NEW YORK (Reuters Health) - Mutations in the CD3D and CD3E genes, which encode the delta and epsilon subunits of CD3, are associated with severe combined immunodeficiency (SCID) characterized by an absence of T cells, according to a report in the November issue of The Journal of Clinical Investigation.
Although deficiencies in CD3gamma and CD3 delta have been described previously in association with SCID, the authors explain, this is the first report of CD3epsilon deficiency as a cause for SCID.
Dr. Francoise Le Deist from INSERM and Hopital Necker-Enfants Malades, Paris, and colleagues investigated the genetic and molecular mechanism underlying a SCID characterized by the selective and complete absence of T cells in three consanguineous families.
None of the samples from five patients and two fetuses from these families contained CD3+ T cells, the authors report. Serum IgG levels were low, and IgA was not detected in any of the patients.
Mutations were identified in exons 2 and 3 of CD3D and in exon 5 of CD3E in these three families, the report indicates. All three mutations resulted in truncations in the extracellular domain of CD3.
Histological studies suggest that T cell development was blocked between the intermediate single-positive thymocyte stage and the double-positive thymocyte stage.
CD3epsilon T cells were not present in the lymph nodes of two patient fetuses with CD3delta deficiency, the researchers note, but they were numerous in the paracortical zone of lymph nodes from a control fetus.
“These observations show that an absence of CD3epsilon or CD3delta completely abrogates human T cell development,” the investigators write.
“We have identified a novel genetic cause of SCID, and, as a result, 10 mechanisms underlying this syndrome have now been characterized,” the authors continue.
“These 10 deficiencies account for most cases of SCID.”
“Therefore accurate molecular diagnosis and genetic counseling as well as potentially further treatments based on gene therapy can now be offered to the majority of SCID patients,” they note.
“Unfortunately, at this moment further studies are not possible, because we have no material from the patient with the CD3 epsilon deficiency, especially the thymus,” Dr. Le Deist told Reuters Health. “So we can’t study the block of T cell differentiation in this case.”
“It is possible that other genes yet to be discovered can result in human SCID when mutated,” writes Dr. Rebecca H. Buckley from Duke University Medical Center, Durham, North Carolina in a related commentary. “Thus knowing all of the abnormal genes that result in human SCID is an important ongoing goal for all who work in this area.”
Source: J Clin Invest 2004;114:1409-1411,1512-1517. [ Google search on this article ]
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