Some Misconceptions about Understanding Autoimmunity through Experiments with Knockouts

Experimental autoimmune encephalomyelitis (EAE) has served as a prototypic model of T cell–mediated, organspecific autoimmune disease, and as a useful model for the human disease, multiple sclerosis (MS) (1). Frei et al. (2) demonstrate that in two strains of mice with a double knockout, where both TNF-α and LT-α are inactivated, that EAE may develop. The disease in these double knockout mice progresses in an apparently typical fashion, concordant with what is observed in the usual inbred strains of mice where EAE is induced: there is clinical paralysis, and histopathology reveals intense perivascular and parenchymal infiltration with CD4+ T cells and demyelination. They conclude, and I agree, that the results are surprising, given the large body of information suggesting that TNF-α and LT-α are important in the pathogenesis of EAE and MS. However, before accepting their ultimate conclusion that, “these results indicate that TNFα and...