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Blood, 1 January 2002, Vol. 99, No. 1, pp. 61-66
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Perforin expression in cytotoxic lymphocytes from patients with
hemophagocytic lymphohistiocytosis and their family members
Kazuhiro Kogawa,
Susan M. Lee,
Joyce Villanueva,
Daniel Marmer,
Janos Sumegi, and
Alexandra H. Filipovich
From the Division of Hematology/Oncology, Children's
Hospital Medical Center, Cincinnati, OH; the Department of Pediatrics,
National Defense Medical College, Tokorozawa, Japan; and the Department
of Pathology, University of Nebraska, Omaha.
Mutations in the perforin gene have been described in some
patients with hemophagocytic lymphohistiocytosis (HLH), but the role of perforin defects in the pathogenesis of HLH remains unclear. Four-color flow cytometric analysis was used to establish normal patterns of perforin expression for control subjects of all ages, and
patterns of perforin staining in cytotoxic lymphocytes (natural killer
[NK] cells, CD8+ T cells, CD56+ T cells) from
patients with HLH and their family members were studied. Eleven
unrelated HLH patients and 19 family members were analyzed
prospectively. Four of the 7 patients with primary HLH showed lack of
intracellular perforin in all cytotoxic cell types. All 4 patients
showed mutations in the perforin gene. Their parents, obligate carriers
of perforin mutations, had abnormal perforin-staining patterns.
Analysis of cytotoxic cells from the other 3 patients with primary HLH
and remaining family members had normal percentages of
perforin-positive cytotoxic cells. On the other hand, the 4 patients
with Epstein-Barr virus-associated HLH typically had depressed numbers
of NK cells but markedly increased proportions of CD8+ T
cells with perforin expression. Four-color flow cytometry provides diagnostic information that, in conjunction with evidence of
reduced NK function, may speed the identification of
life-threatening HLH in some families and direct further genetic
studies of the syndrome.
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