Massive Apoptosis in Lymphoid Organs in Animal Models for Primary and Secondary Progressive Multiple Sclerosis

• Published in: The American journal of pathology Vol. 167; no. 6; pp. 1631 - 1646
• Main Authors: Tsunoda, Ikuo, Libbey, Jane E., Kuang, Li-Qing, Terry, Emily Jane, Fujinami, Robert S.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.12.2005; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Apoptosis; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biological and medical sciences; Cytokines - analysis; Disease Models, Animal; Disease Progression; DNA Fragmentation; Electrophoresis, Agar Gel; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Investigative techniques, diagnostic techniques (general aspects); Lymph Nodes - immunology; Lymphocytes - immunology; Lymphocytes - pathology; Medical sciences; Mice; Mice, Inbred Strains; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; Original Research Paper; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Recurrence; Spleen - immunology; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Progressive; Animal model; Nervous system diseases; Anatomic pathology; Multiple sclerosis; Secondary; Lymphoid organ; Cell death; Central nervous system disease; Primary; Inflammatory disease; Apoptosis
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)61247-3

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-γ 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.