SMAD3 and autoimmune disease: In mouse, deficiency of Smad2 or Smad3 results in an enhanced Th1 response and develops lethal autoimmune diseases early in life (72), while nonobese diabetic mice lacking Smad4 exhibits spontaneous activation of CD4+ T cells, accompanying by increased serum IFN-γ and auto-antibodies, which in turn accelerated the disease progression (73).