Patients with Hereditary Hemorrhagic Telangectasia (HHT) Exhibit a Deficit of Polymorphonuclear Cell and Monocyte Oxidative Burst and Phagocytosis: A Possible Correlation with Altered Adaptive Immune Responsiveness in HHT

Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare genetic disease characterized by mutations occurring in the endoglin and ALK-1, two receptors of transforming growth factor-beta1. From a pathogenic point of view, a possible involvement of the immune system in HHT has been suggested since a mononuclear cell infiltrate was found around the area of telangiectases. Up until now, no information has been available about the role played by leukocytes in HHT and the mechanisms elicited by secretion of their mediators. However, the fact that a deficit of adaptive immunity in HHT has been reported in a companion paper in this issue will represent a great contribution to the understanding of HHT pathogenesis. The purpose of this study was to evaluate whether patients with HHT manifest also alterations in the innate immune response. Therefore, the phenotype of T, B and natural killer lymphocytes, serum immunoglobulin levels, phagocytosis and oxidative burst activity exerted by polymorphonuclear cells (PMN) and monocytes (MO) were analyzed in 22 patients. Twenty individuals demonstrated single or multiple deficits of PMN and MO functions, while the immunophenotype of lymphocytes and serum concentrations of immunoglobulins were normal. To the best of our knowledge, this is the first demonstration of a reduction in PMN and MO functions in HHT, thus suggesting a higher susceptibility to infectious complications in these patients. The relationship between innate immune deficits and T helper 1 and monocyte-derived cytokine dysfunction in HHT, as previously reported, is discussed.

The role of endoglin in post-ischemic revascularization

“…This phenotype was rescued by the injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients. This result is in agreement with the reduction in monocyte function (including oxidative burst and phagocytosis) in HHT patients [242] and in mouse monocytes lacking endoglin [243]. Moreover, a different role for endoglin isoforms in the regulation of monocyte-macrophage functions has been proposed because L-endoglin overexpression promotes a pro-inflammatory M1-like macrophage phenotype, whereas S-endoglin favors the expression of anti-inflammatory M2 macrophage markers [96].…”

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

“…2 More recently recognised features include pulmonary arterial hypertension 10 ; juvenile polyposis 11 ; pulmonary hypertension in the context of high output cardiac failure secondary to hepatic AVMs, when PH may be reversible after hepatic AVM treatment [12][13][14][15][16] ; a prothrombotic state associated with elevated plasma levels of factor VIII 17 , and potential immune dysfunction. 18 Three of the genes mutated in HHT have been identified: endoglin (resulting in HHT1, OMIM #187300) 19 ; ACRVL1/ALK1; (resulting in HHT2, OMIM#600376) 20 , and more rarely, SMAD4 (mutated in HHT in association with juvenile polyposis, JPHT OMIM #175050) 11 . Many hundreds of different mutations have been described in HHT families, with no common mutation identified ( 21 , summarised in 3 ).…”

Hereditary haemorrhagic telangiectasia: a clinical and scientific review

“…29,30 Genotype -phenotype relationships Recent large series support early observations, finding pulmonary and cerebral AVMs more common in HHT1 (ENG mutations), and hepatic AVMs more common in HHT2 (ACVRL1 mutations). 31 -36 Although there was an initial suggestion that overall severity of disease is greater in HHT1 than in HHT2, 37 this study predated the Deep venous thrombosis, pulmonary emboli As per national guidelines, eg, 10 Immune dysfunction 11 Uncertain %, Estimated prevalence across all age groups. Haem., haemorrhage frequency scale 0 to ++++.…”