Multiple sclerosis (MS) is the most common CNS-demyelinating disease of humans, 
showing clinical and pathological heterogeneity and a general resistance to 
therapy. We first discovered that abnormal myelin hypercitrullination, even in 
normal-appearing white matter, by peptidylarginine deiminases (PADs) correlates 
strongly with disease severity and might have an important role in MS 
progression. Hypercitrullination is known to promote focal demyelination through 
reduced myelin compaction. Here we report that 2-chloroacetamidine (2CA), a 
small-molecule, PAD active-site inhibitor, dramatically attenuates disease at 
any stage in independent neurodegenerative as well as autoimmune MS mouse 
models. 2CA reduced PAD activity and protein citrullination to pre-disease 
status. In the autoimmune models, disease induction uniformly induced 
spontaneous hypercitrullination with citrulline+ epitopes targeted frequently. 
2CA rapidly suppressed T cell autoreactivity, clearing brain and spinal cord 
infiltrates, through selective removal of newly activated T cells. 2CA 
essentially prevented disease when administered before disease onset or before 
autoimmune induction, making hypercitrullination, and specifically PAD enzymes, 
a therapeutic target in MS models and thus possibly in MS.