John Libbey Eurotext

Hématologie

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Primary immunodeficiencies Volume 1, issue 5, Septembre - Octobre 1995

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INSERM U. 429 et unité d'immuno-hématologie, hôpital des Enfants-Malades, 149, rue de Sèvres, 75783 Paris Cedex 15.

Herein are described recent advances in the molecular characterization of primary lymphoid immunodeficiencies (PID). Molecular basis of several forms of severe combined immunodeficiencies (SCID) have now been elucidated including DNA dependent protein-kinase deficiency in the murine scid and IL2 receptor gamma chain (or gamma c) deficiency in human X-linked SCID. It is remarkable to note that gamma c belongs to the receptor for five different cytokines i.e. IL2,4,7,9 and 15. Defects in antigen presentation related to lack of HLA class II gene expression and abnormal TAP peptide transporter have been described. In the former setting, defective expression of HLA class II molecules study led to the identification of several gene products involved in the regulation of HLA class II gene transcription. Defective T cell signalling in PID has been observed in several conditions caused by CD3 gamma or epsilon polypeptides deficiencies or to ZAP 70 tyrosine kinase deficiency. Abnormal accumulation of T and B lymphocytes, sometimes associated with autoimmunity has been recently described as a consequence of mutation in the fas-encoding gene. Defect in fas-mediated lymphocyte apoptosis is thus causative of a lymphoproliferative syndrome. Recently, the genetic basis of Wiskott-Aldrich syndrome (WAS) has been unravelled ; WAS is caused by mutations of a newly discovered gene " WASP ", the function of which remaining unclear. Finally, B-cell maturation deficiencies have now been molecularly defined. X-L agammaglobulinemia characterized by a faulty B-cell differentiation is caused by a deficiency in btk, a tyrosine kinase expressed all along the B-cell differentiation pathway. Lack of CD40 ligand expression by activated T-cells has been found responsible for an X-linked defect in lg class switch thus resulting in lgG, lgA and lgE deficiencies while lgM and lgD are secreted. These examples illustrate how use of modern tools of genetics has contributed to the molecular understanding of PID, thus providing basis for improved diagnosis and therapy as well as models for the study of the development and the function of the immune system.