Severe combined immune deficiency (SCID) is clinical syndrome marked by congenital absence of antigen-specific T and B lymphocyte responses. Defects in the proteins necessary for T lymphocyte ontogeny and activation have been previously demonstrated to cause SCID. Because of the crucial role of interleukin 2 (IL2) and its receptor (IL2R) in T lymphocyte proliferation, defects in the IL2/IL2R axis would be expected to cause SCID. I have identified a patient with an IL2 production defect, which is now emerging as a relatively common form of SCID. Recently, I have also identified a patient with a new form of SCID due to defective expression of the IL2R alpha chain (Tac). Normal function of the IL2/IL2R axis involves a complex system of gene regulation, ligand-receptor interactions and signal transduction. Therefore many individual defects in the IL2/IL2R axis could cause SCID, including mutations in the coding sequences of IL2 or IL2R, the cis-acting regulatory regions of the IL2 or IL2R genes, or the transactivating proteins required for appropriate gene expression. In the patient with absent IL2 production, I have demonstrated by RNA polymerase chain reaction (PCR) that IL2 mRNA levels are very low, suggesting either a cis or trans regulatory defect. The purpose of this grant is to characterize the primary defects of the IL2/IL2R axis that can cause SCID. Patients of the IL2/IL2R axis will be identified by cellular immunologic studied. Defects in IL2 or IL2R transcription will be assayed by RNA PCR. In patients with abnormal transcription, transfection of chloramphenicol acetyl transferase reporter genes will be used to distinguish cis- and trans-acting defects. The immunologic and transcriptional studies will be used to devise genomic and cDNA cloning strategies aimed at identifying the primary genetic defects in the IL2/IL2R axis. Analysis of these defects will contribute to our understanding or normal IL2 and IL2 function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI025071-05
Application #
2062869
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1990-03-01
Project End
1995-02-28
Budget Start
1994-03-01
Budget End
1995-02-28
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027