Second, the Fc regions in antigen:antibody complexes can bind to the C1q complement protein (see Section 2-7) and initiate the classical complement cascade, which recruits and activates phagocytes to engulf and destroy pathogens. Third, the Fc portion can deliver antibodies to places they would not reach without active transport. These include transport of IgA into mucous secretions, tears, and milk, and the transfer of IgG from the pregnant mother into the fetal blood circulation. In both cases, the Fc portion of IgA or IgG engages a specific receptor, the neonatal Fc receptor (FcRn), that actively transports the immunoglobulin through cells to reach different body compartments. Podocytes in the kidney glomerulus express FcRn to help remove IgG that has been filtered from the blood and accumulated at the glomerular basement membrane.
The role of the Fc portion in these effector functions has been demonstrated by studying immunoglobulins that have had one or more Fc domains cleaved off enzymatically or modified genetically. Many microorganisms have responded to the destructive potential of the Fc portion by evolving proteins that either bind it or cleave it, and so prevent the Fc region from working; examples are Protein A and Protein G of Staphylococcus and Protein D of Haemophilus. Researchers have exploited these proteins to help map the Fc region and also as immunological reagents. Not all immunoglobulin classes have the same capacity to engage each of the effector functions (see Fig. 5.20). For example, IgG1 and IgG3 have a higher affinity than IgG2 for the most common type of Fc receptor.
5-14 IgM and IgD are derived from the same pre-mRNA transcript and are both expressed on the surface of mature B cells.
The immunoglobulin CH genes form a large cluster spanning about 200 kb to the 3ʹ side of the JH gene segments (see Fig. 5.19). Each CH gene is split into several exons (not shown in the figure), with each exon corresponding to an individual immunoglobulin domain in the folded C region. The gene encoding the μ C region lies closest to the JH gene segments, and therefore closest to the assembled VH-region exon (VDJ exon) after DNA rearrangement. Once rearrangement is completed, transcription from a promoter just 5ʹ to the rearranged VDJ exon produces a complete μ heavy-chain transcript. Any JH gene segments remaining between the assembled V gene and the Cμ gene are removed during RNA processing to generate the mature mRNA. The μ heavy chains are therefore the first to be expressed, and IgM is the first immunoglobulin to be produced during B-cell development.
Immediately 3ʹ to the μ gene lies the δ gene, which encodes the C region of the IgD heavy chain (see Fig. 5.19). IgD is coexpressed with IgM on the surface of almost all mature B cells, but is secreted in only small amounts by plasma cells. The unique function of IgD is still unclear and a matter of active research. Because IgD has hinge regions that are more flexible than those in IgM, IgD has been suggested to be an auxiliary receptor that may facilitate the binding of antigens by naive B cells. Mice lacking the Cδ exons show normal B-cell development and can generate largely normal antibody responses, but show a delay in the process of affinity maturation of antibody for antigens. We return to this topic in Chapter 10, when we discuss somatic hypermutation.