A transcriptomics study of hereditary angioedema attacks

Castellano, Giuseppe; Divella, Chiara; Sallustio, Fabio; Montinaro, Vincenzo; Curci, Claudia; Zanichelli, Andrea; Bonanni, Erika; Suffritti, Chiara; Caccia, Sonia; Bossi, Fleur; Gallone, Anna; Schena, Francesco Paolo; Gesualdo, Loreto; Cicardi, Marco

doi:10.1016/j.jaci.2018.03.016

Cited by 20 publications

(17 citation statements)

References 58 publications

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“…Interestingly, circulating peripheral blood cells of C1-INH deficient patients express increased amounts uPAR during swelling attacks (43). Furthermore, these patients benefit from prophylactic treatment with the antifibrinolytic agent tranexamic acid, which reduces both the frequency and severity of HAE attacks (44).…”

Section: Plasminflammation: Plasmin In Hae-c1-inhmentioning

confidence: 99%

Plasminflammation—An Emerging Pathway to Bradykinin Production

Maas

2019

Front. Immunol.

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Plasminogen activation is essential for fibrinolysis—the breakdown of fibrin polymers in blood clots. Besides this important function, plasminogen activation participates in a wide variety of inflammatory conditions. One of these conditions is hereditary angioedema (HAE), a rare disease with characteristic attacks of aggressive tissue swelling due to unregulated production and activity of the inflammatory mediator bradykinin. Plasmin was already implicated in this disease decades ago, but a series of recent discoveries have made it clear that plasmin actively contributes to this pathology. Collective evidence points toward an axis in which the plasminogen activation system and the contact system (which produces bradykinin) are mechanistically coupled. This is amongst others supported by findings in subtypes of HAE that are caused by gain-of-function mutations in the genes that respectively encode factor XII or plasminogen, as well as clinical experience with the antifibrinolytic agents in HAE. The concept of a link between plasminogen activation and the contact system helps us to explain the inflammatory side effects of fibrinolytic therapy, presenting as angioedema or tissue edema. Furthermore, these observations motivate the development and characterization of therapeutic agents that disconnect plasminogen activation from bradykinin production.

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Section: Plasminflammation: Plasmin In Hae-c1-inhmentioning

confidence: 99%

Plasminflammation—An Emerging Pathway to Bradykinin Production

Maas

2019

Front. Immunol.

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“…The average C1-INH plasma level in HAE is ∼40%% normal (Yang et al, 2016;Castellano et al, 2018;Cicardi and Zuraw, 2018;De Maat et al, 2018), yet this is sufficient to provide normal FIGURE 7 | Proposed complex of CR1+7S with Additional Plasma Factors Associated with AD. Crystallographic structures from Protein Data Bank for selected RCA proteins in complex with Complement C3b.…”

Section: Overwhelmed C1-inhibitor Leads To Overactive Complementmentioning

confidence: 99%

Complement Activation in the Central Nervous System: A Biophysical Model for Immune Dysregulation in the Disease State

Peoples

Strang²

2021

Front. Mol. Neurosci.

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Complement, a feature of the innate immune system that targets pathogens for phagocytic clearance and promotes inflammation, is tightly regulated to prevent damage to host tissue. This regulation is paramount in the central nervous system (CNS) since complement proteins degrade neuronal synapses during development, homeostasis, and neurodegeneration. We propose that dysregulated complement, particularly C1 or C3b, may errantly target synapses for immune-mediated clearance, therefore highlighting regulatory failure as a major potential mediator of neurological disease. First, we explore the mechanics of molecular neuroimmune relationships for the regulatory proteins: Complement Receptor 1, C1-Inhibitor, Factor H, and the CUB-sushi multiple domain family. We propose that biophysical and chemical principles offer clues for understanding mechanisms of dysregulation. Second, we describe anticipated effects to CNS disease processes (particularly Alzheimer's Disease) and nest our ideas within existing basic science, clinical, and epidemiological findings. Finally, we illustrate how the concepts presented within this manuscript provoke new ways of approaching age-old neurodegenerative processes. Every component of this model is testable by straightforward experimentation and highlights the untapped potential of complement dysregulation as a driver of CNS disease. This includes a putative role for complement-based neurotherapeutic agents and companion biomarkers.

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“…The network for genetic control of BK metabolism is just evolving, and genetic studies may elucidate unknown aspects of angioedema pathogenesis and heterogeneity 5 by identifying further genes potentially involved in the regulation of BK production, its cleavage, and edema formation 8 …”

Section: Pathophysiology Of Hereditary Angioedemamentioning

confidence: 99%

Hereditary angioedema in children and adolescents – A consensus update on therapeutic strategies for German‐speaking countries

Wahn

Aberer

Aygören‐Pürsün

et al. 2020

Pediatric Allergy Immunology

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Background/Methods: At a consensus meeting in August 2018, pediatricians and dermatologists from German-speaking countries discussed the therapeutic strategy for the treatment of pediatric patients with type I and II hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) for Germany, Austria, and Switzerland, taking into account the current marketing approval status. HAE-C1-INH is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible and an optimal management of the disease are important to avoid ineffective therapies and to properly treat swelling attacks. This article provides recommendations for developing appropriate treatment strategies in the management of HAE-C1-INH in pediatric patients in German-speaking countries. An overview of available drugs in this age-group is provided, together with their approval status, and study results obtained in adults and pediatric patients. Results/Conclusion: Currently, plasma-derived C1 inhibitor concentrates have the broadest approval status and are considered the best available option for on-demand treatment of HAE-C1-INH attacks and for short-and long-term prophylaxis across all pediatric age-groups in German-speaking countries. For on-demand treatment of children aged 2 years and older, recombinant C1-INH and bradykinin-receptor antagonist icatibant are alternatives. For long-term prophylaxis in adolescents, the parenteral kallikrein inhibitor lanadelumab has recently been approved and can be recommended due to proven efficacy and safety. | 975 WAHN et Al.

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A transcriptomics study of hereditary angioedema attacks

Cited by 20 publications

References 58 publications

Plasminflammation—An Emerging Pathway to Bradykinin Production

Plasminflammation—An Emerging Pathway to Bradykinin Production

Complement Activation in the Central Nervous System: A Biophysical Model for Immune Dysregulation in the Disease State

Hereditary angioedema in children and adolescents – A consensus update on therapeutic strategies for German‐speaking countries

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