This review discusses the role of redox-sensitive cysteine cathepsins during MHC-II- restricted MOG antigen processing, and MOG- induced experimental autoimmune encephalomyelitis (EAE). The phagosomal redox environment can modify the activity of multiple cysteine cathepsins and these proteases can, in turn, perturb antigen processing and presentation, particularly of MOG. Mice deficient in NOX2 exhibit protection from EAE, which is likely due to inefficient MOG- antigen processing and presentation, and less likely to be due to other T cell mediated effects. NOX2 controlled redox-sensitive cysteine cathepsins B, S, and L are redundant for the processing and presentation of MOG antigens and EAE, despite older inhibitor studies suggesting otherwise, but mice simultaneously deficient in multiple cathepsins (via genetic or pharmacological inhibition) have been shown to be protected from EAE, and have a MHC-II processing deficiency. Collectively .....