What is the MHC?

In the fifty years since the rules of histocompatibility were first established, the major histocompatibility complex (MHC) has become one of the most intensively studied regions of the vertebrate genome. Therefore, it seems rather odd that one of the first questions posed at a recent workshop on MHC evolution was ‘what exactly is the MHC?’ Nevertheless, the question was astute because it encompasses a variety of fascinating conundrums. For example, why are nearly all the genes encoding class I and II molecules so closely linked and what mechanisms have kept them together? What about notable exceptions such as genes encoding CD1 and &-microglobulin (&-m) should we consider them fully fledged MHC members, or outriders that have set out alone? When and why did the TAP and LMP genes become part of the MHC? Furthermore, what of the class III region did it barge in on the complex by chance or does it contain genes that are important for MHC integrity? Indeed, do any of the nonimmunological genes within the complex have a role in MHC function? How and why is MHC polymorphism generated, and at what rate?