Complement disorders and hereditary angioedema

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Complement disorders and hereditary angioedema Michael M. Frank, MD Journal of Allergy and Clinical Immunology Volume 125, Issue 2, Pages S262-S271 (February 2010) DOI: 10.1016/j.jaci.2009.10.063 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 The 3 complement activation pathways. The classical pathway is usually activated by antibody. The lectin pathway is activated by the recognition molecule MBL binding to structures with the appropriate repetitive sugars. The ficolins are MBL-like molecules that can also activate this pathway. The alternative pathway does not have a recognition molecule as such. It is initiated by the binding of factor B to C3, which can then be cleaved by factor D. Because C3 always undergoes slow hydrolysis, the pathway is always undergoing some degree of activation. Properdin stabilizes the complex and can also initiate alternative pathway activation. C3b itself is an efficient activator of the alternative pathway, and classical pathway activation leading to C3 deposition on a target rapidly activates the alternative pathway. Journal of Allergy and Clinical Immunology 2010 125, S262-S271DOI: (10.1016/j.jaci.2009.10.063) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 The 2-chain molecule C3 is shown first. There are no receptors that recognize this molecule. The C3 convertase of the classical or alternative pathway cleaves off C3a, an anaphylatoxin. The remainder of the molecule C3b undergoes a marked molecular rearrangement and now is recognized by CD35 (CR1), as well as by the recently recognized receptor on Kupffer cells, CRIg. C3b binds factor H and now can be cleaved by factor I to iC3b. iC3b is recognized by CD11b/CD18 and CD11c/CD18. These 2-chain receptors are on all phagocytes and dendritic cells. They aid in the processing of antigen. In serum the cleavage of C3 stops at this point, but when an immune complex is bound to cellular CD35 or when C3 is deposited on a cell with CD35 or other membrane-bound complement control molecules, such as CD46, it is cleaved further by factor I to C3c and C3dg. C3dg can be trimmed to C3d and C3g. C3d and C3dg are recognized by CD21 found on B cells and dendritic cells. Antigen with multiple bound C3d molecules can interact with both CD21 and the B-cell receptor, which can augment the immune response. Journal of Allergy and Clinical Immunology 2010 125, S262-S271DOI: (10.1016/j.jaci.2009.10.063) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Functions of C1-INH. Journal of Allergy and Clinical Immunology 2010 125, S262-S271DOI: (10.1016/j.jaci.2009.10.063) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions