Trapped in the epineurium : Early entry into the endoneurium is restricted to neuritogenic T cells in experimental autoimmune neuritis

Mausberg, Anne K.; Szepanowski, Fabian; Odoardi, Francesca; Flügel, Alexander; Kleinschnitz, Christoph LSF; Stettner, Mark; Kieseier, Bernd C.

Background: Autoimmune polyneuropathies are acquired inflammatory disorders of the peripheral nervous system (PNS) characterized by inflammation, demyelination, and axonal degeneration. Although the pathogenesis has not been fully elucidated, T cells recognizing self-antigens are believed to initiate inflammation in a subgroup of patients. However, the route and time of T cell entry into the PNS have not yet been described in detail. In this study, we analyzed both kinetics as well as localization of retrovirally transfected green fluorescent protein (GFP)-expressing neuritogenic T lymphocytes in experimental autoimmune neuritis (EAN).
Methods: T lymphocytes obtained from rats following EAN induction by immunization with peripheral nerve protein peptide P2₅₅₋₇₈ were retrovirally engineered to express GFP. Non-specific T cells were negatively selected by in vitro restimulation, whereas GFP-expressing neuritogenic T cells (reactive to P2₅₅₋₇₈) were adoptively transferred into healthy rats (AT-EAN). Antigen-specific T cell tracking and localization was performed by flow cytometry and immunohistochemistry during the course of disease.
Results: After induction of autoimmune neuritis, P2-reactive T cells were detectable in the liver, spleen, lymph nodes, lung, peripheral blood, and the sciatic nerves with distinct kinetics. A significant number of GFP⁺ T cells appeared early in the lung with a peak at day four. In the peripheral nerves within the first days, GFP-negative T cells rapidly accumulated and exceeded the number of GFP-expressing cells, but did not enter the endoneurium. Very early after adoptive transfer, T cells are found in proximity to peripheral nerves and in the epineurium. However, only GFP-expressing neuritogenic T cells are able to enter the endoneurium from day five after transfer.
Conclusions: Our findings suggest that neuritogenic T cells invade the PNS early in the course of disease. However, neuritogenic T cells cross the blood-nerve barrier with a certain delay without preference to dorsal roots. Further understanding of the pathophysiological role of autoagressive T cells may help to improve therapeutic strategies in immune-mediated neuropathies.

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Mausberg, A.K., Szepanowski, F., Odoardi, F., Flügel, A., Kleinschnitz, C., Stettner, M., Kieseier, B.C., 2018. Trapped in the epineurium: Early entry into the endoneurium is restricted to neuritogenic T cells in experimental autoimmune neuritis. https://doi.org/10.1186/s12974-018-1259-5
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