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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2001-12-0260.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2891-2898
IMMUNOBIOLOGY
Hemophagocytic lymphohistiocytosis is associated with
deficiencies of cellular cytolysis but normal expression of
transcripts relevant to killer-cell-induced apoptosis
E. Marion Schneider,
Ingrid Lorenz,
Michaela Müller-Rosenberger,
Gerald Steinbach,
Martina Kron, and
Gritta E. Janka-Schaub
From the Section of Experimental Anesthesiology,
Departments of Anesthesiology, Clinical Chemistry, and Biometry and
Medical Documentation, University of Ulm; and the Department of
Pediatric Hematology and Oncology, University Clinic of Hamburg,
Germany.
In 65 patients with hemophagocytic lymphohistiocytosis (HLH), we
found an as yet undescribed heterogeneity of defects in cellular cytotoxicity when assay conditions were modified by the incubation time, the presence of mitogen, or interleukin-2 (IL-2). The standard 4-hour natural killer (NK) test against K562 targets was negative in
all patients. In patients deficient in type 1 (n = 21), type 2 (n = 5), and type 4 (n = 8) HLH, negative NK function could be reconstituted by mitogen, by IL-2, or by prolongation of the incubation time (16 hours), respectively. Most patients (n = 31) displayed the type 3 defect, defined by a lack of any cellular cytotoxicity independent of assay variations. The characteristic hypercytokinemia also concerned counterregulatory cytokines, such as proinflammatory interferon- (IFN-), simultaneously elevated with suppressive IL-10 in 38% of types 1-, 2-, and 4-deficient patients and in 71% of type 3-deficient patients. Elevated IFN- alone correlated with high liver enzymes, but sCD95-ligand and sCD25
did not though these markers were expected to indicate the extent of
histiocytic organ infiltration. Outcome analysis revealed more deaths
in patients with type 3 deficiency (P = .017). Molecular defects were associated with homozygously mutated perforin only in 4 patients, but other type 3 patients expressed normal transcripts of
effector molecules for target-cell apoptosis, including perforin and
granzyme family members, as demonstrated by RNase protection analysis.
Thus, target-cell recognition or differentiation defects are likely to
explain this severe phenotype in HLH. Hyperactive phagocytes combined
with NK defects may imply defects on the level of the
antigen-presenting cell.
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