Thymic involution,a co‐morbidity factor in amyotrophic lateral sclerosis |
| |
Authors: | Akop Seksenyan Noga Ron‐Harel David Azoulay Liora Cahalon Michal Cardon Patricia Rogeri Minhee K Ko Miguel Weil Shlomo Bulvik Gideon Rechavi Ninette Amariglio Eli Konen Maya Koronyo‐Hamaoui Raz Somech Michal Schwartz |
| |
Institution: | 1. Maxine‐Dunitz Neurosurgical Institute, Cedars‐Sinai Medical Center, Los Angeles, CA, USA;2. These authors contributed equally to this study.;3. Department of Neurobiology, the Weizmann Institute of Science, Rehovot, Israel;4. Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel;5. Hematology Department, Laniado Hospital, Netanya, Israel;6. Cancer Research Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv, Israel;7. Department of Diagnostic Imaging, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv, Israel;8. Pediatric Immunology Service, Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv, Israel |
| |
Abstract: | Amyotrophic lateral sclerosis (ALS) is a devastating disease, characterized by extremely rapid loss of motor neurons. Our studies over the last decade have established CD4+ T cells as important players in central nervous system maintenance and repair. Those results, together with recent findings that CD4+ T cells play a protective role in mouse models of ALS, led us to the current hypothesis that in ALS, a rapid T‐cell malfunction may develop in parallel to the motor neuron dysfunction. Here, we tested this hypothesis by assessing thymic function, which serves as a measure of peripheral T‐cell availability, in an animal model of ALS (mSOD1 superoxide dismutase] mice; G93A) and in human patients. We found a significant reduction in thymic progenitor‐cell content, and abnormal thymic histology in 3–4‐month‐old mSOD1 mice. In ALS patients, we found a decline in thymic output, manifested in the reduction in blood levels of T‐cell receptor rearrangement excision circles, a non‐invasive measure of thymic function, and demonstrated a restricted T‐cell repertoire. The morbidity of the peripheral immune cells was also manifested in the increase of pro‐apoptotic BAX/BCXL2 expression ratio in peripheral blood mononuclear cells (PBMCs) of these patients. In addition, gene expression screening in the same PBMCs, revealed in the ALS patients a reduction in key genes known to be associated with T‐cell activity, including: CD80, CD86, IFNG and IL18. In light of the reported beneficial role of T cells in animal models of ALS, the present observation of thymic dysfunction, both in human patients and in an animal model, might be a co‐pathological factor in ALS, regardless of the disease aetiology. These findings may lead to the development of novel therapeutic approaches directed at overcoming the thymic defect and T‐cell deficiency. |
| |
Keywords: | neurodegeneration immunomodulation neuroprotection thymus involution amyotrophic lateral sclerosis protective autoimmunity T cells immune deficiency |
|
|