Massive apoptosis in lymphoid organs in animal models for primary and secondary progressive multiple sclerosis.
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.
Tsunoda
Ikuo
I
Department of Neurology, University of Utah School of Medicine, Salt Lake City, 84132-2305, USA.
Libbey
Jane E
JE
Kuang
Li-Qing
LQ
Terry
Emily Jane
EJ
Fujinami
Robert S
RS
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000032:analysis; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D018450:Disease Progression; D004587:Electrophoresis, Agar Gel; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology*; D005260:Female; D008198:Lymph Nodes / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology*; D012008:Recurrence; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
D016207:Cytokines