Brain, Vol. 126, No. 6, E1,
June 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg161
Letters to the Editor |
1 Department of Neurology, Clinical Research Group for Multiple Sclerosis and Neuroimmunology,University of Würzburg, Würzburg and 2 Department of Neuroimmunology, Max Planck Institute for Neurobiology, Martinsried, Germany
Correspondence to: Ralf Gold. Email: r.gold{at}mail.uni-wuerzburg.de. Or Christopher Linington. E-mail: lining{at}neuro.mpg.de
We appreciate the comments of Dr Bergamaschi and his interesting single case of NMO that was successfully treated with GA.
In our editorial (Gold and Linington, 2002
), we discussed the histopathological findings in NMO and pointed out that they are indicative, but not confirmatory of a possible Th-2-driven immunopathology in NMO. We would like to stress once again that the presence of antibodies deposited within the lesions in NMO is by no means proof for the involvement of what are loosely termed ‘Th-2 mediated’ immune effector mechanisms in disease pathogenesis. Unfortunately, this reflects the common error of equating an antibody-mediated disease pathology with a cellular response skewed in favour of Th-2 T cell responses. The immunoglobulin isotypes associated with IL-4 driven (i.e. Th-2 T cell associated) isotype switching in man are IgE and IgG4 (Janeway et al., 2001) neither of which are known to play any role in the pathogenesis of either multiple sclerosis or NMO. Moreover these immunoglobulin isotypes do not activate the complement cascade and are therefore unlikely to be responsible for the reported deposition of complement activation products on the myelin surface.
Based on the published studies on mechanisms of immunotherapy in multiple sclerosis, we noted that glatiramer acetate therapy may augment the immune response in NMO and thus may be more problematic. When the editorial was written, we were aware of the very interesting findings on BDNF production by GA-specific T cells from Dr Hohlfeld’s group (Ziemssen et al., 2002), but as they were not yet published we decided to leave them out. The possibility that BDNF production by GA-specific T cells was in part responsible for the clinical improvement seen in Dr Bergamaschi’s patient is certainly intriguing and warrants further investigation. In particular one must address whether or not this effect can increase the production of BDNF above that produced by other immune cells already in the multiple sclerosis lesion (Stadelmann et al., 2002) to produce a biologically significant effect.
We certainly agree that the use of GA in NMO should not be rejected out of hand but feel that early treatment with highly active immunosuppressive drugs such as mitoxantrone (Hartung et al., 2002) should be considered in this severe disease.
References
Gold R, Linington C. Devic’s disease: bridging the gap between laboratory and clinic. Brain 2002; 125: 1425–7.
Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360: 2018–25.[CrossRef][Web of Science][Medline]
Janeway CA, Travers P, Walport M, Shlomchik MJ. Immunobiology – the immune system in health and disease. New York: Churchill Livingstone, 2001.
Stadelmann C, Kerschensteiner M, Misgeld T, et al. BDNF and gp145trkB in multiple sclerosis brain lesions: Neuroprotective interactions between immune and neuronal cells? Brain 2002; 125: 75–85.
Ziemssen T, Kumpfel T, Klinkert WEF, et al. Glatiramer acetate-specific T-helper 1-and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain 2002; 125: 2381–2391.
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