Complement C4A (Chido/Rodgers blood group) | Elisa - Clia - Antibody - Protein

Background

Complement component 4A (C4A) is a crucial protein in the classical and lectin pathways of the complement system, a key part of the innate immune response. C4A, along with C4B, is encoded by the C4 gene located in the major histocompatibility complex (MHC) class III region on chromosome 6. These genes are highly polymorphic and play significant roles in immune response by contributing to the opsonization of pathogens and the formation of the membrane attack complex (MAC).

Protein Structure

• Domain Composition: C4A is a large glycoprotein consisting of 1,745 amino acids with a molecular weight of approximately 200 kDa. It is synthesized as a single polypeptide chain and subsequently cleaved into three fragments: α, β, and γ chains.
• Key Functional Domains:
• α Chain: Contains the site for cleavage by C1s enzyme, leading to the formation of C4a and C4b fragments.
• Thioester Bond: Critical for the covalent binding of C4b to pathogen surfaces, facilitating opsonization.
• Chido/Rodgers Blood Group Antigens: Located on the C4A protein, these antigens are recognized in blood transfusion compatibility and are defined by specific polymorphisms within the C4 gene.

Classification and Subtypes

• C4A and C4B: Two isoforms, C4A and C4B, are distinguished by slight differences in their amino acid sequences, leading to functional variations. C4A has a preference for binding to amino groups, whereas C4B favors hydroxyl groups.
• Polymorphisms: Extensive genetic polymorphism in the C4 gene gives rise to multiple allelic variants, contributing to individual differences in immune response and disease susceptibility.

Function and Biological Significance

• Complement Activation: C4A is activated by cleavage into C4a and C4b by the C1s enzyme during the classical pathway of complement activation. C4b then binds to the pathogen surface, marking it for destruction by phagocytes.
• Opsonization: C4b, a larger fragment, binds covalently to microbial surfaces and enhances phagocytosis by immune cells.
• Formation of C3 and C5 Convertases: C4b combines with C2a to form the C3 convertase (C4b2a) and subsequently the C5 convertase, leading to the cleavage of C3 and C5, and the formation of the MAC.

Clinical Issues

• Deficiencies: Deficiencies in C4A can lead to an increased risk of autoimmune diseases such as systemic lupus erythematosus (SLE) and recurrent infections due to impaired opsonization and pathogen clearance.
• Autoimmune Diseases: Variants in the C4 gene have been associated with susceptibility to autoimmune conditions, including SLE and rheumatoid arthritis.
• Transplantation: The presence of specific C4A and C4B allotypes can affect transplant compatibility and the likelihood of rejection.

Summary

Complement C4A is an essential component of the immune system, participating in the classical and lectin pathways of complement activation. It plays a critical role in opsonization, immune complex clearance, and the formation of the MAC. Genetic variations in C4A influence susceptibility to autoimmune diseases and transplant compatibility. Understanding the structure and function of C4A is crucial for comprehending its role in immune defense and its implications in clinical conditions.