However, this clear-cut immunodysregulation of the Th1/Th2 balance in EAE and MS may be part of a hidden complex of interactions underlying EAE and MS [20] . The Th1-driven nature of the EAE/MS disease was challenged by the finding that IFNγ-and IFNγ-receptor-deficient mice, as well as mice that lack other molecules involved in Th1 differentiation, such as IL12p35, IL12 receptor β2 (IL12Rβ2), and IL18, were not protected from EAE, but instead were more susceptible to the disease [21] [22] [23] [24] [25] . Unexpectedly, mice deficient in IL12α (IL12p35), a component of the Th1 paradigm, are vulnerable to EAE. Similarly, IL12Rβ2deficient mice develop more severe clinical manifestations of EAE, whereas IL12p40-deficient mice are resistant to EAE [23, 24, 26] . These discrepancies and conflicting data indicate that an imbalance in the Th1/Th2 milieu cannot explain the overall immunopathogenic mechanisms underlying EAE and MS.