Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases - PubMed (original) (raw)

. 2010 Dec;95(12):2080-7.

doi: 10.3324/haematol.2010.029389. Epub 2010 Sep 7.

Karin Beutel, Andrea Maul-Pavicic, Thomas Vraetz, Jens Thiel, Klaus Warnatz, Ilka Bondzio, Ute Gross-Wieltsch, Michael Schündeln, Barbara Schütz, Wilhelm Woessmann, Andreas H Groll, Brigitte Strahm, Julia Pagel, Carsten Speckmann, Gritta Janka, Gillian Griffiths, Klaus Schwarz, Udo zur Stadt, Stephan Ehl

Affiliations

Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

Jan Rohr et al. Haematologica. 2010 Dec.

Abstract

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.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

NK cell degranulation and cytotoxicity. (A) NK-cell degranulation upon target cell recognition was examined by analyzing CD107 expression after incubation of PBMCs with K562 target cells. Plots were gated on CD3− CD56+ NK cells. (B) NK-cell degranulation ex vivo. ΔCD107 was calculated as the percentage of NK cells expressing CD107 after stimulation with K562 minus the percentage of NK cells expressing CD107 after incubation with medium. Open symbols represent MUNC-13-4 deficient patients, closed symbols MUNC-18-2 deficient patients. The box plot for controls represents mean and 25th/75th percentile, whiskers represent the 10th/90th percentile. (C) NK-cell degranulation after 48 h of prestimulation with PHA and IL-2. (D) NK-cell cytotoxicity on K562 target cells. The NK cell to target ratio was calculated based on the percentage of NK cells as determined by flow cytometry. The shaded area delineates the mean values ±2 SD observed in more than 50 healthy controls.

Figure 2.

Figure 2.

Cytotoxic T-cell degranulation and cytotoxicity. (A) CTL degranulation was examined by analyzing CD107 expression after incubation of PBMCs with PHA and IL-2 for 48 h, followed by stimulation with anti-CD3/CD28-coated microbeads. Plots were gated on CD3+ CD8+ T cells. (B) Summary of results obtained in “typical” and “atypical FHL” patients and healthy controls. Open symbols represent MUNC-13-4 deficient, closed symbols MUNC-18-2 deficient patients. (C) T-cell cytotoxicity was examined using d7–d9 PHA blasts as effectors and L1210 cells coated with anti-CD3 mAb as targets. The CTL-to-target-ratio was was calculated based on the percentage of CD3+CD8+ T cells as determined by flow cytometry of the PHA/IL-2 culture. The shaded area delineates the mean values ± 2 SD observed in more than 50 healthy controls.

Figure 3.

Figure 3.

Serum immunoglobulin levels and B-cell phenotype. (A) Lowest IgG serum levels documented for atypical FHL patients during the observation period. Open symbols represent MUNC 13-4 deficient, closed symbols MUNC 18-2 deficient patients. (B) Flow cytometric determination of the percentage of marginal zone like (IgD+ CD27+; MZB) and switched memory (IgD− CD27+; SMB) B lymphocytes. Plots are gated on CD19+ cells. (C) Summary of B-cell phenotyping results obtained in early- and late-onset patients. Shaded areas represent represent normal values extending to the 5th percentile.

Figure 4.

Figure 4.

NKT cells and CD8+ T-cell phenotype and TCR Vβ repertoire. (A) Flow cytometric enumeration of Vα24 Vβ11 CD3+ NKT cells. At least 100,000 CD3+ T cells were analyzed. The absolute number of NKT cells per 100,000 CD3+ T cells is shown. Open symbols represent MUNC 13-4 deficient, closed symbols MUNC 18-2 deficient patients. (B) Analysis of CD8+ T-cell activation markers. The percentage of CD3+CD8+ T cells expressing HLA-DR and the percentage expressing neither CD27 nor CD28 is indicated. The shaded areas represent normal values extending to the 5th percentile. (C) TCR Vβ chain expression of the 7 most frequently used Vβ chains on CD8+ and CD4+ T cells. Black columns represent control values, open columns represent data from P8.

Similar articles

Cited by

References

    1. Filipovich AH. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol Allergy Clin North Am. 2008;28(2):293–313. viii. - PubMed
    1. Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21(5):245–53. - PubMed
    1. Fischer A, Latour S, de Saint Basile G. Genetic defects affecting lymphocyte cytotoxicity. Curr Opin Immunol. 2007;19 (3):348–53. - PubMed
    1. Cetica V, Pende D, Griffiths GM, Aricò M. Molecular basis of familial hemophagocytic lymphohistiocytosis. Haematologica. 2010;95(4):538–41. - PMC - PubMed
    1. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources