The magnitude of the antigen‐specific T cell response is separated from the severity of spinal cord histopathology in remitting‐relapsing experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. The remitting-relapsing experimental autoimmune encephalomyelitis (EAE) in the SJL mouse strain is a common animal model for MS and similar to the human disease it is considered to be T helper cell mediated. Besides interferon-γ secreting T(H)1 cells in particular the T(H)17 subset is believed to be highly pathogenic. Spreading of the T(H)1 and T(H)17 response to newly emerging determinants has been used to explain clinical disease relapse, but if the magnitude of the T(H)1/T(H)17 response is linked to clinical relapse severity has remained unresolved. Here, we assessed clinical EAE severity, the extent of spinal cord histopathology and the magnitude of the antigen-specific T helper cell and autoantibody response in proteolipid protein peptide 139-151 (PLP:139-151)-immunized SJL mice in clinical remission and relapse. We demonstrate that spinal cord histopathology comprised inflammation, demyelination as well as axonal loss and correlated well with clinical disease severity. Although the degree of spinal cord histopathology and clinical severity was separated from the PLP:139-151-specific T(H)1/T(H)17 cell and antibody response, it was linked to the number of infiltrating macrophages and activated microglia. In particular, there was a correlation between their secretion product interleukin-1β and the degree of axonal loss. Although CD4(+) T cells seem to be mainly involved in disease initiation, we suggest that it is the downstream activation of the innate immune response that defines the magnitude of the disease outcome.

Interleukin-1β and Interleukin-1 Receptor Antagonist Appear in Grey Matter Additionally to White Matter Lesions during Experimental Multiple Sclerosis

“…The combination of IL-1β or IL-1ra mRNA in situ hybridization histochemistry with immunohistochemistry for CD68 indicated that infiltrating macrophages and/or activated endogenous microglial cells in WM and GM are the main sources of IL-1β and IL-1ra mRNA production during conditions of cr-EAE, which is in line with research showing increased expression of IL-1β in activated microglia and macrophages in EAE [41], [62], [63] and in MS [38]. Although we cannot exclude the possibility that IL-1β or IL-1ra is expressed by T-cells or endothelial cells, our data suggest that if so, it will be a minor contribution to the production of IL-1β or IL-1ra during cr-EAE.…”

Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages

“…Consistent with in vivo experiments, we confirmed that Fasudil converts M1 macrophages, expressing CD16/32, IL‐12, and iNOS to M2 macrophages, expressing CD23, CD206, IL‐10, and Arg‐1, in vitro. It has recently been shown that macrophages/microglia of different phenotypes manifest completely different biological characteristics . In the EAE model, M1 macrophages play a major pathogenic role in disease initiation whereas M2 macrophages contribute to disease recovery .…”

Predicting local tissue mechanics using immunohistochemistry

“…Pelleted food and water was provided ad libitum and mice were kept in an artificial 12/12 hours dark/light cycle. As these mice served as controls in a study on experimental autoimmune encephalomyelitis (Koser et al, in preparation), they were injected with a mixture of PBS and Complete Freund’s adjuvant (complete injection volume: 200 μL) subcutaneously in the flanks 1562 days before the measurements (15).…”