Acta Neuropathologica

, Volume 127, Issue 4, pp 523–538 | Cite as

Early loss of oligodendrocytes in human and experimental neuromyelitis optica lesions

  • Claudia Wrzos
  • Anne Winkler
  • Imke Metz
  • Dieter M. Kayser
  • Dietmar R. Thal
  • Christiane Wegner
  • Wolfgang Brück
  • Stefan Nessler
  • Jeffrey L. Bennett
  • Christine Stadelmann
Original Paper


Neuromyelitis optica (NMO) is a chronic, mostly relapsing inflammatory demyelinating disease of the CNS characterized by serum anti-aquaporin 4 (AQP4) antibodies in the majority of patients. Anti-AQP4 antibodies derived from NMO patients target and deplete astrocytes in experimental models when co-injected with complement. However, the time course and mechanisms of oligodendrocyte loss and demyelination and the fate of oligodendrocyte precursor cells (OPC) have not been examined in detail. Also, no studies regarding astrocyte repopulation of experimental NMO lesions have been reported. We utilized two rat models using either systemic transfer or focal intracerebral injection of recombinant human anti-AQP4 antibodies to generate NMO-like lesions. Time-course experiments were performed to examine oligodendroglial and astroglial damage and repair. In addition, oligodendrocyte pathology was studied in early human NMO lesions. Apart from early complement-mediated astrocyte destruction, we observed a prominent, very early loss of oligodendrocytes and oligodendrocyte precursor cells (OPCs) as well as a delayed loss of myelin. Astrocyte repopulation of focal NMO lesions was already substantial after 1 week. Olig2-positive OPCs reappeared before NogoA-positive, mature oligodendrocytes. Thus, using two experimental models that closely mimic the human disease, our study demonstrates that oligodendrocyte and OPC loss is an extremely early feature in the formation of human and experimental NMO lesions and leads to subsequent, delayed demyelination, highlighting an important difference in the pathogenesis of MS and NMO.


Neuromyelitis optica Demyelination Oligodendrocyte death Experimental autoimmune encephalomyelitis Astrocyte 



We acknowledge the excellent technical support by Brigitte Maruschak, Jasmin Reichl, Katja Schulz, Angela Dettmar, Heidi Brodmerkel, Olga Kowatsch and Uta Scheidt and thank Christine Crozier and Cynthia Bunker for their help with language editing. C.S. and W.B. were supported by the DFG (TR-SFB43 “The brain as a target of inflammatory processes”). J.L.B. was supported by grants from the Guthy-Jackson Foundation and the National Institutes of Health (EY022936). We are indebted to our patients and their relatives.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

401_2013_1220_MOESM1_ESM.tif (30.1 mb)
Supplementary Figure 1: Perivenous parenchymal and inflammatory pathology in NMO and ctrl rAb-injected rats after EAE induction. 30 h after i.v. transfer of ctrl rAb into rats with gpMBP72-85-EAE no loss of astrocytic proteins is observed (a: AQP4, b: GFAP, c: S100β, d: EAAT2). In contrast, rats injected with NMO rAb show a well delineated perivenous loss of astrocytes (i: AQP4, j: GFAP, k: S100b, l: EAAT2). Additionally, ctrl rAb-transferred rats do not show the altered myelin staining (e: LFB/PAS) which is observed in NMO rAb-transferred animals (m). Obvious axonal loss is not a feature in either experimental group (h, p: Bielschowsky silver impregnation). However, T cell (f, n: CD3) and macrophage infiltration (g, o: ED1) is prominent also in ctrl rAb-injected rats due to immunization with gp MBP72-85. Foamy phagocytes are, however, predominantly observed in NMO rAb-injected rats. Note that EAAT2 is barely expressed in WM. Scale bars: 200 μm (TIFF 30863 kb)
401_2013_1220_MOESM2_ESM.tif (27.3 mb)
Supplementary Figure 2: Time course of early myelin damage in focal NMO. 24 h after focal injection of NMO rAb MBP IHC (a) appears pale whereas MAG (d), MOG (g), CNP (j) and PLP (m) are focally reduced, but largely preserved. 3 days after lesion induction MBP (b) and MAG (e) immunoreactivity has almost disappeared, whereas MOG (h), CNP (k) and PLP (n) are still reasonably preserved. After one week, myelin cannot be seen using MBP (c), MAG (f) and CNP (l) IHC, whereas MOG (i) and PLP (o) IHC still detect myelin sheaths in the lesion. Monastral blue marks the injection site. Scale bar: 100 μm (a-o) (TIFF 27921 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Claudia Wrzos
    • 1
  • Anne Winkler
    • 1
  • Imke Metz
    • 1
  • Dieter M. Kayser
    • 2
  • Dietmar R. Thal
    • 3
  • Christiane Wegner
    • 1
  • Wolfgang Brück
    • 1
  • Stefan Nessler
    • 1
  • Jeffrey L. Bennett
    • 4
  • Christine Stadelmann
    • 1
  1. 1.Institute of NeuropathologyUniversity Medical Centre GöttingenGöttingenGermany
  2. 2.Institute of Pathology, Städtisches Klinikum GörlitzGörlitzGermany
  3. 3.Institute of Pathology/Laboratory for NeuropathologyUniversity of UlmUlmGermany
  4. 4.Departments of Neurology and OphthalmologyUniversity of DenverColoradoUSA

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