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


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.
Rohr
Jan
J
Centre of Pediatrics and Adolescent Medicine, University Medical Centre, Freiburg, Germany.
Beutel
Karin
K
Maul-Pavicic
Andrea
A
Vraetz
Thomas
T
Thiel
Jens
J
Warnatz
Klaus
K
Bondzio
Ilka
I
Gross-Wieltsch
Ute
U
Schündeln
Michael
M
Schütz
Barbara
B
Woessmann
Wilhelm
W
Groll
Andreas H
AH
Strahm
Brigitte
B
Pagel
Julia
J
Speckmann
Carsten
C
Janka
Gritta
G
Griffiths
Gillian
G
Schwarz
Klaus
K
zur Stadt
Udo
U
Ehl
Stephan
S
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D005787:Gene Frequency; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007153:Immunologic Deficiency Syndromes / Q000150:complications* / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics*; D051938:Munc18 Proteins / Q000235:genetics*; D009154:Mutation; D022821:RNA Splice Sites / Q000235:genetics
D007074:Immunoglobulin G; D008565:Membrane Proteins; D051938:Munc18 Proteins; D022821:RNA Splice Sites; C497940:STXBP2 protein, human; C507969:UNC13D protein, human
J Immunol. 2004 Mar 15;172(6):3454-61
15004145
Br J Haematol. 2008 Oct;143(1):75-83
18710388
Pediatr Blood Cancer. 2009 Aug;53(2):184-90
19353621
Blood. 2002 Sep 15;100(6):2266-7
12229880
Blood Rev. 2007 Sep;21(5):245-53
17590250
Hum Mol Genet. 2005 Mar 15;14(6):827-34
15703195
J Pediatr. 1980 Apr;96(4):669-73
7188959
Pediatr Blood Cancer. 2010 Jul 15;55(1):134-40
20486178
Blood. 2002 Mar 1;99(5):1544-51
11861266
Arthritis Rheum. 2007 Mar;56(3):995-9
17328077
Cell. 2003 Nov 14;115(4):461-73
14622600
J Med Genet. 2008 Jan;45(1):15-21
17873118
Turk J Pediatr. 2009 Jul-Aug;51(4):371-4
19950846
Blood. 2005 Jun 1;105(11):4424-8
15728124
J Med Genet. 2008 Mar;45(3):134-41
17993578
Immunol Allergy Clin North Am. 2008 May;28(2):293-313, viii
18424334
Am J Hematol. 2007 Jun;82(6):427-32
17266056
J Clin Invest. 2009 Dec;119(12):3765-73
19884660
J Med Genet. 2006 Dec;43(12):953-60
16825436
J Exp Med. 2005 Mar 7;201(5):695-701
15738056
Blood. 2006 Jul 1;108(1):81-7
16551969
Eur J Pediatr. 2002 Dec;161(12):656-9
12447665
Nat Med. 2005 Mar;11(3):340-5
15711562
Blood. 2005 May 1;105(9):3442-8
15632205
Blood. 2007 Sep 15;110(6):1906-15
17525286
J Clin Invest. 2005 Apr;115(4):1049-59
15761493
Pediatr Blood Cancer. 2007 Feb;48(2):124-31
16937360
Lancet. 1975 Apr 26;1(7913):935-40
48119
J Immunol. 2003 Oct 15;171(8):4149-55
14530337
J Immunol. 2004 Jun 15;172(12):7350-8
15187111
Blood. 2004 Feb 15;103(4):1244-52
14576041
Pediatr Blood Cancer. 2006 Apr;46(4):482-8
16365863
Am J Hum Genet. 2009 Oct;85(4):482-92
19804848
Science. 1999 Dec 3;286(5446):1957-9
10583959
J Pediatr Hematol Oncol. 2006 Dec;28(12):831-3
17164654
J Immunol. 2005 Mar 15;174(6):3153-7
15749842
Blood. 2007 Jun 15;109(12):5234-7
17311987
Arthritis Rheum. 2008 Feb;58(2):567-70
18240215
Haematologica. 2010 Apr;95(4):538-41
20378576
Crit Rev Oncol Hematol. 2002 Dec;44(3):273-82
12467967
Haematologica. 2007 Jul;92(7):978-81
17606450
Blood. 2006 Oct 1;108(7):2316-23
16778144
J Clin Invest. 2009 May;119(5):1350-8
19425169
Curr Opin Immunol. 2007 Jun;19(3):348-53
17433652
J Med Genet. 2006 Apr;43(4):e14
16582076