Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons

Shailender Singh,Paul Van Der Valk,Wolfgang Brück,Imke Metz,Sandra Amor,Christine Stadelmann

doi:10.1007/s00401-013-1082-0

Abstract

Microglial nodules in the normal-appearing white matter have been suggested as the earliest stage(s) of multiple sclerosis (MS) lesion formation. Such nodules are characterized by an absence of leukocyte infiltration, astrogliosis or demyelination, and may develop into active demyelinating MS lesions. Although the etiology of MS is still not known, inflammation and autoimmunity are considered to be the central components of this disease. Previous studies provide evidence that Wallerian degeneration, occurring as a consequence of structural damage in MS lesions, might be responsible for observed pathological abnormalities in connected normal-appearing white matter. As innate immune cells, microglia/macrophages are the first to react to even minor pathological changes in the CNS. Biopsy tissue from 27 MS patients and autopsy and biopsy tissue from 22 normal and pathological controls were analyzed to determine the incidence of microglial nodules. We assessed MS periplaque white matter tissue from early disease stages to determine whether microglial nodules are associated with altered axons. With immunohistochemical methods, the spatial relation of the two phenomena was visualized using HLA-DR antibody for MHC II expression by activated microglia/macrophages and by applying antibodies against damaged axons, i.e., SMI32 (non-phosphorylated neurofilaments) and amyloid precursor protein as well as neuropeptide Y receptor Y1, which marks axons undergoing Wallerian degeneration. Our data demonstrate that the occurrence of microglial nodules is not specific to MS and is associated with degenerating as well as damaged axons in early MS. In addition, we show that early MS microglial nodules exhibit both pro- and antiinflammatory phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1082-0) contains supplementary material, which is available to authorized users.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory CNS disease characterized by multifocal inflammation, extensive demyelination, gliosis and axonal damage
Identification of microglial nodules in the tissue blocks containing periplaque white matter (PPWM) was based on sequential immunohistochemical staining of tissue sections for MHC II (HLA-DR) and myelin markers, i.e., luxol fast blue (LFB)/periodic acid-Schiff (PAS), PLP, MBP, MOG and MAG (Fig. 1)
We observed that the microglial nodules in PPWM occurred more frequently in patients with early active and late active lesions compared to patients with inactive lesions (Table 1)

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory CNS disease characterized by multifocal inflammation, extensive demyelination, gliosis and axonal damage. The etiology of MS is still not known, and the first cellular events in the MS brain remain to be clarified. Microglia are the resident immune cells that react to even minor pathological events in the CNS [27], and microglial activation might arguably be considered an initial pathogenetic event in MS. Inflammation and microglia/macrophage activation may cause myelin/axonal damage or, alternatively, the cells may scavenge damaged myelin/axonal debris. A cluster of activated microglia/macrophages is commonly termed a ‘microglial nodule’ without a strict definition of the cell number.

Objectives

Methods

Results

Conclusion