Severe Combined Immunodeficiencies (SCID) is a group ofheterogeneous immune disorders that afflict infants within the first fewmonths after birth. These children suffer from severe wasting and oftensuccumb to a variety of opportunistic infections.SCID is attributed to inherited defects but the precise genetic cause isunknown in about 30 percent of all cases. A pair of articles publishedin the June 10 issue of Science report that mutations in a particularsignal transduction enzyme are responsible for one distinctive form ofSCID. The articles are entitled "Human Severe CombinedImmunodeficiency Due to a Defect in ZAP-70, a T Cell TyrosineKinase" and "Zap-70 Deficiency in an Autosomal Recessive Form ofSevere Combined Immunodeficiency."The disease-provoking mutations occur in ZAP-70, a T cell tyrosinekinase that has an essential role in T cell activation and maturation.SCID patients are severely immunocompromised and usually haveabnormal T and B cells. In the particular clinical syndrome associatedwith ZAP-70 mutations, patients have a normal or moderately elevatedT cell count overall.What is peculiar about the T cell count is that, instead of the normalbalance between CD4 and CD8 cells, there are essentially no CD8 cellsand virtually all of the circulating T cells are the CD4 type.A team of scientists at the University of San Francisco and theUniversity of Minnesota reported in Science that they studied twounrelated families with SCID children with this characteristic CD4-CD8 pattern to help identify the molecular genetic defect causing thedisease.According to Arthur Weiss, of University of California's HowardHughes Medical Institute in San Francisco, "These patients areotherwise normal except for the specific defects in T cells. ZAP-70 is alogical target for immunosuppressive therapy. Drugs that inhibit thekinase activity of ZAP-70, or interfere with the ability of ZAP-70 tobind to the T cell antigen receptor complex are likely candidates asspecific T cell immunosuppressives.The ZAP-70 deficiency is due to an autosomal recessive inheritancepattern. Mutations in the kinase domain of ZAP-70 were identified bycomparing the genetic patterns of parents and siblings who wereimmunologically normal with the genes of the SCID child.Small deletions were found after cloning the ZAP-70 coding sequencesin the patient with SCID from one family. Deleting essential geneticmaterial probably causes a frameshift mutation within the kinasedomain. Consequently the DNA is not properly translated and themutant protein is less stable than normal. The molecular mistaketranslates into a clinical malfunction of the immune system.The molecular analysis of a second family revealed that children with asimilar SCID syndrome had mutations involving a base pair transition(exchanging one base for another) and a nine base pair insertion. Thesemutations also resulted in malfunctioning ZAP-70 proteins that werecatalytically inactive.The link between the genetic defect and SCID is the first evidence thatZAP-70 is required for normal T cell function. The study suggests thatnot only is ZAP-70 involved in T cell receptor signal transduction butthat the CD4 and CD8 cells may each depend on different intracellularsignaling pathways during thymic development. n

-- Bonnie Joy Sedlak Special To BioWorld Today

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