Neurologic and Psychiatric Manifestations of Bradykinin-Mediated Angioedema: Old and New Challenges

Neurologic manifestations have been occasionally described in patients with bradykinin-mediated angioedema. The existing literature is currently limited to case series and case reports mainly described in the hereditary forms (HAE) concerning central nervous system (CNS) involvement. On the contrary, very little is known about peripheral and autonomic nervous system manifestations. CNS involvement in HAE may present with symptoms including severe headaches, visual disturbance, seizures, and various focal and generalized deficits. In addition, a stroke-like clinical picture may present in HAE patients. In turn, some drugs used in patients with cardiovascular and neurologic disorders, such as recombinant tissue plasminogen activator (r-tPA) and angiotensin-converting enzyme inhibitors (ACEI), may produce medication-induced angioedema, resulting in a diagnostic challenge. Finally, most patients with HAE have higher levels of psychological distress, anxiety, and depression. With this review, we aimed to provide an organized and detailed analysis of the existing literature on neurologic and psychiatric manifestations of HAE to shed light on these potentially invalidating symptoms and lay the foundation for further personalized diagnostic pathways for patients affected by this protean disease

Immunogenicity and Safety of Anti-SARS-CoV-2 mRNA Vaccines in a Cohort of Patients with Hereditary Angioedema

Many factors may trigger hereditary angioedema (HAE) attacks. This study aims to gain insights into the benefits and potential risks of COVID-19 vaccination in HAE patients, focusing particularly on the possibility of triggering attacks. We enrolled 31 patients with HAE undergoing two doses of the SARS-CoV-2 mRNA Comirnaty-BioNTech/Pfizer vaccine. To evaluate the possible influence of the vaccine on disease control and attack frequency, we administered the angioedema control test (AECT) 4-week version before (T0), 21 days after the first dose (T1), and between 21 and 28 days after the second dose (T2). Despite 5 patients (16.1%) experiencing attacks within 72 h of the first dose administration, no significant variation in attack frequency was observed before and after vaccination [F(2,60) = 0.123; p = 0.799]. In addition, patients reported higher AECT scores at T1 and T2 compared to T0 [F(2,44) = 6.541; p < 0.05; post hoc p < 0.05)], indicating that the disease was rather more controlled after vaccinations than in the previous period. All patients showed a positive serological response to the vaccine without significant differences from healthy controls (U = 162; p = 0.062). These observations suggest that the vaccine administration is safe and effective in HAE patients

hereditary angioedema attack what happens to vasoactive mediators

Abstract Hereditary angioedema is a disabling, life-threatening condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) leading to bradykinin accumulation and recurrent episodes of edema attack. Vascular leakage is a complex process sustained by the coordinated production of several permeabilizing factors including vascular endothelial growth factors (VEGFs), angiopoietins (ANGPTs) and phospholipase A2 enzymes (PLA2). We previously reported that patients with C1-INH-HAE in remission have increased plasma levels of VEGFs, ANGPTs and secreted PLA2. In this study, we sought to analyze plasma levels of these mediators in 15 patients with C1-INH-HAE during the acute attack compared to remission. Plasma concentrations of VEGF-A, VEGF-C and VEGF-D were not altered during attack compared to remission. Moreover, VEGF-D concentrations were not altered also in remission phase compared to controls. Concentrations of ANGPT1, a vascular stabilizer, were increased during attacks compared to symptoms-free periods, whereas ANGPT2 levels were not altered. The ANGPT2/ANGPT1 ratio was decreased during angioedema attacks. Platelet activating factor acetylhydrolase activity was increased in patients with C1-INH-HAE in remission compared to controls and was decreased during angioedema attacks. Our results emphasize the complexity by which several vasoactive mediators are involved not only in the pathophysiology of C1-INH-HAE, but also during angioedema attacks and its resolution

