Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome.
Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and/or basal gangl...
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Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0324268 |
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| author | Allison R Hanaford Asheema Khanna Vivian Truong Katerina James Ryan Liao Yihan Chen Michael Mulholland Ernst-Bernhard Kayser Kino Watanabe Erin Shien Hsieh Philip G Morgan Surojit Sarkar Vandana Kalia Simon C Johnson |
| author_facet | Allison R Hanaford Asheema Khanna Vivian Truong Katerina James Ryan Liao Yihan Chen Michael Mulholland Ernst-Bernhard Kayser Kino Watanabe Erin Shien Hsieh Philip G Morgan Surojit Sarkar Vandana Kalia Simon C Johnson |
| author_sort | Allison R Hanaford |
| collection | DOAJ |
| description | Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and/or basal ganglia. Recent studies in the Ndufs4(-/-) mouse model of LS indicate that disease is causally driven by the immune system. Both microglia and peripherally originating macrophages are enriched in the lesions of Ndufs4(-/-) mice and pharmacologic elimination of these cell types prevents disease indicating a crucial role for innate immune cells. Here, we investigated the role of the adaptive immune system in Ndufs4(-/-) disease pathogenesis. We crossed Ndufs4(-/-) mice with mice expressing a null form of interleukin 2 receptor gamma (Il2rg) and monitored disease onset and progression. Il2rg knockout (KO) mice have dramatically depleted numbers of B-, T-, the adaptive immune system's key cellular actors, and NK-cells. We observed no difference in neurological disease progression or overall survival between Ndufs4(-/-)/Il2rg(WT) and Ndufs4(-/-)/Il2rg(KO) mice, strongly suggesting that T cells, B cells, and NK cells do not play a significant role in CNS disease pathogenesis in Ndufs4(-/-) mice. Combined with previous studies indicating a causal role for macrophages, we conclude that LS CNS pathology is primarily driven by the monocyte/macrophage innate immune system. |
| format | Article |
| id | doaj-art-98064ea36d124d6cb8fe4030821d63bc |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-98064ea36d124d6cb8fe4030821d63bc2025-08-20T03:20:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032025-01-01206e032426810.1371/journal.pone.0324268Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome.Allison R HanafordAsheema KhannaVivian TruongKaterina JamesRyan LiaoYihan ChenMichael MulhollandErnst-Bernhard KayserKino WatanabeErin Shien HsiehPhilip G MorganSurojit SarkarVandana KaliaSimon C JohnsonLeigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease and characterized by neurological and metabolic abnormalities. The hallmark of the disease is the presence of progressive, bilateral, symmetric neurodegenerative lesions in the brainstem and/or basal ganglia. Recent studies in the Ndufs4(-/-) mouse model of LS indicate that disease is causally driven by the immune system. Both microglia and peripherally originating macrophages are enriched in the lesions of Ndufs4(-/-) mice and pharmacologic elimination of these cell types prevents disease indicating a crucial role for innate immune cells. Here, we investigated the role of the adaptive immune system in Ndufs4(-/-) disease pathogenesis. We crossed Ndufs4(-/-) mice with mice expressing a null form of interleukin 2 receptor gamma (Il2rg) and monitored disease onset and progression. Il2rg knockout (KO) mice have dramatically depleted numbers of B-, T-, the adaptive immune system's key cellular actors, and NK-cells. We observed no difference in neurological disease progression or overall survival between Ndufs4(-/-)/Il2rg(WT) and Ndufs4(-/-)/Il2rg(KO) mice, strongly suggesting that T cells, B cells, and NK cells do not play a significant role in CNS disease pathogenesis in Ndufs4(-/-) mice. Combined with previous studies indicating a causal role for macrophages, we conclude that LS CNS pathology is primarily driven by the monocyte/macrophage innate immune system.https://doi.org/10.1371/journal.pone.0324268 |
| spellingShingle | Allison R Hanaford Asheema Khanna Vivian Truong Katerina James Ryan Liao Yihan Chen Michael Mulholland Ernst-Bernhard Kayser Kino Watanabe Erin Shien Hsieh Philip G Morgan Surojit Sarkar Vandana Kalia Simon C Johnson Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome. PLoS ONE |
| title | Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome. |
| title_full | Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome. |
| title_fullStr | Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome. |
| title_full_unstemmed | Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome. |
| title_short | Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome. |
| title_sort | disruption of adaptive immunity does not attenuate disease in the ndufs4 model of leigh syndrome |
| url | https://doi.org/10.1371/journal.pone.0324268 |
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