Roles of Immune Cells in Hereditary Angioedema

Ferrara, Anne Lise; Cristinziano, Leonardo; Petraroli, Angelica; Bova, María; Gigliotti, Maria Celeste; Marcella, Simone; Modestino, Luca; Varricchi, Gilda; Braile, Mariantonia; Galdiero, Maria Rosaria; Spadaro, Giuseppe; Loffredo, Stefania

doi:10.1007/s12016-021-08842-9

Cited by 17 publications

(11 citation statements)

References 160 publications

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“…Adaptive immunity has not been thoroughly analyzed in HAE pathogenesis. A few studies show alterations in T-cell profiles and/or cytokine production [ 5 ] . On the other hand, it has been observed that adaptive immune responses may be involved in the development of autoimmune disease in patients with HAE, mainly through alterations in B-cell activation and survival [ 3 , 6 ] .…”

Section: Discussionmentioning

confidence: 99%

Remission of hereditary angioedema attacks associated with starting teriflunomide in a patient with multiple sclerosis

Lopez

Romero

2023

European Journal of Case Reports in Internal Medicine

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Background: Hereditary angioedema is a rare hereditary and potentially life-threatening disorder characterized by recurrent attacks of cutaneous and submucosal swelling. In spite of the advances made in terms of pathophysiology, underlying mechanisms are not fully clear and this, in turn, hinders the development of effective therapies. Currently, on demand treatment is considered first-class, with few cost-effective, long-term prophylactic options. Case presentation: Here we describe the case of a 34-year-old man diagnosed with hereditary angioedema at the age of 10, who used to suffer several angioedema attacks per month. He was given prophylactic treatment with antifibrinolytic agents and androgens without improvement. Moreover, he was treated with plasma-derived C1-INH concentrate or icatibant for on-demand treatment of moderate and severe angioedema attacks. At the age of 33, after suffering sudden vision loss and lower limb paresthesia, he was studied and diagnosed with multiple sclerosis. Teriflunomide was administered at a dosage of 14 mg/day. Angioedema attacks disappeared 40 days after starting treatment. Conclusion: Thus, we suggest considering the pathophysiologic mechanisms on which teriflunomide could be active and consider this drug carefully as an option for prophylaxis purposes. Yet, its effectiveness on this condition should be further studied.

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Section: Discussionmentioning

confidence: 99%

Remission of hereditary angioedema attacks associated with starting teriflunomide in a patient with multiple sclerosis

Lopez

Romero

2023

European Journal of Case Reports in Internal Medicine

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“…Disruption in the number of lymphocytes when comparing HAE patients and healthy subjects can be somehow surprising. Since the cells mediate adaptive immune responses, they seem to be uninvolved in HAE [ 17 ]. Only a few studies have reported abnormal T and B cell counts or abnormal distribution of T cell surface IgG-receptors [ 18 , 19 ].On the contrary, the study from Lopez-Lera et al on the profiling of the RNA expression of peripheral blood mononuclear cells (PBMC) from C1-INH-HAE patients did not prove alterations in the expression pattern of PBMC in association with frequency and severity of disease [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…Probably, the HAE attack duration can be altered by the cross-play between immune cells producing vasoactive mediators, including bradykinin, histamine, complement components, or vasoactive mediators. Such molecules activate certain immune cell subtypes contributing to vascular endothelial processes that lead to hyperpermeability and tissue edema [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of Bradykinin Receptors in Hereditary Angioedema Due to C1-Inhibitor Deficiency

Dyga

Obtułowicz

Mikołajczyk

et al. 2022

IJMS

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Background: Hereditary angioedema (HAE) is a rare, genetic disease caused by the decreased level or function of the C1 inhibitor. The primary mediator of symptoms in HAE is bradykinin acting through its two receptors, namely receptors 1 (BR1) and 2 (BR2). Although BR2 is well characterized, the role of BR1 remains unclear. Objective: To study the role of bradykinin receptors 1 (BR1) in the etiopathogenesis of HAE. Methods: A total of 70 individuals, 40 patients with HAE, and 30 healthy subjects were recruited to the study. HAE was diagnosed in accordance with the international guideline. The level of bradykinin receptors was determined in populations of CD3+, CD4+, CD8+, and CD14++CD16−, CD14++CD16+ monocytes. In addition, the level of disease activity-specific markers was measured. Results: There were statistically significant differences in the subpopulation of lymphocytes and monocytes between patients with HAE compared to healthy subjects. The level of BR1 and BR2 on PBMCs was comparable in healthy subjects and HAE patients during remission with significant overexpression of both receptors, triggered by HAE attack. Moreover, a significant increase in TNF-alpha and IL-1 plasma levels was observed among HAE patients. Conclusions: BR1 expression may play an important role in the pathomechanism of HAE.

