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. We have focused our current studies on patients with the Wiskott-Aldrich syndrome (WAS), X-linked hyper-IgM syndrome, selective IgA deficiency, Common Variable Immune Deficiency (CVID) and X-linked agammaglobulinemia and isolated growth hormone deficiency (XLA/GHD). We continue to study the function of the Wiskott-Aldrich Syndrome Protein (WASP). We have identified patients with spontaneous genetic reversions in the WASP gene and these studies have provided evidence for a selective advantage of gene corrected cells. This observation raises the possibility of a gene correction therapeutic strategy for the Wiskott-Aldrich syndrome. In fact, using such a strategy we have corrected the abnormal structural and functional phenotype of primary T-cells from WAS patients. Further studies on hemotopoetic stem cells are planned. We have also shown that the evaluation of cellular chimerism with regard to WASP expression in WAS patients after bone marrow transplantation can be easily accomplished by flow cytometry. Use of this approach should provide insight into the necessary elements for stem cell correction of the WAS lead to more scientifically-grounded bone marrow treatment strategies for the WAS.Two Phase I clinical trials have recently been completed: 1) recombinant CD40 ligand treatment of patients with X-linked hyper IgM syndrome and 2) BLyS treatment of selective IgA deficiency. Phase II clinical trials are currently being planned for both diseases. Studies have suggested a genetic basis for CVID and selective IgA deficiency. We view these diseases as allelic in nature and the result from a """"""""leaky"""""""" failure of immunoglobulin class-switch recombination. To gain possible insight into aberrant gene expression, we are using cDNA microarrays to analyze differential gene expression in stimulated CVID and normal B-cells. We have identified a candidate gene for CVID and selective IgA deficiency. This gene is mutated in approximately 30% of the 100 patient samples already analyzed. We currently have in hand another 300 patient samples for analysis. Knowledge of the candidate gene reveals a pathway of function which is deserving of additional investigations which are currently being planned. X-linked agammaglobulinemia and isolated growth hormone deficiency (XLA/GHD) shares many features with the more common X-linked agammaglobulinemia (XLA) or Bruton's disease caused by mutations in Bruton's tyrosine kinase (Btk). We have shown XLA/GHD to be distinct from XLA since the former patients have no abnormalities in Btk expression including normal catalytic activity. We have shown that patients with XLA/GHD have mutations in a gene called E74-like factor 4(ELF4), or myeloid elf-1-like factor(MEF)-GeneID: 56501. This gene is mutated in all 5 affected male patients, all 3 female disease carriers are heterozygous for the mutation and the mutation was not observed in over 600 normal X-chromosomes examined. Current studies are focusing on the functional consequences of this gene mutation
| 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 |
