title: Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice.
abstract: Spinal muscular atrophy (SMA) has long been solely considered a neurodegenerative disorder. However, recent work has highlighted defects in many other cell types that could contribute to disease aetiology. Interestingly, the immune system has never been extensively studied in SMA. Defects in lymphoid organs could exacerbate disease progression by neuroinflammation or immunodeficiency. Smn depletion led to severe alterations in the thymus and spleen of two different mouse models of SMA. The spleen from Smn depleted mice was dramatically smaller at a very young age and its histological architecture was marked by mislocalization of immune cells in the Smn2B/- model mice. In comparison, the thymus was relatively spared in gross morphology but showed many histological alterations including cortex thinning in both mouse models at symptomatic ages. Thymocyte development was also impaired as evidenced by abnormal population frequencies in the Smn2B/- thymus. Cytokine profiling revealed major changes in different tissues of both mouse models. Consistent with our observations, we found that survival motor neuron (Smn) protein levels were relatively high in lymphoid organs compared to skeletal muscle and spinal cord during postnatal development in wild type mice. Genetic introduction of one copy of the human SMN2 transgene was enough to rescue splenic and thymic defects in Smn2B/- mice. Thus, Smn is required for the normal development of lymphoid organs, and altered immune function may contribute to SMA disease pathogenesis.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.|Department of Cellular and Molecular Medicine.|Centre for Neuromuscular Disease, University of Ottawa.
authors.forename: Marc-Olivier
authors.initials: MO
authors.lastname: Deguise
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.|Centre for Neuromuscular Disease, University of Ottawa.
authors.forename: Yves
authors.initials: Y
authors.lastname: De Repentigny
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.|Centre for Neuromuscular Disease, University of Ottawa.
authors.forename: Emily
authors.initials: E
authors.lastname: McFall
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.|Faculty of Science, University of Ottawa, Ottawa, Ontario, Canada, K1N 9B4.
authors.forename: Nicole
authors.initials: N
authors.lastname: Auclair
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology.
authors.forename: Subash
authors.initials: S
authors.lastname: Sad
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6.|Department of Cellular and Molecular Medicine.|Centre for Neuromuscular Disease, University of Ottawa.|Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein