EBV-induced expression and HLA-DR-restricted presentation by human B cellsof alpha B-crystallin, a candidate autoantigen in multiple sclerosis

The development of multiple sclerosis is most likely influenced by autoimmu ne responses to central nervous system myelin proteins as well as by infect ions with common viruses such as EBV and human herpesvirus-6, However, much remains to be established on how these factors interact. In this study, we show that upon EBV infection, human B cells start to express alpha B-cryst allin, a small stress proteid that was identified previously as an immunodo minant Ag of CNS myelin in multiple sclerosis patients. EBV-induced express ion of alpha B-crystallin in B cells leads to HLA-DR-restricted presentatio n of the protein and to activation of proinflammatory alpha B-crystallin-sp ecific Th cells. While alpha B-crystallin is present in EBV-infected human B cells, the protein is absent from human lymphoid tissues under normal con ditions. This is in sharp contrast to other stress proteins such as heat-sh ock protein (hsp)27 and hsp60 that are ubiquitously expressed in these tiss ues. In addition, the absence of alpha B-crystallin from lymphoid tissues i n humans is unique as compared with other mammals. All other species examin ed, including rodents, sheep, and primates, showed constitutive expression of alpha B-crystallin in secondary lymphoid tissues and sometimes even in t he thymus, Since constitutive lymphoid expression most likely results in im munologic tolerance, such a state of tolerance to alpha B-crystallin can be expected for all of these species, but not for humans. When taken together , our data provide evidence for a novel mechanism by which common viral inf ections can trigger myelin-directed autoimmunity in a way that is unique fo r humans.