Impaired Release of Neutrophil Extracellular Traps and Anemia-Associated T Cell Deficiency in Hereditary Hemorrhagic Telangiectasia

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is characterized by mucocutaneous telangiectases and visceral vascular malformations. Individuals suffering from HHT have a significantly increased risk of bacterial infections, but the mechanisms involved in this are not clear. White blood cell subpopulations were estimated with flow cytometry in 79 patients with HHT and 45 healthy individuals, and association with clinicopathological status was assessed. A prominent decrease in absolute numbers of T cells in HHT was revealed (0.7 (0.5–1.1) vs. 1.3 (0.8–1.6), 106/mL, p < 0.05), and in multivariate regression analysis, hemoglobin level was associated with lymphopenia (OR = 0.625, 95% CI: 0.417–0.937, p < 0.05). Although no changes in absolute numbers of neutrophils and monocytes were observed, we revealed a significant impairment of neutrophil antibacterial functions in HHT (n = 9), compared to healthy individuals (n = 7), in vitro. The release of neutrophil extracellular traps (NETs) against Pseudomonas aeruginosa MOI10 was significantly suppressed in HHT (mean area per cell, mm2: 76 (70–92) vs. 121 (97–128), p < 0.05), due to impaired filamentous actin organization (% of positive cells: 69 (59–77) vs. 92 (88–94), p < 0.05). To conclude, this study reveals the categories of patients with HHT that are prone to immunosuppression and require careful monitoring, and suggests a potential therapeutic strategy based on the functional activation of neutrophils.

Altered Expressions of CXCR4 and CD26 On T-Helper Lymphocytes in Hereditary Hemorrhagic Telangiectasia

“…As already published [5,7], HHT is associated with a T and NK lymphopenia despite the absence of any comorbidities or treatment known to cause lymphopenia [18]. The decrease of the T-helpers could be a consequence of a dysfunctional CXCL12/CXCR4 axis since we observed a weak but signi cant correlation between their CXCR4 surface expression and their absolute counts in the blood.…”

“…Patients are also concerned by musculoskeletal infections involving Staphylococcus aureus, which may be associated with bacteremia, provoked by prolonged nose packing or/and lesions of the nasal mucosa [2,3]. In addition to these mechanical factors, innate immunity is suspected to be altered in HHT: functional de cits of neutrophils and monocytes/macrophages (phagocytosis, oxidative burst, NETs formation) have been reported in humans [4,5] and mice [6], but the underlying mechanism is still unknown. Intriguingly, immunological studies have highlighted a T and NK lymphopenia predominant on naive T-helper cells [5,7].…”

“…In addition to these mechanical factors, innate immunity is suspected to be altered in HHT: functional de cits of neutrophils and monocytes/macrophages (phagocytosis, oxidative burst, NETs formation) have been reported in humans [4,5] and mice [6], but the underlying mechanism is still unknown. Intriguingly, immunological studies have highlighted a T and NK lymphopenia predominant on naive T-helper cells [5,7]. Although very low lymphocyte counts were observed in some patients, no clear association with infectious risk has been established to date.…”

Hereditäre hämorrhagische Teleangiektasie: Symptome und diagnostische Latenz

“…Die meisten Patienten mit neurologischen Symptomen weisen keine Gefäßanomalien der Hirn-, sondern der Lungenstrombahn auf. Zudem werden Veränderungen im Immunsystem bei Patienten mit HHT diskutiert [23][24][25][26], die ebenfalls die Bildung von Eiteransammlungen und Infektionen begünstigen könnten. In unserer Kohorte erlitt auch ein Patient mit mikroskopischen pulmonalen Shunts Grad 2 einen Abszess.…”

Endoglin/CD105-Based Imaging of Cancer and Cardiovascular Diseases: A Systematic Review

“…This rare, autosomal dominantly inherited disease is characterized by mutations in the endoglin gene, resulting in pulmonal arteriovenous malformations and telangiectasia-mediated epistaxis [ 17 ]. Next to endothelial cell defects, HHT1 patients have an impaired immune system, characterized by lymphopenia of CD4+ (helper) T cells, CD8+ (cytotoxic) T cells, and natural killer cells, in addition to functional deficits in neutrophils, polymorphonuclear cells, and monocytes [ 18 , 19 , 20 ].…”