Exosomes: The missing link between microchimerism and acquired tolerance?

It has become increasingly clear that the immune system of viviparous mammals is much more in the business of acquiring tolerance to non-self antigens, than it is in rejecting cells that express them (for a recent review, highlighting the role of Treg cells, see ref. (1) ). It is also clear that both self-tolerance, and acquired tolerance to non-self is a dynamic process, with a natural ebb and flow. As has been often said of an effective team defense in sports, tolerance will "bend but does not break." How microchimerism, defined as the presence of extremely rare [1/10(4)-1/10(6)] cells of a genetically different individual, can induce either new immunogenetic pressures that push self-tolerance to the breaking point, or alternatively, provide relief from pre-existing immunogenetic risk, preventing development of autoimmune disease, remains a mystery. Indeed, the inability to directly correlate DNA-level microchimerism detected in blood samples by qPCR, with naturally occurring regulation to minor H and MHC alloantigens expressed by the rare cells themselves, has been frustrating to researchers in this field. (2) [Haynes, W.J. et al, this issue] However, recent developments in the areas of transplantation and reproductive immunology offer clues to how the effects of microchimerism can be amplified, and how a disproportionate immune impact might occur from a very limited cell source.