Genetic Variants Leading to Urticaria and Angioedema and Associated Biomarkers

Advances in next generation sequencing technologies, as well as their expanded accessibility and clinical use over the past 2 decades, have led to an exponential increase in the number of identified single gene disorders. Among these are primary atopic disorders—inborn errors of immunity resulting in severe allergic phenotypes as a primary presenting feature. Two cardinal aspects of type I immediate hypersensitivity allergic reactions are hives and angioedema. Mast cells (MCs) are frequent primary drivers of these symptoms, but other cells have also been implicated. Even where MC degranulation is believed to be the cause, mediator-induced symptoms may greatly vary among individuals. Angioedema—particularly in the absence of hives—may also be caused by hereditary angioedema conditions resulting from aberrant regulation of contact system activation and excessive bradykinin generation or impairment of vascular integrity. In these patients, swelling can affect unpredictable locations and fail to respond to MC-directed therapies. Genetic variants have helped delineate key pathways in the etiology of urticaria and nonatopic angioedema and led to the development of targeted therapies. Herein, we describe the currently known inherited and acquired genetic causes for these conditions, highlight specific features in their clinical presentations, and discuss the benefits and limitations of biomarkers that can help distinguish them. Advances in next generation sequencing technologies, as well as their expanded accessibility and clinical use over the past 2 decades, have led to an exponential increase in the number of identified single gene disorders. Among these are primary atopic disorders—inborn errors of immunity resulting in severe allergic phenotypes as a primary presenting feature. Two cardinal aspects of type I immediate hypersensitivity allergic reactions are hives and angioedema. Mast cells (MCs) are frequent primary drivers of these symptoms, but other cells have also been implicated. Even where MC degranulation is believed to be the cause, mediator-induced symptoms may greatly vary among individuals. Angioedema—particularly in the absence of hives—may also be caused by hereditary angioedema conditions resulting from aberrant regulation of contact system activation and excessive bradykinin generation or impairment of vascular integrity. In these patients, swelling can affect unpredictable locations and fail to respond to MC-directed therapies. Genetic variants have helped delineate key pathways in the etiology of urticaria and nonatopic angioedema and led to the development of targeted therapies. Herein, we describe the currently known inherited and acquired genetic causes for these conditions, highlight specific features in their clinical presentations, and discuss the benefits and limitations of biomarkers that can help distinguish them. Managing Chronic Urticaria and Angioedema: Novel InsightsThe Journal of Allergy and Clinical Immunology: In PracticeVol. 11Issue 8PreviewChronic urticaria and angioedema are recurrent conditions that significantly impact patients' quality of life. Over the past 2 decades, extensive research has been conducted to elucidate the underlying mechanisms and improve the management of these conditions. Recent investigations of the pathophysiology of chronic spontaneous urticaria (CSU) have highlighted the role of autoimmune mechanisms, and 2 endotypes have been characterized: type I autoallergic CSU, associated with immunoglobulin E (IgE) antibodies against autoantigens, and type IIb autoimmune CSU, driven by autoantibodies that activate mast cells, including anti- FcεRI (high-affinity receptor for the Fc region of IgE) and anti-IgE. Full-Text PDF