Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation.
Chronic active Epstein-Barr virus infection (CAEBV) is a rare disease in which previously healthy persons develop severe, life-threatening illness. Mutations in the perforin gene have been found in familial hemophagocytic lymphohistiocytosis, which shares some features with CAEBV. We studied a patient who died at age 18, 10 years after the onset of CAEBV. The patient had high titers of antibodies to EBV, EBV RNA in lymph nodes, T-cell lymphoproliferative disease, and hemophagocytic lymphohistiocytosis. DNA sequencing showed novel mutations in both alleles of the perforin gene that resulted in amino acid changes in the protein. The quantity of the native form of perforin from the patient's stimulated peripheral blood mononuclear cells (PBMCs) was extremely low and immunoblotting showed accumulation of an uncleaved precursor form of perforin. Stimulated PBMCs from the patient were defective for Fas-independent cytotoxicity. These data imply that mutations in this patient resulted in reduced perforin-mediated cytotoxicity by his lymphocytes. This is the first case in which perforin mutations have been shown to result in accumulation of the uncleaved, immature form of perforin. Mutations in the perforin gene are associated with some cases of CAEBV with hemophagocytic lymphohistiocytosis.
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Harutaka
H
Katano
Mir A
MA
Ali
Andriani C
AC
Patera
Marta
M
Catalfamo
Elaine S
ES
Jaffe
Hiroshi
H
Kimura
Janet K
JK
Dale
Stephen E
SE
Straus
Jeffrey I
JI
Cohen
D000293:Adolescent; D000328:Adult; D000906:Antibodies; D002648:Child; D002908:Chronic Disease; D003601:Cytotoxicity Tests, Immunologic; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D015870:Gene Expression; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008198:Lymph Nodes / Q000473:pathology / Q000821:virology; D008214:Lymphocytes / Q000187:drug effects / Q000821:virology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D010290:Parents; D054353:Perforin; D010641:Phenotype; D010835:Phytohemagglutinins / Q000494:pharmacology; D052899:Pore Forming Cytotoxic Proteins
D000906:Antibodies; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D010835:Phytohemagglutinins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin