New insights into antibody structure with implications for specificity, variable region restriction and isotype choice

The mystery surrounding the mechanisms by which antibody diversity is generated was largely settled in the 1970s by the discoveries of variable gene rearrangements and somatic hypermutation. This led to the paradigm that immunoglobulins are composed of two independent domains — variable and constant — that confer specificity and effector functions, respectively. However, since these early discoveries, there have been a series of observations of communication between the variable and constant domains that affects the overall antibody structure, which suggests that immunoglobulins have a more complex, interconnected functionality than previously thought. Another unresolved issue has been the genesis of ‘restricted’ antibody responses, characterized by the use of only a few variable region gene segments, despite the enormous potential combinatorial diversity. In this Perspective, we place recent findings related to immunoglobulin structure and function in the context of these immunologically important, historically unsolved problems to propose a new model for how antibody specificity is achieved without autoreactivity.