Working hypothesis as to the cause of MS. (I) In a genetically susceptible host, common microbes both activate the APCs through toll receptors and contain protein sequences cross-reactive with self myelin antigens. This leads to what can be defined as the minimal requirement for inducing an autoimmune, inflammatory CNS disease in mammals. (II) Underlying immunoregulatory defects, such as decreases of regulatory T cells in the circulation of patients with MS, allow the further pathologic activation of autoreactive T cells (96). (III) Activated myelin-reactive T cells migrate into the CNS and recognize antigen presented by microglia, local APCs. Th1 cytokines are secreted and an inflammatory cascade is initiated. (IV) Regulation of autoimmune responses. Naturally occurring mechanisms may exist to regulate autoimmune responses including the induction of autoreactive Th2 (IL-4, IL-5, IL-13), Th3 (TGF-β), or Tr1 (IL-10) cytokine–secreting T cells that migrate to the CNS and downregulate (red arrow) inflammatory Th1 autoreactive T cells (green arrow). Therapies may attempt to induce Th2 (Copaxone, altered peptide ligands), Th3 (mucosal antigen), or Tr1 (β-IFNs, steroids). Th_P, precursor T cell.