Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect

被引:65
作者
Carvelli, Julien [1 ]
Piperoglou, Christelle [2 ]
Farnarier, Catherine [2 ]
Vely, Frederic [2 ,3 ]
Mazodier, Karin [1 ]
Audonnet, Sandra [2 ]
Nitschke, Patrick [4 ]
Bole-Feysot, Christine [5 ]
Boucekine, Mohamed [6 ]
Cambon, Audrey [7 ]
Hamidou, Mohamed [8 ]
Harle, Jean-Robert [9 ]
de Saint Basile, Genevieve [10 ]
Kaplanski, Gilles [1 ]
机构
[1] Aix Marseille Univ prime, CHU Concept, AP HM, Serv Med Interne & Immunol Clin, Marseille, France
[2] Marseille Immunopole, Hop La Timone, AP HM, Lab Immunol, Marseille, France
[3] Aix Marseille Univ, CNRS, INSERM, Ctr Immunol Marseille Luminy, Marseille, France
[4] Univ Paris 05, Plateforme Bioinformat, Paris, France
[5] Inst Imagine, Plateforme Genom, Paris, France
[6] Aix Marseille Univ, Ctr Studies & Res Hlth Serv & Qual Life, Marseille, France
[7] Hop Instruct Armees St Anne, Serv Med Interne, Toulon, France
[8] CHU Nantes, Hotel Dieu, Serv Med Interne, Nantes, France
[9] Hop La Timone, AP HM, Serv Med Interne, Marseille, France
[10] INSERM, Inst Imagine, UMR 1163, Paris, France
关键词
MACROPHAGE ACTIVATION SYNDROME; JUVENILE IDIOPATHIC ARTHRITIS; NATURAL-KILLER-CELLS; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; INTERFERON-GAMMA; PERFORIN GENE; MUTATION; A91V; IMMUNOPATHOLOGY; INTERLEUKIN-6;
D O I
10.1182/blood.2019003664
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condi-tion. Primary HLH occurs early in life as a result of monogenic biallelic mutations affecting lymphocyte cytotoxicity. Secondary HLH occurs mostly in adults secondary to infection, lymphoma, or rheumatic disease. In this latter setting, lymphocyte cytotoxicity status is not known. We conducted a systematic evaluation of natural killer (NK) cell cytotoxicity in adult patients with secondary HLH. Adult patients with secondary HLH were prospectively studied ex vivo for total lymphocyte count and subtype, NK cell phenotype, perforin expression and degranulation, and natural or antibody-dependent cell cytotoxicity, in comparison with patients affected by the same underlying disease without HLH (disease controls [DCs]) and with healthy controls (HCs). Screening for variants of cytotoxity genes was systematically performed. 68 patients were included in the HLH group and 34 each in the DC and HC groups. In HLH patients, severe and transient lymphopenia, activated NK cell phenotype (eg, increased CD69, ICAM-1, HLADR, and CCR5 expression), and decreased capacity of interferon 7 production were observed; mean perforin expression was normal; and degranulation tests and NK cell cytotoxicity were not different from those in DCs. A monoallelic variant of uncertain significance affecting a lymphocyte cytotoxicity gene or the perforin variant A91V was observed in almost 50% of the patients. We detected no major intrinsic cytotoxicity dysfunction in secondary HLH patients compared with DCs and no predicted pathogenic gene variant. The activated NK phenotype profile associated with decreased interferon 7 production seems similar to those of other hyperinflammatory diseases such as sepsis or systemic juvenile idiopathic arthritis.
引用
收藏
页码:542 / 552
页数:11
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