Thymic involution, a co-morbidity factor in amyotrophic lateral sclerosis.
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.
Seksenyan
Akop
A
Maxine-Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Ron-Harel
Noga
N
Azoulay
David
D
Cahalon
Liora
L
Cardon
Michal
M
Rogeri
Patricia
P
Ko
Minhee K
MK
Weil
Miguel
M
Bulvik
Shlomo
S
Rechavi
Gideon
G
Amariglio
Ninette
N
Konen
Eli
E
Koronyo-Hamaoui
Maya
M
Somech
Raz
R
Schwartz
Michal
M
D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015329:Gene Rearrangement, T-Lymphocyte; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D013950:Thymus Gland / Q000276:immunology / Q000503:physiopathology*