Complement and humoral immunity

Abstract

The complement system was discovered almost a century ago as an important effector in antibody-dependent killing of microorganisms. Since this early period much was learned aboutthe biochemistry and structure of complement proteins and their function in mediating inflammation. More recently, a prominent role for complement was identified in linkage of innate and adaptive immunity. In this review, I will discuss our current understanding of the importance of complement in enhancing the humoral immune response to both model antigens and pathogens. As discussed below, it is evident that the complement system participates in marking of "foreign" pathogens and "presenting" them to B cells in a manner that enhances both antibody production and long-term memory. In this special issue of Vaccine, we see examples of how complement is critical in the immune response to bacterial and viral pathogens. Moreover, the finding that most organisms have co-evolved proteins to evade complement detection underscores its importance in host protection.

Figure 1

Co-valent binding of complement C3 and C4 “mark” antigens as foreign. Recognition of foreign antigen by antibody (classical pathway) or lectin binding protein (lectin pathway) leads to covalent attachment of C4b and C3b to the antigen. C4b provides an anchor for the C3 convertase which is composed of a heterodimer of C2aC4b. One enzyme complex will activate up to 1000 C3 molecules. In addition to C4b, C3b and its cleavage fragments are ligands for complement receptors, in particular CD21 and CD35. Thus, the initial covalent attachment of C4 and C3 to foreign antigen not only provides an anchor for continuation of the cascade but ligands for complement receptors important in “instructing the humoral response”.

Figure 2

Complement receptors CD21 and CD35 link innate and adaptive immunity via B cell co-receptor and retention of antigen on FDC. Both genes are encoded at the Cr2 locus in the mouse and CD21 is a splice product of CD35. Recognition of split products of C3 (and C4) on a foreign surface provides ligand for complement receptors CD21 (CR2) and CD35 (CR1). In mice the receptors co-localize on B cells and follicular dendritic cells (FDC). On B cells, they form a functional co-receptor with CD19 and CD81. Engagement of the B cell receptor (BCR) with antigen coupled to C3d results in co-ligation of the co-receptor and BCR enhancing downstream signaling and lowers the threshold for B cell activation. In addition, foreign antigen uptake on FDC via C3d tag is essential for clonal selection of B cells within the germinal center and efficient maintenance of long term antibody responses and memory.

Figure 3

Recognition of C3-tagged antigen via CD21 and CD35 enhances B cell differentiation at 3 major stages. Complement receptors CD21 and CD35 play an important role in at least three stages of B cell differentiation. Stage 1: co-ligation of C3d-antigen with BCR lowers threshold of B cell activation leading to migration of the activated B cell to the T cell:B cell boundary where cognate interaction occurs and B cells receive co-stimulation via CD40. Stage 2: Activated B cells enter a germinal center where they begin further differentiation including rapid cell division, somatic cell hypermutation (SHM) and class switch recombination (CSR). Stage 3: following clonal selection (binding of antigen on FDC) the GC B cell differentiates into an effector cell (plasma cell) or memory B cell. Maintenance of B effector and memory cells is dependent on presence of antigen on FDC.

Figure 4

Transport of immune complexes by B cells into the LN follicles is CR dependent. Recognition of foreign antigens entering the host following vaccination (or infection) by antibody or lectin proteins results in activation and binding of complement. Immune complexes are transiently retained by subcapsular sinus (SCS) macrophages and subsequently shuttled to follicular B cells in the underlying B cell zone. In the presence of C3d tag, complexes are taken-up by B cells via CD21/CD35 and transported into the follicles where they are transferred to FDC. An alternative pathway of delivery to FDC is via fibroblast reticular cell FRC) conduits. Small antigens (less than 70 KDa) actively drain from the SCS into the conduits which terminate near FDC. Thus, complement tagged antigens are rapidly delivered to FDC independent of B cell transport. Gaps in the conduits also provide an opportunity for cognate B cells to sample small antigens draining from the SCS.