Weissert R, Wallstrom E, Storch MK, et al. the very early stages of retinal lesions which eventually culminate in damage to Mller cells and to the retinal nerve fiber layer. Finally, a study on cerebrospinal fluid (CSF) barrier pathology demonstrated that NMOSD immunopathology extends beyond perivascular astrocytic foot processes to include the pia, the ependyma, and the choroid plexus, and that diffusion of antibodies from the CSF could further influence lesion formation in NMOSD patients. Summary The pathological changes observed in AQP4-antibody positive and MOG-antibody positive NMOSD patients are strikingly similar to those found in corresponding animal models, and many mechanisms which determine lesion localization in experimental animals seem to closely reflect the human situation. in the absence of ADCC or CDCC , and in some intracerebrally AQP4-abs-injected animals with slow progression of tissue destruction [12,38,39], they can produce IL-6 and other chemokines [40,41] which may open the BBB in a T-cell-independent way . However, most lesions in NMOSD patients  and corresponding T-cell-based rat models [8,13,19,20] develop rapidly , and astrocytes might not have enough time to significantly contribute to the formation of a proinflammatory environment. Early lesions in NMOSD patients  and rodent models [8,14] contain high numbers Mouse monoclonal to CDH2 of neutrophils. These Benazepril HCl cells favor the interactions of CNS antigen-specific T cells with the BBB at the earliest time points of lesion formation [43C45] and are important amplifiers of lesion formation and growth [14,46]. All the evidence summarized above places activated CNS antigen-specific T cells at the center stage of lesion formation in NMOSD. Based on experimental models of CNS inflammation, we know – that the availability of an antigen for T-cell activation determines the site of lesion formation , – that the activation of CNS antigen-specific T cells is necessary for lesion induction [13,17,18], Benazepril HCl and – that the ratio between CNS antigen-specific T cells and pathogenic antibodies determines whether single large lesions resembling typical lesions in NMOSD or multiple sclerosis (MS), or multifocal small lesions resembling lesions in acute disseminated encephalomyelitis, form . We also know that the sites of lesion formation are further affected by MHC and non-MHC genes, by sex, and by the mode of sensitization , and that the MHC haplotype may determine whether T cells recognize an antigen in its posttranslationally modified and/or unmodified form . In the next part of this article, we will show how the knowledge obtained from experimental models translates to mechanisms of lesion localization in NMOSD. Open in a separate window Box 1 no caption available MECHANISMS DRIVING LESION LOCALIZATION IN SPINAL CORD AND OPTIC NERVES The amounts of CNS antigens available for antigen presentation, T-cell activation, and antibody binding are the most important factors driving lesion formation in NMOSD, as spinal cord and optic Benazepril HCl nerves have higher AQP4 expression levels than the brain, both in humans and rats . Moreover, the pathological changes in the spinal cord in the early course of NMOSD, that is the formation of perivascular lesions with AQP4 loss around radial vessels in the posterior and lateral columns, and the growth of lesions at the gray/white matter junction [51??], are very similar to the changes observed in AQP4-abspositive Lewis rats with T-cell-induced CNS inflammation [13,19,20,51??,52,53]. In NMOSD patients, these lesions will then fuse with each other over time, extend towards Benazepril HCl the central spinal cord gray matter, and become larger in spinal cord gray matter, as this site contains higher numbers of AQP4-expressing astrocytes, translating to a higher availability of AQP4 for antigen presentation, T-cell activation, and antibody binding. Further lesion growth eventually culminates in spinal cord necrosis and atrophy [51??]. The mechanisms underlying initiation and evolution of spinal cord lesions in NMOSD also recapitulate important aspects of the formation of brain lesions in MS [51??]: In AQP4-abpositive NMOSD, initial lesions preferentially form in the posterior and lateral columns which have a poor circulatory reserve, whereas in MS brains, plaques preferentially develop in hypo-perfused CNS white matter [51??,54C57]. In AQP4-abspositive NMOSD patients, astrocyte-destructive lesions with subsequent axonal damage also form in the anterior visual pathway containing the optic nerves, the chiasm, and the optic tracts, resulting from the extension of meningeal inflammatory infiltrates and AQP4 loss into the pial septa and parenchyma of these structures [58??]. Lesions with AQP4 loss were also observed in the.