Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect
Open Access
- 30 July 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 136 (5), 542-552
- https://doi.org/10.1182/blood.2019003664
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition. 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 γ 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 γ production seems similar to those of other hyperinflammatory diseases such as sepsis or systemic juvenile idiopathic arthritis.Keywords
This publication has 51 references indexed in Scilit:
- Functional impact of A91V mutation of the PRF1 perforin geneHuman Immunology, 2013
- Phenotype and Functions of Natural Killer Cells in Critically-Ill Septic PatientsPLOS ONE, 2012
- Familial Hemophagocytic Lymphohistiocytosis May Present during Adulthood: Clinical and Genetic Features of a Small SeriesPLOS ONE, 2012
- Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLHBlood, 2011
- Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in miceJCI Insight, 2011
- Fast and accurate long-read alignment with Burrows–Wheeler transformBioinformatics, 2010
- Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancerProceedings of the National Academy of Sciences of the United States of America, 2009
- A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosisBlood, 2005
- A91V is a polymorphism in the perforin gene not causative of an FHLH phenotypeBlood, 2004
- An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorderBlood, 2004