title: Abnormal signal transduction in a patient with severe combined immunodeficiency disease.
abstract: We have studied an 8-yr-old male patient with adenosine deaminase-positive severe combined immunodeficiency disease with a normal number of peripheral CD3+, T cell receptor-alpha beta+ T cells. The majority of these T cells expressed the CD8 molecule and were oligoclonal in nature as proven by Southern blot analysis of the T cell receptor genes. T cells failed to proliferate in vitro either upon stimulation with T cell mitogens or when stimulated with a combination of the phorbol ester phorbol myristate acetate and the Ca-ionophore ionomycin. High doses of recombinant IL-2, when added to in vitro cultures, were able to restore proliferation induced by phorbol myristate acetate and ionomycin but the response to concanavalin A remained severely defective. However, activation of the patient's T cells with phytohemagglutinin or concanavalin A induced an increase of free cytoplasmic Ca++, which was 2- to 5-fold higher than in normal CD8+ T cells. Furthermore, phorbol myristate acetate or phytohemagglutinin induced the translocation of protein kinase C from cytosol to plasma membrane. Analysis of membrane phospholipid composition of the patient's T cells disclosed that the ratio of phosphatidylcholine to phosphatidylserine was 5-fold higher than in normal T cells. The abnormal Ca++ response after activation with T cell mitogens as well as the high phosphatidylcholine/phosphatidylserine ratio may be causally linked to the defective in vitro T cell proliferation. Because the capacity of T lymphocytes to produce or respond to IL-2 may vary, the oligoclonality of the T cells of the patient should be considered as well in the explanation of defective cell proliferation.
authors.affiliation: Department of Immunology, University Hospital for Children and Youth, Het Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands.
authors.forename: G T
authors.initials: GT
authors.lastname: Rijkers
authors.forename: J G
authors.initials: JG
authors.lastname: Scharenberg
authors.forename: J J
authors.initials: JJ
authors.lastname: Van Dongen
authors.forename: H J
authors.initials: HJ
authors.lastname: Neijens
authors.forename: B J
authors.initials: BJ
authors.lastname: Zegers
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte; D016827:CD8 Antigens; D002118:Calcium / Q000378:metabolism; D002648:Child; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D016827:CD8 Antigens; D007376:Interleukin-2; D010743:Phospholipids; D011493:Protein Kinase C; D002118:Calcium