Figure 1.

Agonistic signaling by antibodies. (A) Bivalent IgG of any subclass may dimerize or crosslink target antigens, such as HLA molecules. Many studies have demonstrated that HLA ligation on endothelial cells, vascular smooth muscle cells, and antigen-presenting cells induces intracellular signaling via tyrosine kinases. HLA signaling promotes cell proliferation, migration, and increased expression of survival proteins such as Bcl-2 and Bcl-XL. In addition, HLA cross-linking triggers exocytosis of endothelial vesicles called Weibel–Palade bodies, which contain vasoactive mediators and the adhesion molecule P-selectin. Increased cell surface P-selectin in turn supports increased adherence of leukocytes. (B) Anti-AT1R antibodies act agonistically, binding to an epitope on this multi-pass transmembrane receptor and stimulating increased IL-8 expression and tissue factor production. AT1R agonism is also implicated in malignant hypertension in a variety of diseases as well as transplantation. (C) Some molecules of human IgG4 have been shown to form monovalent Fab arms that may cross-dimerize with other clones of IgG4 to create bispecific antibodies. Although not experimentally demonstrated, in theory, such monovalent and bispecific IgG4 molecules would be incapable of cross-linking HLA and might in fact block other subclasses from binding.