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

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.

MP4- and MOG:35–55-induced EAE in C57BL/6 mice differentially targets brain, spinal cord and cerebellum☆

“…It is unclear whether this difference resides in the nature of the antigen. MP4 contains the PLP:178-191 determinant and PLP-induced EAE in other mouse strains is indeed characterized by massive chronic demyelination (Tsunoda et al, 2005). The fact that we did not observe demyelination using the isolated PLP:178-191 peptide might be related to this peptide being a cryptic determinant in the B6 mouse.…”

Sequential polymicrobial infections lead to CNS inflammatory disease: Possible involvement of bystander activation in heterologous immunity

“…IL-12 and IFN-γ would then activate autoimmune T helper (Th) 1 cells. In this study, we found that MCMV challenge induced higher anti-PLP IgG2c (formerly IgG2a of Igh-1b allotype) (Jouvin-Marche et al, 1989;Tsunoda et al, 2005aTsunoda et al, ,2005b responses and that the anti-PLP IgG2c/G1 ratio in MCMV challenge was higher than in VV and LCMV challenge. Since Th1 and Th2 cells help with the Ig isotype switch to IgG2a (2c) and IgG1, respectively, our results are consistent with the fact that MCMV infection skews immune responses toward Th1.…”

“…There was no statistical difference in PLP antibody titers between VV-challenged mice and naïve mice. We also measured anti-PLP IgG1 and IgG2c (formerly IgG2a of Igh-1b allotype) (Jouvin-Marche et al, 1989;Tsunoda et al, 2005aTsunoda et al, ,2005b. We found that anti-PLP IgG1 and IgG2c titers were low in all mouse groups.…”

“…After blocking, serial dilutions of sera were added to the plates and incubated for 90 min. After washing, a peroxidase-conjugated anti-mouse IgG (H + L) (Invitrogen, Carlsbad, CA), IgG1 (Caltag laboratories, Burlingame, CA), or IgG2c antibody (Southern Biotechnology Associates, Inc., Birmingham, AL) Tsunoda et al, 2005aTsunoda et al, ,2005b was added for 90 min. The plates were colorized with o-phenylenediamine dihydrochloride (Sigma-Aldrich, St. Louis, MO) and were read at 492 nm on a Titertek Multiskan Plus MK II spectrophotometer (Flow Laboratories, McLean, VA).…”

Regulatory Role of CD1d in Neurotropic Virus Infection

“…Culture supernatants were harvested 48 h after stimulation. IFN-␥ and IL-4 were measured using the enzyme-linked immunosorbent assay system OptEIA set (BD PharMingen, San Jose, CA), according to the manufacturer's instructions (44).…”