Immunopathology Complement Activation Complement Molecular Mechanisms Related Products Hot Services Q&A Resources
Are you struggling with the complexities of Acquired Angioedema (AAE) diagnosis and treatment, facing challenges in identifying the underlying complement dysregulation, or finding effective long-term management strategies? At Creative Biolabs, our comprehensive suite of complement analysis tools and custom antibody development services empowers you to precisely characterize the specific complement pathway abnormalities driving AAE and develop targeted therapeutic interventions.
Immunopathology Features
Angioedema without the presence of allergy continues to represent a medical paradox. This disorder is characterized by facial, laryngeal, genital or intra-abdominal swelling or swelling of the extremities. Much work has been undertaken to understand the genetics, pathogenesis, and clinical management of the angioedema. The angioedema is classified as hereditary and acquired types.
Acquired angioedema (AAE)
Acquired angioedema (AAE) is a rare condition characterized by edema. It can be immunologic, non-immunologic or idiopathic and is usually caused by the allergy and occurs together with other allergic symptoms and urticaria. This disorder was discovered in a patient who had angioedema and acquired C1-inhibitor (C1-INH) deficiency, which leads to the demonstration that an autoimmune mechanism may be the cause of the C1-INH deficiency.
Angioedema could be acquired and mainly in associate with lymphoproliferative disorders or occasionally with autoimmune, neoplastic, or infectious diseases, it could be classified into two subtypes, AAE-I and AAE-II.
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AAE-I is linked to lymphomas, chronic lymphocytic leukemia, undefined lymphoproliferative diseases. Other disorders include multiple myeloma, myelofibrosis, and monoclonal gammopathies.
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AAE-II is defined by the presence of an autoantibody recognizing the C1-INH. Epitope mapping report demonstrated that two potential epitopes in the intact C1-INH that binds to the C1-INH autoantibodies are peptide 2 (residue 438-449) and peptide 3 (residue 448-459).
Cause of AAE
C1-INH is a protease inhibitor whose function is to prevent the spontaneous hyperactivation of the complement system. Deficiency of C1-INH leads to the angioedema, hereditary angioedema (deficiency of C1-INH gene) and acquired angioedema (autoantibody directed against C1-INH).
Diagnosis of AAE
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Testing C1-INH and C4
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C1-INH and C4 are both normal→The deficiency of C1-INH is very unlikely.
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C1-INH and C4 are both (C1-INH below 50% of normal on two separate determinations)→diagnosis of C1-INH deficiency are made.
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Only C4 is low. The activity of C1-INH needs to be determined. If the activity of C1-INH is below 50% of normal on two separate determinations→diagnosis of C1-INH deficiency is made.
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Differentiating hereditary and acquired deficiency
This test includes the determination of C1q which is reduced in 70% of the patients who are suffering from AAE but remains normal in hereditary angioedema patients.
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Autoantibody Test
Autoantibodies directed against C1-INH should be detected for any angioedema-suspected patient. A solid-phase ELISA with simplicity and highly-sensitivity has been developed.
Symptom
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Red skin welts
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Swollen throat
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Discolored skin patches
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Vomiting
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Abdominal pain
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Diarrhea
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Skin swelling
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Gastrointestinal swelling
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Respiratory tract swelling
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Swelling (foot, lip, eyelid)
Complement Activation Pathways and AAE Pathogenesis
The pathogenesis of AAE primarily involves the classical pathway of the complement system, with indirect effects potentially involving the alternative and lectin pathways. Here's a breakdown:
Table 1 AAE-related complement activation pathways.
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Complement Activation Pathways
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AAE Pathogenesis
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Classical Pathway
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AAE is characterized by an acquired deficiency of functional C1-INH. This deficiency results in the unregulated activation of the classical complement pathway.
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In the absence of adequate C1-INH, the C1 complex (C1q, C1r, C1s) becomes hyperactive. The serine proteases C1r and C1s excessively cleave C4 and C2, leading to the overconsumption of these complement components.
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Bradykinin production.
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The chronic activation of the classical pathway in AAE often results in low levels of C4 and C1q, which serve as important diagnostic markers to differentiate AAE from HAE, where C1q levels are typically normal.
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Alternative Pathway
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Not considered a primary driver of AAE pathogenesis.
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Persistent activation of the classical pathway may result in elevated deposition of C3b.
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Lectin Pathway
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Not considered a primary driver of AAE pathogenesis.
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C1-INH is capable of inhibiting MASP-1 and MASP-2, the serine proteases integral to the lectin pathway. In the context of C1-INH deficiency in AAE, there might be some deregulation of the lectin pathway, potentially contributing to inflammation.
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Molecular Mechanisms of Complement-Mediated
The molecular mechanisms of complement-mediated angioedema in AAE are intricately linked to the acquired deficiency or dysfunction of C1-INH. This deficiency leads to a cascade of events primarily involving the classical complement pathway and the contact system, ultimately resulting in the overproduction of bradykinin.
Table 2 Molecular mechanisms of complement-mediated.
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Key Complement Components
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Functions
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C1-INH
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Crucial Regulator: Deficiency or dysfunction (due to autoantibodies or consumption) leads to uncontrolled activation of the classical pathway and, more importantly, the contact system, resulting in excessive bradykinin production. Its deficiency is the central defect in AAE.
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C1 Complex
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C1-INH primarily regulates the activated forms of C1r and C1s within the C1 complex (C1q, C1r, C1s). With reduced functional C1-INH, the C1 complex becomes hyperactive and is not effectively controlled.
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C4 and C2 Cleavage
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The unregulated C1s protease excessively cleaves its natural substrates, C4 and C2, leading to the formation of C4b2a (the classical pathway C3 convertase). This results in the overconsumption and low levels of C4 observed in AAE.
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Related Hot Products
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Table 3 Featured products.
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Table 4 Complement test services for SS-related complement studies.
Resources
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