Abstract The development of multiple sclerosis is most likely influenced by autoimmune responses to central nervous system myelin proteins as well as by infections 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 αB-crystallin, a small stress protein that was identified previously as an immunodominant Ag of CNS myelin in multiple sclerosis patients. EBV-induced expression of αB-crystallin in B cells leads to HLA-DR-restricted presentation of the protein and to activation of proinflammatory αB-crystallin-specific Th cells. While αB-crystallin is present in EBV-infected human B cells, the protein is absent from human lymphoid tissues under normal conditions. This is in sharp contrast to other stress proteins such as heat-shock protein (hsp)27 and hsp60 that are ubiquitously expressed in these tissues. In addition, the absence of αB-crystallin from lymphoid tissues in humans is unique as compared with other mammals. All other species examined, including rodents, sheep, and primates, showed constitutive expression of αB-crystallin in secondary lymphoid tissues and sometimes even in the thymus. Since constitutive lymphoid expression most likely results in immunologic tolerance, such a state of tolerance to αB-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 infections can trigger myelin-directed autoimmunity in a way that is unique for humans.