Human complement receptor type 2 (CR2; CD21) is a surface-associated glycoprotein
which binds to a variety of endogenous ligands, including the complement component C3 fragments
iC3b, C3dg and C3d, the low-affinity IgE receptor CD23, and the type I cytokine, interferon-alpha.
CR2 links the innate complement-mediated immune response to pathogens and foreign antigens with
the adaptive immune response by binding to C3d that is covalently attached to targets, and which results
in a cell signalling phenomenon that lowers the threshold for B cell activation. Variations or deletions
of the CR2 gene in humans, or the Cr2 gene in mice associate with a variety of autoimmune and
inflammatory conditions. A number of infectious agents including Epstein-Barr virus (EBV), Human Immunodeficiency
Virus (HIV) and prions also bind to CR2 either directly or indirectly by means of C3d-targeted immune complexes.
In this review we discuss the interactions that CR2 undertakes with its best characterized ligands C3d, CD23 and the EBV
gp350/220 envelope protein. To date only a single physiologically relevant complex of CR2 with one of its ligands, C3d,
has been elucidated. By contrast, the interactions with CD23 and EBV gp350/220, while being important from physiologic
and disease-associated standpoints, respectively, are only incompletely understood. A detailed knowledge of the
structure-function relationships that CR2 undergoes with its ligands is necessary to understand the implications of using
recombinant CR2 in therapeutic or imaging agents, or alternatively targeting CR2 to down-regulate the antibody mediated
immune response in cases of autoimmunity.