Tolerogenic effect of fiber tract injury: reduced EAE severity following entorhinal cortex lesion.
Despite transient, myelin-directed adaptive immune responses in regions of fiber tract degeneration, none of the current models of fiber tract injuries evokes disseminated demyelination, implying effective mechanisms maintaining or re-establishing immune tolerance. In fact, we have recently detected CD95L upregulation accompanied by apoptosis of leukocytes in zones of axonal degeneration induced by entorhinal cortex lesion (ECL), a model of layer-specific axonal degeneration. Moreover, infiltrating monocytes readily transformed into ramified microglia exhibiting a phenotype of immature (CD86+/CD80-) antigen-presenting cells. We now report the appearance of the axonal antigen neurofilament-light along with increased T cell apoptosis and enhanced expression of the pro-apoptotic gene Bad in cervical lymph nodes after ECL. In order to test the functional significance of such local and systemic depletory/regulatory mechanisms on subsequent immunity to central nervous system antigens, experimental autoimmune encephalomyelitis was induced by proteolipid protein immunization 30 days after ECL. In three independent experiments, we found significantly diminished disease scores and infiltrates in lesioned compared to sham-operated SJL mice. This is consistent with a previous meta-statistical analysis (Goodin et al. in Neurology 52:1737-1745, 1999) rejecting the O-hypothesis that brain trauma causes or exacerbates multiple sclerosis. Conversely, brain injuries may involve long-term tolerogenic effects towards brain antigens.
Mutlu
Leman
L
Institute of Cell Biology and Neurobiology, Charité, 10098, Berlin, Germany.
Brandt
Christine
C
Kwidzinski
Erik
E
Sawitzki
Birgit
B
Gimsa
Ulrike
U
Mahlo
Jacqueline
J
Aktas
Orhan
O
Nitsch
Robert
R
van Zwam
Marloes
M
Laman
Jon D
JD
Bechmann
Ingo
I
D000818:Animals; D017209:Apoptosis; D001930:Brain Injuries / Q000150:complications*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D018728:Entorhinal Cortex / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007108:Immune Tolerance / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D016900:Neurofilament Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014855:Wallerian Degeneration / Q000209:etiology*; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; D016900:Neurofilament Proteins; D051025:bcl-Associated Death Protein; C044882:neurofilament protein L