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Massive apoptosis in lymphoid organs in animal models for primary and secondary progressive multiple sclerosis
Ikuo Tsunoda1, Jane E Libbey, Li-Qing Kuang
1Department of Neurology, University of Utah School of Medicine, Salt Lake City, 84132-2305, USA.
Abstract:
The mechanism(s) responsible for generating the different forms of multiple sclerosis, primary progressive (PP) and secondary progressive (SP) versus relapsing-remitting (RR), is not well understood. Using myelin oligodendrocyte glycoprotein (MOG)(92-106), we have established animal models that mimic the different types of multiple sclerosis. A.SW mice develop PP or SP-experimental allergic encephalomyelitis (EAE) with large areas of demyelination and high titers of MOG antibody whereas SJL/J mice develop RR-EAE with perivascular T cells and mild demyelination. In A.SW progressive EAE, we found atrophy of the thymus, spleen, and lymph nodes with depletion of T and B cells and massive apoptosis, as demonstrated by immunohistochemistry, terminal dUTP nick-end labeling, and DNA agarose gel electrophoresis. To test whether lymphoid apoptosis itself contributes to disease progression, we injected SJL/J mice with apoptotic thymocytes. Injection of apoptotic cells resulted in greater than 20% of mice developing SP-EAE with ataxia. SJL/J mice with SP-EAE had large areas of demyelination, high MOG antibody titers and atrophic lymphoid organs. Spleen cells from mice with progressive EAE produced less interferon-gamma than those from RR-EAE when stimulated with mitogen. We suggest that induction of lymphoid apoptosis alters the balance of Th1 versus Th2 immune responses and increases MOG antibody production, leading to exacerbation of demyelination and subsequent disease progression.
Insights
Lymphoid apoptosis contributes to progressive multiple sclerosis by altering immune responses and increasing myelin oligodendrocyte glycoprotein antibody production, leading to demyelination. This finding helps understand different multiple sclerosis forms.
Area of Science:
- Immunology
- Neuroscience
- Pathology
Background:
- The mechanisms differentiating multiple sclerosis (MS) forms, such as primary progressive (PPMS), secondary progressive (SPMS), and relapsing-remitting (RRMS), remain unclear.
- Animal models are crucial for studying MS pathogenesis and potential therapeutic targets.
Purpose of the Study:
- To investigate the role of lymphoid apoptosis in the progression of experimental allergic encephalomyelitis (EAE), an animal model for MS.
- To elucidate the mechanisms underlying the distinct EAE forms (PP/SP-EAE vs. RR-EAE) using myelin oligodendrocyte glycoprotein (MOG)(92-106) as a target.
Main Methods:
- Established distinct EAE models in A.SW (PP/SP-EAE) and SJL/J (RR-EAE) mice using MOG(92-106).
- Analyzed lymphoid organ pathology (thymus, spleen, lymph nodes) and cellular apoptosis in A.SW mice with progressive EAE.
- Induced SP-EAE in SJL/J mice by injecting apoptotic thymocytes and assessed disease severity, demyelination, MOG antibody titers, and immune cell function.
Main Results:
- A.SW mice with progressive EAE exhibited lymphoid atrophy, T and B cell depletion, and massive apoptosis.
- SJL/J mice injected with apoptotic thymocytes developed SP-EAE, characterized by significant demyelination, high MOG antibody titers, and lymphoid atrophy.
- Spleen cells from progressive EAE mice produced less interferon-gamma upon stimulation compared to those from RR-EAE mice.
Conclusions:
- Induction of lymphoid apoptosis may drive MS disease progression by shifting the Th1/Th2 immune balance and elevating MOG antibody production.
- This mechanism contributes to increased demyelination and exacerbation of MS symptoms, potentially explaining differences between MS forms.
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