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uchihaThe Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Review Articles

Advances in Immunology
I A N R . M A C K A Y , M. D . , A N D F R E D S . R O S E N , M .D ., Ed i t ors

Second of Two Parts

How do newly encountered antigens activate and bind complement afterentering the body? A subgroup of IgM antibodies, known as natural IgM antibodies, probably has a key role. Natural IgM antibodies are the products of immunoglobulin genes that have not undergone somatic mutation67,68; they can bind to many antigens, including microbial antigens and certain autoantigens. IgM enhances the production of antibodies by a mechanism that depends on C1q.69 Mice lacking serumIgM antibodies have suboptimal responses of IgG antibody to low doses of antigen.70 These findings suggest an important role for complement and natural antibodies in amplifying immune responses evoked by low doses of antigens.

The formation of an antibody–antigen complex (immune complex) is the principal way of activating the classical pathway of the complementsystem. C1q, an integral part of the first component of complement (C1), triggers the activation process when it docks onto antibodies within these immune complexes. In this way, C1q acts to bridge the innate and adaptive immune systems. Complement also has an important role in the induction of antibody responses.62 This was shown first by Pepys, who demonstrated that the formation of antibodies againstT-cell–dependent antigens was reduced in animals in which C3 had been depleted.63,64 This result, which was considered heretical at the time, is consistent with our current knowledge of the way in which B cells become activated. A B cell begins to proliferate when antigen binds to its surface immunoglobulin molecules (antigen receptors). The activation of the B cell is modulated by coreceptors,which include receptors for complement components, especially complement receptor type 2.65 When antigen meets a B cell in the presence of complement, the threshold for the activation of the B cell is lowered. Indeed, when antigen was coupled to C3dg molecules (C3dg is the main fragment of covalently bound C3, which is a ligand for complement receptor type 2), much less antigen (an amount smallerby a factor of up to 10,000) was required to evoke a given level of antibody than was the case for the native antigen.66 This result supports the possibility of using complement as an adjuvant.
From the Rheumatology Section, Division of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Campus, London. Address reprint requests to Dr. Walport at the Division of Medicine,Imperial College School of Medicine, Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom, or at m.walport@ic.ac.uk.

Complement that is activated at sites of tissue injury can cause damage through the deposition of the membrane-attack complex and cell-bound ligands, including C4b and C3b, that activate leukocytes bearing complement receptors. Complement can also amplify injury bymeans of the anaphylatoxins C5a and C3a, which cause the influx and activation of inflammatory cells. The two means by which complement is activated in tissues are through immune complexes, which activate the classical complement pathway, and through tissue ischemia and reperfusion, which expose phospholipids and mitochondrial proteins. These activate complement directly by binding C1q ormannosebinding lectin71-73 or indirectly by binding natural antibodies74 or C-reactive protein, which can activate the classical pathway by binding C1q.75 Necrotic cells and tissues also lack the regulatory molecules that in normal tissues prevent the binding of complement.

There is accumulating evidence that complement activation is an important contributor to the tissue...
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