Figure 1: Speculative model of AQP4-Ab-positive NMO is shown in a chronological manner. At the very first stage of the disease course, break of tolerance against AQP4 leads to production of AQP4-Ab in the periphery without manifesting any symptoms. What causes the compromise of the tolerance is not yet elucidated. Molecular mimicry of AQP4 to certain microbes is one of the possibilities. Onset of the disease might be triggered by either nonspecific inflammation caused by infections or activation of CNS antigen-specific T cells. These stimuli will not only induce the leakage of the BBB, but also alter the inflammatory status both in the periphery and within the CNS. Once the disease develops, the location of the lesions may be determined by the types of T cells infiltrating within the CNS. The presence of AQP4-Ab will further modulate the disease phenotype and produce characteristic lesions of NMO spectrum disorders.