NEW YORK (Reuters Health) - By disrupting the normal death of lymphoid cells, somatic Fas mutations can lead to autoimmune lymphoproliferative syndrome (ALPS), according to the results of two studies published in The New England Journal of Medicine for September 30.
The new findings show that somatic mutations are “not just for cancer anymore,” they can also cause an autoimmune disease -- ALPS, Dr. Jennifer M. Puck and Dr. Stephen E. Straus, from the National Institutes of Health in Bethesda, Maryland, note in a related editorial. It is possible that such mutations may also be found in more common autoimmune diseases, such as rheumatoid arthritis and lupus, they add.
In the first study, Dr. Eliska Holzelova, from Charles University in Prague, Czech Republic, and colleagues analyzed the Fas gene in T cells obtained from six children with ALPS. In all cases, the lymphocytes showed normal sensitivity to Fas-induced apoptosis in vitro.
Somatic heterozygous Fas mutations were identified in all of the children. “Somatic heterozygous mutations of Fas can cause a sporadic form of ALPS by allowing lymphoid precursors to resist the normal process of cell death,” the authors note.
In the second study, Dr. Marco Bregni, from Istituto Scientifico H. San Raffaele in Milan, Italy, and colleagues describe the genetic mutations uncovered in a 27-year-old man with ALPS and a large-B-cell lymphoma.
As in the first study, the patient had a heterozygous mutation in the Fas gene, which probably accounted for the ALPS. In addition, a mutation in the perforin gene was identified that probably caused the lymphoma. The former and latter mutations were inherited from the subject’s father and mother, respectively, who were both healthy.
“Defective Fas-mediated apoptosis could allow the prolonged survival of lymphocytes, which might then become targets of transforming events, whereas defects in Fas-mediated killing and in the granule-exocytosis pathway would impair immune surveillance for transformed cells,” the authors state.
Source: N Engl J Med 2004;351:1388-1390,1409-1424. [ Google search on this article ]
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