| First Author | Vogel AL | Year | 2017 |
| Journal | Eur J Immunol | Volume | 47 |
| Issue | 3 | Pages | 458-469 |
| PubMed ID | 28058717 | Mgi Jnum | J:246491 |
| Mgi Id | MGI:5922109 | Doi | 10.1002/eji.201646855 |
| Citation | Vogel AL, et al. (2017) Deletional tolerance prevents AQP4-directed autoimmunity in mice. Eur J Immunol 47(3):458-469 |
| abstractText | Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system (CNS) mediated by antibodies to the water channel protein AQP4 expressed in astrocytes. The contribution of AQP4-specific T cells to the class switch recombination of pathogenic AQP4-specific antibodies and the inflammation of the blood-brain barrier is incompletely understood, as immunogenic naturally processed T-cell epitopes of AQP4 are unknown. By immunizing Aqp4-/- mice with full-length murine AQP4 protein followed by recall with overlapping peptides, we here identify AQP4(201-220) as the major immunogenic IAb -restricted epitope of AQP4. We show that WT mice do not harbor AQP4(201-220)-specific T-cell clones in their natural repertoire due to deletional tolerance. However, immunization with AQP4(201-220) of Rag1-/- mice reconstituted with the mature T-cell repertoire of Aqp4-/- mice elicits an encephalomyelitic syndrome. Similarly to the T-cell repertoire, the B-cell repertoire of WT mice is "purged" of AQP4-specific B cells, and robust serum responses to AQP4 are only mounted in Aqp4-/- mice. While AQP4(201-220)-specific T cells alone induce encephalomyelitis, NMO-specific lesional patterns in the CNS and the retina only occur in the additional presence of anti-AQP4 antibodies. Thus, failure of deletional T-cell and B-cell tolerance against AQP4 is a prerequisite for clinically manifest NMO. |