Secreted phospholipases A2 in hereditary angioedema with C1-inhibitor deficiency

BackgroundHereditary angioedema (HAE) caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein (C1-INH-HAE) is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. We have recently found that patients with C1-INH-HAE have increased plasma levels of vascular endothelial growth factors and angiopoietins (Angs), which have been associated with vascular permeability in several diseases. Among these and other factors, blood endothelial cells and vascular permeability can be modulated by extracellular or secreted phospholipases A2 (sPLA2s).ObjectiveWe sought to investigate the enzymatic activity and biological functions of sPLA2 in patients with C1-INH-HAE.MethodssPLA2s enzymatic activity was evaluated in the plasma from 109 adult patients with C1-INH-HAE and 68 healthy donors in symptom-free period and attacks. Plasma level of group IIA sPLA2 (hGIIA) protein was measured in selected samples. The effect of C1-INH-HAE plasma on endothelial permeability was examined in vitro using a vascular permeability assay. The role of hGIIA was determined using highly specific sPLA2 indole inhibitors. The effect of recombinant hGIIA on C1-INH activity was examined in vitro by functional assay.ResultsPlasma sPLA2 activity and hGIIA levels are increased in symptom-free C1-INH-HAE patients compared with controls. sPLA2 activity negatively correlates with C1-INH protein level and function. C1-INH-HAE plasma increases endothelial permeability in vitro, and this effect is partially reverted by a specific hGIIA enzymatic inhibitor. Finally, recombinant hGIIA inhibits C1-INH activity in vitro.ConclusionsPLA2 enzymatic activity (likely attributable to hGIIA), which is increased in C1-INH-HAE patients, can promote vascular permeability and impairs C1-INH activity. Our results may pave the way for investigating the functions of sPLA2s (in particular, hGIIA) in the pathophysiology of C1-INH-HAE and may inform the development of new therapeutic targets

Effetti immunomodulanti dell’istamina sulle cellule del sistema immunitario

L’istamina, sintetizzata dai mastociti e dai basofili umani, svolge un ruolo rilevante nella patogenesi delle reazioni infiammatorie e delle malattie allergiche. Essa può essere rilasciata da mastociti tessutali e basofili a seguito dell’attivazione da parte di molteplici stimoli immunologici e non-immunologici. L’istamina induce una serie di effetti immediati, quali vasodilatazione, aumentata permeabilità vascolare e broncocostrizione attraverso l’attivazione del recettore H1 presente sulle cellule muscolari lisce dei bronchi, e sulle cellule endoteliali. Inoltre, essa è in grado di modulare in maniera differenziale le funzioni di numerose cellule coinvolte nelle risposte infiammatorie ed immuni quali eosinofili, neutrofili, linfociti T, monociti, macrofagi e cellule dendritiche. Le risposte elicitate dall’istamina sono estremamente variabili, suggerendo che l’espressione dei recettori dell’istamina (H1, H2, H3 and H4) può essere differente tra cellule della linea monocito-macrofagiche. Lo scopo del nostro studio è stato quello di esaminare inizialmente gli effetti di concentrazioni fisiologiche di istamina sui macrofagi polmonari in vitro e successivamente confrontare l’espressione e l’attività funzionale del recettore H1 nei monociti del sangue periferico, nei macrofagi polmonari (HLM) e nei macrofagi derivati da monociti differenziati in vitro (MDM). Materiali e Metodi: I macrofagi polmonari (HLM) sono stati purificati dal tessuto di pazienti sottoposti a chirurgia toracica mediante gradiente discontinuo di Percoll. I monociti sono stati purificati dal sangue periferico di donatori sani mediante gradiente di densità e selezione immunomagnetica negativa. I macrofagi derivati da monociti (MDM) sono stati ottenuti incubando (7-10 giorni) i monociti con FCS. Le cellule sono state incubate (37°C, 2-18 ore) con concentrazioni crescenti di istamina, agonisti ed antagonisti recettoriali anti-H1 ed anti-H2. Al termine dell’incubazione è stata determinata la secrezione di β-glucuronidasi con tecnica colorimetrica, la produzione di IL-6 ed IL-8 con ELISA ed il calcio intracellulare con tecnica microfluorimetrica. L’espressione del recettore H1 è stata valutata mediante RT-PCR quantitativa e western blot. Risultati: L’istamina induce la secrezione di β-glucuronidasi e di IL-6 nei HLM in maniera concentrazione-dipendente con un massimo rilascio compreso rispettivamente tra 2 e 6 ore di incubazione. L’esocitosi e la secrezione di citochine proinfiammatorie indotte dall’istamina nei HLM sono Ca2+ dipendenti. Gli effetti dell’istamina sono inibiti da un antagonista recettoriale anti-H1 (fexofenadina), ma non dalla ranitidina (antagonista del recettore H2). Esperimenti successivi di PCR quantitativa hanno evidenziato che gli HLM e gli MDM esprimono rispettivamente livelli 3 e 15 volte più elevati di mRNA per l’H1 rispetto ai monociti. Il western blot conferma l’aumento dell’espressione della proteina del recettore H1 durante la differenziazione cellulare da monociti in macrofagi. Per verificare se il recettore overespresso nei macrofagi era funzionalmente attivo abbiamo valutato la secrezione di IL-8 indotta dall’istamina nei monociti e negli MDM. L’istamina induce la produzione di IL-8 in maniera concentrazione dipendente in entrambi i tipi cellulari. Questo effetto è significativamente maggiore negli MDM (aumento di 5,22,8 volte vs. controllo) rispetto a quello osservato nei monociti (aumento di 2,20,6 volte vs. controllo). La secrezione di IL-8 indotta dall’istamina viene inibita dalla levocetirizina (selettivo antagonista del recettore H1) in maniera concentrazione-dipendente con IC50 di 847304 nM. Viceversa, la ranitidina non influenza la secrezione indotta dall’istamina. L’istamina non è in grado di indurre alcun segnale del calcio nei monociti mentre negli MDM induce un significativo incremento del calcio intracellulare che viene completamente inibito dalla levocetirizina. Conclusioni: Questi risultati indicano che l’istamina è un efficace stimolo per l’esocitosi e per la produzione di citochine/chemochine nelle cellule della linea monocito-macrofagica. La differenziazione dei monociti in macrofagi, sia in vivo nel polmone che in vitro, si associa alla up-regolazione del recettore H1. L’aumento dell’espressione del recettore H1 è associato ad un incremento della risposta funzionale dell’istamina. Queste osservazioni suggeriscono che l’istamina può contribuire al mantenimento dell’infiammazione e al rimodellamento tessutale nelle malattie allergiche ed infiammatorie del polmone mediante la produzione di mediatori proinfiammatori ed immunomodulanti rilasciati dalle cellule monocito-macrofagiche, mediante la differente espressione del recettore H1 ed infine attraverso la diversa responsività di tali cellule all’istamina stessa

