Immunoglobulin isotype influences affinity and specificity

For almost half a century the Ig molecule has been considered a bifunctional molecule consisting of two independent regions, a variable (V) region responsible for specificity and affinity, and a constant (C) region responsible for such effector functions as complement activation and interaction with Fc receptors. The origin of this view dates back to the Nobel Prize-winning work of Rodney R. Porter, who used proteolytic digestion in the late 1950s to cleave the Ab molecule into fragments that eventually were known as the antigen (Ag) binding fragment, or Fab, and the Fc domain, so named because it could be easily crystallized (1). Two decades later, the elucidation of the mechanism for the generation of Ab diversity supported this concept by showing that distinct genes encoding V and C regions were rearranged to express the Ig molecule (2). Additional evidence for the independence between V and C region roles came from the demonstration that isotype switching produced new effector functions, while preserving antibody specificity. Furthermore, studies done by Oi et al. (3), using fluorescent labels, failed to provide any evidence of interaction between the two regions. Consistent with this view, X-ray crystallographic studies of Fab fragments showed that V region sequences were separated from the first domain of the C region (CH1) by long polypeptide chains that lacked ordered structure and seemed to insulate the V regions from the C regions, while tethering the two regions into one molecule (4). However, this neat view of one molecule with two independent functional regions is at odds with several observations in the literature, and recent studies, including the study by Tudor et al. in PNAS (5), suggest that the basic model of Ig structure-function needs to be reconsidered and revised. Evidence that the C region can affect V region …