Authors:
Seksenyan A, Ron-Harel N, Azoulay D, Cahalon L, Cardon M, Rogeri P, Ko MK, Weil M, Bulvik S, Rechavi G, Amariglio N, Konen E, Koronyo-Hamaoui M, Somech R, Schwartz M
Summary:
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 (CNS) 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 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 (sjTRECs), a noninvasive 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 etiology. These findings may lead to the development of novel therapeutic approaches directed at overcoming the thymic defect and T cell deficiency.
Source:
Journal of Cellular & Molecular Medicine; (07/24/09)