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Prepublished online as a Blood First Edition Paper on June 14, 2002; DOI 10.1182/blood-2001-12-0260.
Submitted December 20, 2001
Accepted June 3, 2002
Hemophagocytic Lymphohistiocytosis (HLH) is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer cell induced apoptosis
E. Marion Schneider*, Ingrid Lorenz, Michaela Mueller-Rosenberger, Gerald Steinbach, Martina Kron, and Gritta E Janka-Schaub
Sektion Experimentelle Anaesthesiologie, Universitaetsklinikum Ulm, Ulm, Germany
Sektion Experimentelle Anaesthesiologie, Universitaetsklinikum Ulm, Ulm, Germany; Abteilung fuer Paediatrische Haematologie und Onkologie, Universitaetskinderklinik Hamburg, Hamburg, Germany
Abteilung Klinische Chemie, Universitaetsklinikum Ulm, Ulm, Germany
Abteilung fuer Biometrie und Medizinische Dokumentation, Universitaetsklinikum Ulm, Ulm, Germany
Abteilung fuer Paediatrische Haematologie und Onkologie, Universitaetskinderklinik Hamburg, Hamburg, Germany
* Corresponding author; email: marion.schneider{at}medizin.uni-ulm.de.
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 IL-2. The standard 4h natural killer (NK-) test against K562 targets was negative in all patients. In the so-called Type I (n=21), -II (n=5), and -IV (n=8) deficient patients, the negative NK function could be reconstituted by mitogen, by IL-2, or by prolongation of the incubation time (16h), respectively. The majority of patients (n=31) displayed the Type III defect, defined by a lack of any cellular cytotoxicity independently of assay variations. The characteristic hypercytokinemia also concerned counterregulatory cytokines such as pro-inflammatory IFN- being simultaneously elevated with suppressive IL-10 in 38% of Type I,II, IV deficient patients and in 71% of Type III deficient patients. Elevated IFN- alone correlated with high liver enzymes, but sCD95-Ligand and sCD25 did not, although these markers were expected to indicate the extent of histiocytic organ infiltration. Outcome analysis revealed more deaths in patients with Type III deficiency (p=0.017). Molecular defects were associated with homozygously mutated perforin only in 4 patients, but other Type III 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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