-Aldrich syndrome (WAS) produce a non-functional protein whose sequence has been defined while others do not - indicating critical residues for WASP function. The WASP has been shown to interact with several signaling proteins including phospholipase C gamma, PI3' kinase, src and fgr indicating that WASP may play a critical role in cytoskeletal organization and intracellular signaling to the nucleus. We demonstrated a phenotypic abnormality in WAS cells namely aberrant cytoskeletal actin organization and using retroviral-mediated gene transfer we were able to correct this abnormality. A rapid diagnostic test for WAS was developed using permeabilized flow cytometry. Additional proteins interacting with WASP were identified using a """"""""""""""""two hybrid"""""""""""""""" screen and one interacter was a previously unpublished Genbank sequence, HS-PRPL2. Mutations in the WASP protein which occur in patients diminished the WASP-HS-PRPL2 interaction suggesting a physiological relevance. Additional studies of WASP function may shed insight into the increased incidence of lymphoma in these patients.""""""""
| Wada, Taizo; Konno, Akihiro; Schurman, Shepherd H et al. (2003) Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings. J Clin Invest 111:1389-97 |
