calcimycin and Common-Variable-Immunodeficiency

Stimulation of T-lymphocytes derived from some patients with common variable immunodeficiency (CVID) syndrome results in defective proliferation. The underlying mechanism is related to the inability of stimulated cells to secrete IL-2 while the expression of IL-2 receptor (IL-2R) is normal. We have identified a patient whose peripheral T-cells failed to proliferate and secrete IL-2 upon stimulation. The addition of recombinant IL-2 restored proliferation. The defect did not seem to be caused by accessory cell failure since the patient's adherent cells produced IL-1 and IL-6, and addition of allogeneic irradiated cells did not induce proliferation. Stimulation of CVID T-cells with phorbol esters and Ca2+ ionophore induced both IL-2 secretion and proliferation, indicating the absence of a defect in the transcription and/or translation of the IL-2 gene. The patient's T-cells expressed high levels of CD3. The majority of T-cells expressed the CD38 molecule which is normally found on thymocytes or activated T-cells but not peripheral blood T-cells and HLA-DR, another activation marker. However, CD25 (the IL-2R) and CD1, a marker of more immature thymocytes, were not expressed. Finally, the patient's cells were sensitive to an in vitro corticosteroid treatment. The possibilities that this patient's T-cells represent anergic T-cells or not fully matured thymocytes are discussed.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Adrenal Cortex Hormones; Adult; Antigen-Presenting Cells; Antigens, CD; Antigens, CD1; Antigens, Differentiation; Calcimycin; CD3 Complex; Cell Death; Common Variable Immunodeficiency; HLA-DR Antigens; Humans; In Vitro Techniques; Interleukin-2; Lymphocyte Activation; Male; Membrane Glycoproteins; Receptors, Antigen, T-Cell; Receptors, Interleukin-2; Signal Transduction; T-Lymphocytes; Tetradecanoylphorbol Acetate

Many reports have shown that expression of the c-myc protooncogene represents an early event of lymphocyte activation. Calcium influx and activation of protein kinase C synergistically bypass the early signal transduction of lymphocyte activation. In this study, the c-myc message of B cells or B cell lines stimulated by 12-o-tetradecanoylphorbol-13-acetate (TPA), A23187, Staphylococcus aureus Cowan I (SAC), or anti-mu was not expressed or was poorly expressed in common variable immunodeficiency (CVID) patients whose B cells did not differentiate or only poorly differentiated to SAC plus recombinant interleukin 2, whereas the c-myc message of 1 CVID patient's B cells that differentiated well in IgM secretion to SAC plus recombinant interleukin 2 was well expressed when stimulated by TPA, A23187, SAC, or anti-mu. These results suggest that an abnormality exists in the early signal transduction process on some CVID patients' B cells and that it may be in the bypass by calcium influx and direct activation of protein kinase C.

Topics: Adult; B-Lymphocytes; Blotting, Northern; Calcimycin; Calcium; CD3 Complex; CD4 Antigens; CD8 Antigens; Child; Common Variable Immunodeficiency; Dose-Response Relationship, Drug; Female; Gene Expression; Genes, myc; Humans; Immunoglobulin A; Immunoglobulin Fab Fragments; Immunoglobulin G; Immunoglobulin M; Interleukin-2; Lymphocyte Activation; Male; RNA; Staphylococcus aureus; Tetradecanoylphorbol Acetate