Proinflammatory Bacterial Peptidoglycan as a Cofactor for the Development of Central Nervous System Autoimmune Disease

Abstract

Upon stimulation by microbial products through TLR, dendritic cells (DC) acquire the capacity to prime naive T cells and to initiate a proinflammatory immune response. Recently, we have shown that APC within the CNS of multiple sclerosis (MS) patients contain peptidoglycan (PGN), a major cell wall component of Gram-positive bacteria, which signals through TLR and NOD. In this study, we report that Staphylococcus aureus PGN as a single component can support the induction of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model for MS. Mice immunized with an encephalitogenic myelin oligodendrocyte glycoprotein peptide in IFA did not develop EAE. In contrast, addition of PGN to the emulsion was sufficient for priming of autoreactive Th1 cells and development of EAE. In vitro studies demonstrate that PGN stimulates DC-mediated processes, reflected by increased Ag uptake, DC maturation, Th1 cell expansion, activation, and proinflammatory cytokine production. These data indicate that PGN-mediated interactions result in proinflammatory stimulation of Ag-specific effector functions, which are important in the development of EAE. These PGN-mediated processes may occur both within the peripheral lymph nodes as well as in the CNS and likely involve recognition by TLR on DC. Thus, PGN may provide a physiological trigger of DC maturation, and in this way disrupt the normal tolerance to self Ag. As such, PGN signaling pathways may serve as novel targets for the treatment of MS.

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

“…All animals were examined daily for clinical symptoms of EAE as described [21,25,28,30]. Tissues were snapfrozen in liquid nitrogen and stored at −80°C.…”

“…EAE in C57BL/6 mice was induced by immunization with 200 μg MOG in CFA [30] and in Biozzi ABH mice as described above. Lymph nodes from five to ten EAE-affected animals were pooled per experiment to obtain enough cells for restimulation.…”

“…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].…”

Enforced expression of GATA3 allows differentiation of IL‐17‐producing cells, but constrains Th17‐mediated pathology

“…EAE was induced in $10-wk-old mice by subcutaneous injection of 200 mg MOG peptide emulsified in complete Freund's adjuvant (Difco), as described [61]. Mice were daily weighed and scored for clinical signs, as follows: 0, no disease; 0.5, partial tail paralysis; 1, complete tail paralysis; 1.5, limb weakness without tail paralysis; 2, limb weakness and tail paralysis; 2.5, partial limb and tail paralysis; 3, complete hind or front limb paralysis; 3.5, paraplegia; 4, quadriplegia; 5, death due to EAE.…”

Phagocytes Containing a Disease-Promoting Toll-Like Receptor/Nod Ligand Are Present in the Brain during Demyelinating Disease in Primates

“…12 PGN stimulates the innate immune system by binding to the Toll-like receptor (TLR)2/6, although this concept has recently been challenged. 13 Recently identified intracellular PGN receptors are the Nod1 (Card4) and Nod2 (Card15) signaling receptors.…”