Association of Monoclonal Expansion of Epstein-Barr Virus-Negative CD158a ⁺ NK Cells Secreting Large Amounts of Gamma Interferon with Hemophagocytic Lymphohistiocytosis

Abstract

We report the first case of hemophagocytic lymphohistiocytosis (HLH) induced by the monoclonal expansion of Epstein-Barr virus (EBV)-negative NK cells. Consanguinity of the patient's parents made it necessary to discard familial HLH in the patient and her sister with identical HLA markers and demonstrate that no cause other than the expansion of NK cells, which secrete high levels of gamma interferon, was inducing HLH in this patient. CASE REPORTA 17-month-old Ecuadorian girl was admitted to our hospital, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain, in September 2005, because of a fever and cytopenias (leukocytes, 11.6 ϫ 10 9 /liter; hemoglobin, 7.9 g/dl; platelets, 65 ϫ 10 9 /liter) which had persisted for over 3 weeks, splenomegaly (10 cm), hepatomegaly (5 cm), multiple adenopathies, purpura, and edema. The father and mother were cousins and healthy, the patient's gestation and birth had been normal, but recurrent fever episodes were reported from 3 months of age. The girl was vaccinated normally. Biochemical analysis showed normal values for fibrinogen (232 mg/dl; range, 150 to 450 mg/dl) and elevated levels of ferritin (278 ng/ml; normal range, 15 to 150 ng/ml) and triglycerides (311 mg/dl; normal range, 50 to 200 mg/dl). Serology demonstrated anti-cytomegalovirus

Advances in understanding the pathogenesis of HLH

“…Indeed, haemophagocytosis is not only seen in HLH, but has also been reported in critically ill patients with a variety of infectious or inflammatory disorders (Kuwata et al , ; Goel et al , ). HLH disease activity results primarily from excessive release of IFNγ (Lopez‐Alvarez et al , ) from activated T cells, which leads to continual expansion and activation of the polyclonal CD8 + T cell, histiocyte, and macrophage population (Jordan et al , ). Activated CD8 + T lymphocytes and macrophages infiltrate multiple organs, including the bone marrow, the lymph nodes, the spleen, the liver and the brain, and secrete high levels of inflammatory cytokines (Takada et al , ), chemokines and other substances, which lead to the cardinal clinical and laboratory findings.…”

Overexpression of KIR inhibitory ligands (HLA-I) determines that immunosurveillance of myeloma depends on diverse and strong NK cell licensing

“…Cytotoxic activity of freshly purified, un-stimulated NK cells was evaluated using K562 cell line or cryopreserved myeloma PCs as targets, following previously described methods. 54 Briefly, targets were stained with 0.25 mM 5-(and 6-) carboxyfluorescein diacetate succinimidyl ester (CFSE, Molecular probes, Leiden, The Netherlands) for 10 min at 37 C, extensively washed to remove any rest of CFSE and resuspended in complete medium. NK cell effectors were washed in complete medium and viability of both target and effector cells examined with 0.5% trypan-blue.…”

COVID-19 Complications in a Newly Diagnosed HIV Patient: A Case of Multiple Herpesvirus Reactivation and HLH Post-ART Initiation

“…Nevertheless, it is unclear if initiation of antiretroviral therapy contributed to his worsening hyperinflammatory state, and whether delay in starting ART in patients with COVID-19 who have advanced HIV is prudent. Indeed, there is a shift in cytokine production from a Th-2 to a Th-1 profile after initiation of ART, with increases in interleukin-2 and interferon-γ, as well as stimulation of monocytes and macrophages, resulting in production of TNFα and IL-6, which are also implicated in HLH and severe COVID-19 [ 5 , 9 , 14 , 19 , 40 ]…”

“…HLH is a life-threating condition characterized by excessive immune activation and systemic inflammation that can lead to multi-organ failure [ 17 , 18 ]. The end-organ damage seen in HLH is due to overproduction of interferon-γ by activated T-lymphocytes, which in turn activates CD8+ T-cells, macrophages, and histiocytes, resulting in secretion of pro-inflammatory cytokines and infiltration of multiple tissues [ 19 – 21 ]. Macrophage activation syndrome (MAS), a form of HLH, is a complication of autoimmune diseases such as systemic onset juvenile idiopathic arthritis and juvenile systemic lupus erythematous [ 18 , 22 ].…”