The online version of this article (https://doi.org/10.1186/s13024-018-0271-7) contains supplementary material, which is available to authorized users.
Giovanni Nardo and Maria Chiara Trolese contributed equally to this work.
The major histocompatibility complex I (MHCI) is a key molecule for the interaction of mononucleated cells with CD8+T lymphocytes. We previously showed that MHCI is upregulated in the spinal cord microglia and motor axons of transgenic SOD1G93A mice.
To assess the role of MHCI in the disease, we examined transgenic SOD1G93A mice crossbred with β2 microglobulin-deficient mice, which express little if any MHCI on the cell surface and are defective for CD8+ T cells.
The lack of MHCI and CD8+ T cells in the sciatic nerve affects the motor axon stability, anticipating the muscle atrophy and the disease onset. In contrast, MHCI depletion in resident microglia and the lack of CD8+ T cell infiltration in the spinal cord protect the cervical motor neurons delaying the paralysis of forelimbs and prolonging the survival of SOD1G93A mice.
We provided straightforward evidence for a dual role of MHCI in the peripheral nervous system (PNS) compared to the CNS, pointing out regional and temporal differences in the clinical responses of ALS mice. These findings offer a possible explanation for the failure of systemic immunomodulatory treatments and suggest new potential strategies to prevent the progression of ALS.
Additional file 1: Figure S1. MHCI depletion affect the number of CD3+ / CD4+ T cells but not their extent of infiltration in the spinal cord during the disease progression. Figure S2. MHCI depletion reduces the impairment of the cervical motor neurons in mSOD1 mice. Figure S3. MHCI depletion lowered the CD68 mRNA levels in the spinal cord of mSOD1 mice. Figure S4. MHCI depletion did not affect the extent of astrocytosis in the cervical and the lumbar spinal cord of G93A+/+ mice. Figure S5. MHCI expression is lower in the cervical than in the lumbar spinal cord of G93A+/+ mice. Figure S6. MHCI depletion accelerates denervation of hindlimb muscles in mSOD1mice. Figure S7. MHCI depletion inhibits the proliferation of the terminal Schwann cells and the size of AChR clusters in SOD1 mutant mice. Figure S8. MHCI depletion accelerates the atrophy of hindlimbs muscles in SOD1 mutant mice. Figure S9. MHCI depletion preserves the diaphragm innervation in SOD1 mutant mice. Figure S10. GFAP and phospho-ERK expression are reduced in the sciatic nerve of NTG-/- mice. Figure S11. Myelin basic protein isoforms are markedly dwonregulated in the sciatic nerve of G93A-/- mice at 140 d. Figure S12. Regional and temporal differences defines the disease progression of mSOD1 mice. (DOCX 21 kb)
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- Counteracting roles of MHCI and CD8+ T cells in the peripheral and central nervous system of ALS SOD1G93A mice
Maria Chiara Trolese
Massimiliano de Paola
- BioMed Central