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 LT-α are not essential for the development of EAE,” it is worthwhile to consider the limitations of the first-generation knockouts that have been employed in their study. Certain misconceptions have arisen concerning the interpretation of experiments with these contemporary knockouts. This is especially true when trying to understand the role of critical effector molecules like cytokines, in the development of complex phenotypes, like the paralysis and inflammation seen in EAE. Many of these cytokine molecules have diverse biological activities, and many of the functions of these molecules can be duplicated by other cytokines. Thus, in animals with disrupted or “knocked out” cytokine genes, one may expect many diverse changes in several physiological processes, and one might find that after all is done, that another gene and its product can replace the function of the gene that was disrupted.