The purpose of these studies is to develop a more complete understanding of the cellular and molecular lesions that result in immunodeficiency diseases. There are four main foci of research: 1) Identifying stages of developmental arrest in T lymphocytes from patients with immunodeficiencies; 2) Evaluation of cytokine and T-cell antigen receptor repertoire patterns in immunodeficiencies; 3) Examination of the maturation arrest in B lymphocytes in patients with severe combined immunodeficiency (SCID); and 4) Identifying mutations in the recombinase activating genes as the molecular pathogenesis of SCID. In previous GCRC studies we have demonstrated that a form of combined immunodeficiency with neutropenia results from excessive production of TNF- from aberrantly-activated histiocytes. We have demonstrated that inflammatory TH1-type cytokines, TNF- and INF-, are overproduced in relation to the TH2-type, anti-inflammatory cytokines, IL-4 and IL-5, in Omenn Syndrome. Additionally, T lymphocytes are oligoclonally expanded in Omenn Syndrome, possibly as a result of impaired apoptosis, and result in some of the pathologic features of this disorder. We have found that B lymphocytes in X-linked SCID appear to have a maturation arrest at a fetal repertoire developmental stage. This finding could explain why there is poor B lymphocyte function in X-linked SCID despite successful T lymphocyte engraftment with bone marrow transplantation. Our primary studies have been to identify mutations in the recombinase activating gene-1 (RAG-1) in patients with SCID. Mutations have been found in four patients suspected of having RAG-1 deficiency. Each of the identified mutations reside in areas of the gene that have been previously demonstrated to be required for normal function. Future goals are: 1) fully explore the role of RAG-1 mutations in immunodeficiencies; 2) further explore the role of abnormal cytokine expression in causing cytopenias and immunodeficiencies; 3) examine for defects in apoptosis in Omenn Syndrome; and 4) examine for the maturation defect in X-linked SCID B lymphocytes can be overcome with cytokine co-stimulation. The results are anticipated to eventually allow better treatment of patients with immunodeficiencies.
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