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“…Таким образом, допускается существование нескольких локальных факторов, стимулирующих выработку брадикинина в конкретном месте, в частности в мягких тканях лица, рук, ног, гениталий, а также на слизистых оболочках, выстилающих дыхательный и пищеварительный тракты [23]. Выдвигают предположения о вовлеченности врожденной и адаптивной иммунной системы в ангиоотек [15]. Так, моноциты, макрофаги, гранулоциты, лимфоциты, базофилы, эндотелиальные клетки прямо или косвенно могут участвовать в иммунопатогенезе ангиоотека.…”

Section: Discussionunclassified

“…В частности, была показана положительная корреляция между повышенными значениями уровня фактора роста эндотелия сосудов (VEGF), продуцируемого различными клетками, в том числе эндотелиальными, и тяжестью течения НАО [21]. В дополнение к этому, макрофаги секретируют широкий спектр медиаторов, включая компоненты комплемента, такие как C1-INH, который, как известно, является ключевым фактором развития НАО [15]. Возможно также носительство мутаций в генах, которые оказывают негативный синергический эффект на развитие и течение НАО, что косвенно подтверждается различными триггерами данного заболевания (колебания уровней гормонов, в первую очередь эстрогена, ингибиторы ангиотензин-превращающего фермента (ACI), травма, манипуляции с верхними дыхательными путями и медицинские процедуры, в том числе хирургическое и стома-тологическое вмешательство, эмоциональный стресс, инфекции) [13].…”

Section: Discussionunclassified

Application of bioinformatical analysis to identify candidate genes associated with hereditary angioedema

2022

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Primary immunodeficiencies (PID) are a heterogeneous group of hereditary diseases that lead to impaired immune defense. Often, the diagnosis cannot be made without identifying mutations that lead to the development of the disease. For many PIDs, there is no clear understanding of the etiology, pathogenesis, and genes involved. There is an obvious need to identify candidate genes potentially capable of leading to the development of PIDs.Hereditary angioedema (HAE) is a rare genetically determined disease, accompanied by recurrent edema of soft tissues and submucosal membranes, posing a threat to the life of patients. Diagnosis is based on the clinical presentation, family history, laboratory values of C1-esterase inhibitor, complement component 4, complement component 1q, antibodies to C1 and genetic testing for a number of mutations in the genes SERPING1, F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6. However, pathogenesis may involve other genes in which the negative effect of mutations has not yet been studied. HAE is a non-monogenic disease that may involve an extensive network of genes. It seems important to determine the groups of the most probable candidate genes presumably involved in the development of pathology.Aim – to identify, using bioinformatics analysis, candidate genes for the development/pathogenesis of HAE and to reveal their biological context.The analysis was based on a group of genes, mutations in which are significantly associated with HAE: SERPING1, F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6. To analised genetic and protein–protein networks and identify the biological context of the selected candidate genes, a number of web resources were used: HumanNetv3, GeneMania, FUMA GWAS in the GENE2FUNC mode.One hundred potential candidate genes in which mutations can be associated with HAE have been identified. The biological context of the identified genes was determined. The data of the biological context, genetic and protein-protein interactions made it possible to exclude a number of genes from the list of the most likely participants in pathogenesis and divide the remaining ones into groups with a greater or lesser potential for involvement. The group of the most likely HAO candidate genes includes PLAT, HRG, SERPINA1, SERPINF2, MASP2, GRB14, C1QBP, DOK2, KLKB1, F11, TEK, KLK10, KRT1, APOH, CPB2, F2.The results obtained can provide significant assistance in the study of the HAE molecular mechanism, as well as in the diagnosis and prognosis of the disease course. The identified candidate genes have the potential to serve as diagnostic biomarkers for patients with unexplained angioedema.The use of bioinformatic methods makes it possible to determine the list of candidate genes that are presumably involved in the disease pathogenesis or aggravate its course, and to obtain up-to-date information about the biological context of the identified genes. Understanding the genetic underpinnings and pathophysiology of PID may help define new diagnostic and therapeutic targets.

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Roles of Immune Cells in Hereditary Angioedema

Cited by 17 publications

References 160 publications

Remission of hereditary angioedema attacks associated with starting teriflunomide in a patient with multiple sclerosis

Remission of hereditary angioedema attacks associated with starting teriflunomide in a patient with multiple sclerosis

The Role of Bradykinin Receptors in Hereditary Angioedema Due to C1-Inhibitor Deficiency

Application of bioinformatical analysis to identify candidate genes associated with hereditary angioedema

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