Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases
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Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. / Rohr, Jan; Beutel, Karin; Maul-Pavicic, Andrea; Vraetz, Thomas; Thiel, Jens; Warnatz, Klaus; Bondzio, Ilka; Gross-Wieltsch, Ute; Schündeln, Michael; Schütz, Barbara; Woessmann, Wilhelm; Groll, Andreas H; Strahm, Brigitte; Pagel, Julia; Speckmann, Carsten; Janka-Schaub, Gritta; Griffiths, Gillian; Schwarz, Klaus; Zur Stadt, Udo; Ehl, Stephan.
In: HAEMATOLOGICA, Vol. 95, No. 12, 12.2010, p. 2080-2087.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases
AU - Rohr, Jan
AU - Beutel, Karin
AU - Maul-Pavicic, Andrea
AU - Vraetz, Thomas
AU - Thiel, Jens
AU - Warnatz, Klaus
AU - Bondzio, Ilka
AU - Gross-Wieltsch, Ute
AU - Schündeln, Michael
AU - Schütz, Barbara
AU - Woessmann, Wilhelm
AU - Groll, Andreas H
AU - Strahm, Brigitte
AU - Pagel, Julia
AU - Speckmann, Carsten
AU - Janka-Schaub, Gritta
AU - Griffiths, Gillian
AU - Schwarz, Klaus
AU - Zur Stadt, Udo
AU - Ehl, Stephan
PY - 2010/12
Y1 - 2010/12
N2 - BACKGROUND: Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed.DESIGN AND METHODS: We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2.RESULTS: All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8(+) T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal.CONCLUSIONS: Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.
AB - BACKGROUND: Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed.DESIGN AND METHODS: We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2.RESULTS: All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8(+) T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal.CONCLUSIONS: Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.
KW - Adolescent
KW - Adult
KW - Alleles
KW - B-Lymphocytes/immunology
KW - CD8-Positive T-Lymphocytes/immunology
KW - Cell Degranulation/immunology
KW - Cell Line, Tumor
KW - Cells, Cultured
KW - Child
KW - Child, Preschool
KW - Cytotoxicity, Immunologic/immunology
KW - Flow Cytometry
KW - Gene Frequency
KW - Humans
KW - Immunoglobulin G/blood
KW - Immunologic Deficiency Syndromes/complications
KW - K562 Cells
KW - Killer Cells, Natural/immunology
KW - Lymphohistiocytosis, Hemophagocytic/complications
KW - Membrane Proteins/genetics
KW - Munc18 Proteins/genetics
KW - Mutation
KW - RNA Splice Sites/genetics
U2 - 10.3324/haematol.2010.029389
DO - 10.3324/haematol.2010.029389
M3 - SCORING: Journal article
C2 - 20823128
VL - 95
SP - 2080
EP - 2087
JO - HAEMATOLOGICA
JF - HAEMATOLOGICA
SN - 0390-6078
IS - 12
ER -