Autoimmune Encephalomyelitis and Uveitis Induced by T Cell Immunity to Self β-Synuclein

Abstract

β-synuclein is a neuronal protein that accumulates in the plaques that characterize neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. It has been proposed that immunization to peptides of plaque-forming proteins might be used therapeutically to help dissociate pathogenic plaques in the brain. We now report that immunization of Lewis rats with a peptide from β-synuclein resulted in acute paralytic encephalomyelitis and uveitis. T cell lines and clones reactive to the peptide adoptively transferred the disease to naive rats. Immunoblotting revealed the presence of β-synuclein in heavy myelin, indicating that the expression of β-synuclein is not confined to neurons. These results add β-synuclein to the roster of encephalitogenic self Ags, point out the potential danger of therapeutic autoimmunization to β-synuclein, and alert us to the unsuspected possibility that autoimmunity to β-synuclein might play an inflammatory role in the pathogenesis of neurodegeneration.

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

“…Indeed, T cell responses against neuronal antigens have been demonstrated in MS patients and EAE- affected animals [8][9][10], and T cell-mediated EAE symptoms can be induced by immunization with neuronal antigens [11,13,14]. Despite this, we did not detect T cell proliferation against NF-L in CLN from EAE mice immunized with MOG or MOG [8][9][10][11][12][13][14][15][16][17][18][19][20][21] . The lack of T cell proliferation we consistently found might be due to the absence of intermolecular spreading or to the fact that the draining antigens may act immunosuppressively on proliferation within the draining lymph nodes.…”

“…EAE was induced by immunization with spinal cord homogenate or myelin oligodendrocyte glycoprotein (MOG) [8][9][10][11][12][13][14][15][16][17][18][19][20][21] in CFA as described [27,28]. Deep and superficial CLN were also isolated from CCR7-deficient (n=4) and wild-type mice (n=4) [29] with chronic EAE, obtained from stock bred at the animal facility of the Max Delbrück Center for Molecular Medicine (Berlin, Germany).…”

“…A single cell suspension was obtained by passing the lymph nodes through a 70-μm gauze. Lymph node cells, 2×10 5 , were seeded into 96-well round-bottomed plates (Nunc) and stimulated with the indicated concentrations of MOG [8][9][10][11][12][13][14][15][16][17][18][19][20][21] , MOG (both from Advanced Biotechnology Center, Imperial College London), recombinant mouse NF-L (rmNF-L) [40], or ovalbumin (Worthington). After 4 days, T cell proliferation was determined by incorporation of [ 3 H]-thymidine for 18 h (Amersham Biosciences) as described [30].…”

“…Two experiments were using C57BL/6 mice in which EAE was induced by injection with MOG 35-55 (n=5-10 per experiment). One additional experiment was using Biozzi ABH mice (n=10) in which EAE was induced by injection with MOG [8][9][10][11][12][13][14][15][16][17][18][19][20][21] . Figure 5 shows a representative experiment, in which we observed dose-dependent T cell proliferation against the immunizing peptide MOG No proliferation against the irrelevant control antigen OVA was seen.…”

“…In addition, T cells from MS patients proliferate in response to the neuronal antigens synapsin and neuron-specific enolase (NSE) [8,9]. In mice, T-cell-mediated autoimmunity against neuronal antigens leads to central nervous system (CNS) inflammation and experimental autoimmune encephalomyelitis (EAE) symptoms [10][11][12][13][14].…”