Lymphatic system and gut microbiota affect immunopathology of neuroinflammatory diseases, including multiple sclerosis, neuromyelitis optica and Alzheimer's disease.

Microbial infections lead to neurological damages either by direct infection in the nervous tissues or by uncontrolled immune responses (immunopathology). For example, in Zika virus infection, microcephaly can be caused by the former, i.e., direct viral infection in the brain, while Guillain-Barré syndrome (GBS) seems to be antibody-mediated immunopathology. Although a variety of factors affect immunopathology, two essential systems maintaining whole-body homeostasis had long been neglected: 1) the lymphatic system and 2) microbiota. Only recently, the role of the lymphatic system in immunopathology is beginning to be clarified. During infection, increased lymphatic flow limits edema and prevent tissue dendritic cell retention, while lymphostasis can lead to chronic inflammation. The role of gut microbiota, particularly bacterial community, in immunopathology has also been clarified recently; "bad bacteria" are proposed to exacerbate any immunopathology. For example, Helicobacter pylori is associated with not only gastritis but also extra-intestinal diseases, including neuromyelitis optica (NMO) and Alzheimer's disease. However, H. pylori and another bad bacterium Clostridium perfringens type A have been proposed to be protective against multiple sclerosis (MS). The above discrepancy on the roles of microbiota can be attributed to several conflicting factors, such as oversimplification, methodology, and taxonomy, which are summarized as "10 pitfalls of microbiota studies."