Histamine-induced activation of human lung macrophages

Background: Histamine plays a central role in the pathogenesis of allergic and inflammatory diseases by modulating vascular and airway responses. Increasing evidence suggests that histamine also regulates the function of inflammatory and immune cells. Macrophages are primarily involved in inflammatory diseases of the lung. We explored the ability of low concentrations of histamine to induce the release of proinflammatory mediators from human lung macrophages. Methods: Macrophages purified (>95%) from lung parenchyma by Percoll density gradients and adherence to polystyrene dishes were incubated (37°C, 2-24 h) with histamine (10-9-10-6 M). At the end of incubation, the release of β-glucuronidase and IL-6 was determined. Results: Histamine induced a concentration-dependent release of β-glucuronidase and IL-6 with a maximum release after 2 and 6 h of incubation, respectively. Exocytosis induced by histamine was noncytotoxic and was Ca2+- and temperature-dependent. The effect of histamine was inhibited by the H1 receptor antagonist fexofenadine but not by the H2 antagonist ranitidine. Conclusions: These data indicate that histamine is an effective stimulus for exocytosis and cytokine production from human lung macrophages. These effects are inhibited by pharmacological concentrations of fexofenadine. Our results suggest that histamine may contribute to the long-term evolution of lung inflammation and tissue remodelling in allergic diseases by modulating the production of proinflammatory and immunoregulatory mediators by macrophages. Copyright © 2001 S. Karger AG, Basel

Human mast cells and basophils in HIV-1 infection

Mast cells and basophils (FcεRI+ cells) are classically involved in allergic disorders. HIV-1 glycoprotein gp 120 acts as a viral superantigen by interacting with the heavy chain, variable 3 (VH3) region of IgE to induce cytokine release from FcεRI+ cells. The chemokine receptors CCR3 and CXCR4, co-receptors for HIV-1, are expressed by FcεRI+ cells. Via its interaction with CCR3, HIV-1 transactivation (Tat) protein is a potent chemoattractant for FcεRI+ cells. Incubation of basophils with Tat protein upregulates the surface expression of the CCR3 receptor. There is some evidence that human FcεRI+ cells could be infected in vitro by M-tropic HIV-1 strains

Role of human FcεRI+ cells in HIV-1 infection

Enhanced serum IgE levels in adults and children with HIV-1 infection could be a marker of poor prognosis. HIV-1 infection is believed to involve a switch toward a "TH2-like" cytokine pattern. HIV-1 gp120 from different clades is a potent stimulus for histamine release from human basophils and mast cells. Gp120 also induces IL-4 and IL-13 synthesis from basophils. It functions as a viral superantigen by interacting with the VH3 region of IgE to induce mediator release from human FcεRI+ cells. The chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES, is expressed by basophils and lung mast cells. By interacting with the CCR3 receptor on FcεRI+ cells, HIV-1 Tat protein is a potent chemoattractant for basophils and lung mast cells. Tat protein also induces IL-4 and IL-13 release from basophils. Incubation of basophils with Tat protein upregulates the surface expression of the CCR3 receptor, a co-receptor of HIV-1 infection. Extracellular Tat affects the directional migration of human FcεRI+ cells, CCR3 expression and TH2 cytokines release. We have shown that HIV-1 proteins gp120 and Tat trigger the release of cytokines critical for TH2 polarization from FcεRI+ cells through two distinct mechanisms. In addition, Tat upregulates the β-chemokine receptor CCR3, making FcεRI+ cells more susceptible to infection with CCR3 tropic HIV-1 isolates