Studies were performed to examine the human immune response in normal individuals and 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 (sIL-2R) and demonstrated abnormal levels of sIL-2R in patients with several disorders of abnormal immune function including cancer and AIDS. A recently discovered lymphokine, IL-15, shares many similarities with IL-2. We showed that IL-15 stimulates the release of sIL-2R from both resting and activated cells in vitro suggesting that in certain disorders IL-15 may contribute to abnormalities of immune function and elevated sIL-2R levels in vivo. Investigations continued on the primary immunodeficiency disorders. Examination of the tyrosine kinase (BTK) responsible for X- linked agammaglobulinemia (XLA) in patients with XLA and isolated growth hormone deficiency (XLA/GHD) revealed a normal abundance/normal-size BTK transcript, a normal BTK sequence and normal amounts of expressed BTK protein. 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 Wiskott- Aldrich syndrome (WASP) has not been defined. We produced mAbs to WASP and studied its expression and function in normal and WASP patients. This cytoplasmic protein is expressed in platelets, monocytes, T cells and B cells. Some patients with WASP produce a nonfunctional 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. Cell lines from patients who fail to make the protein will be targets for in vitro gene therapy experiments.
| 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 |
