The complex alteration in the network of IL-17-type cytokines in patients with hereditary angioedema

Abstract

Hereditary angioedema (HAE) is a rare autosomic-dominant disorder characterized by a deficiency of C1 esterase inhibitor which causes episodic swellings of subcutaneous tissues, bowel walls and upper airways that are disabling and potentially life-threatening. We evaluated n = 17 patients with confirmed HAE diagnosis during attack and remission state and n = 19 healthy subjects. The samples were tested for a panel of IL (Interleukin)-17-type cytokines (IL-1β, IL-6, IL-10, granulocyte-macrophage colony stimulating factor (GM-CSF), IL-17, IL-21, IL-22, IL-23) and transforming growth factor-beta (TGF-β) subtypes. Data indicate that there are variations of cytokine levels in HAE subjects comparing the condition during the crisis respect to the value in the remission phase, in particular type 17 signature cytokines are increased, whereas IL-23 is unmodified and TGF-β3 is significantly reduced. When comparing healthy and HAE subjects in the remission state, we found a significant difference for IL-17, GM-CSF, IL-21, TGF-β1 and TGF-β2 cytokines. These results confirm and extend our previous findings indicating that in HAE there is operating an inflammatory activation process, which involves also T helper 17 (Th17) cytokines and TGF-β isoforms, associated with localized angioedema attacks and characterized by elevated bradykinin levels.

Does hereditary angioedema make COVID-19 worse?

“…Compared with healthy controls, the levels of IL-17, IL-21, TGF-β, and granulocyte-macrophage colony stimulating factor (GM-CSF) are significantly higher in HAE patients in remission. 10 These cytokines, plus IL-6, increase further in HAE patients during attacks compared with remission. 10 The above-mentioned cytokines are all produced by Th17 and other type 17 cells, including γδ T cells, natural killer cells, natural killer T cells, and innate lymphoid cells.…”

“… 10 These cytokines, plus IL-6, increase further in HAE patients during attacks compared with remission. 10 The above-mentioned cytokines are all produced by Th17 and other type 17 cells, including γδ T cells, natural killer cells, natural killer T cells, and innate lymphoid cells. 54 , 55 , 56 Some of these cytokines (IL-6, IL-21 and TGF-β) can stimulate Th0 to differentiate to Th17 subsets, which play an important role in inducing local inflammation.…”

“… 9 Certain cytokines such as interleukin-1 (IL-1) and transforming growth factor-β (TGF-β), may also play a role in the pathophysiology of HAE. 10 Therefore, it is reasonable to hypothesize that there might be an interaction between COVID-19 and HAE. As of now, there are no reports of HAE patients infected with SARS-CoV-2, and there is, therefore, no information on the course of COVID-19 in patients with HAE.…”

“… 30 Thus, the depletion of ACE2 by SARS-CoV-2 infection results in impaired DABK inactivation. Binding of DABK to B1R can prompt neutrophil infiltration, increased capillary leakage 10 which comprise the key features of acute respiratory distress syndrome (ARDS), and lead to more severe lung injury and inflammation. 30 , 31 The accumulation of DABK might result in negative feedback of BK degradation and leave BK binding to B2R on the surface of endothelial cells.…”

Epigenetic alterations on C1-inhibitor expression may influence hereditary angioedema attack frequency and C4 levels

“…Cytokine studies before and during HAE attacks suggest that attacks are associated with changes in the balance of inflammatory and anti‐inflammatory cytokines. Excess interleukin (IL)‐23 signatures noted during attacks could skew the system towards pathogenic T helper type 17 (Th17) and autoimmunity [5]. Such clinical variability suggests that epigenetic alterations and changes leading to functional consequences in other members of the SERPIN superfamily have been described [6].…”