(mentions CMT) Activation of the RAGE pathway: a general mechanism in the pathogenesis of polyn

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Neurol Res. 2007 Jan;29(1):103-10.

Activation of the RAGE pathway: a general mechanism in the

pathogenesis of polyneuropathies?

Haslbeck KM, Neundorfer B, Schlotzer-Schrehardtt U, Bierhaus A,

Schleicher E, i E, Haslbeck M, Hecht M, Nawroth P, Heuss D.

Department of Neurology, University Erlangen/Nurnberg,

Schwabachanlage 6, 91054 Erlangen, Germany.

OBJECTIVES: Binding of ligands to the receptor for advanced

glycation end products (RAGE) results in activation of the

transcription factor NF-kappaB and subsequent expression of NF-

kappaB regulated cytokines and is a possible pathomechanism in

diabetic and in vasculitic polyneuropathies (PNP). We wanted to

investigate whether the newly discovered RAGE pathway also

contributes to the pathogenesis of various other PNP.

METHODS: The presence of the RAGE ligand Nepsilon-

Carboxymethyllysine (CML), the receptor itself and NF-kappaBp65 was

studied in sural nerve biopsies of patients with alcohol-associated

PNP (n=5), PNP owing to vitamin B12 deficiency (n=5), chronic

inflammatory demyelinating PNP (CIDP, n=10), Charcot-Marie-Tooth

disease (CMT) I or II (n= 10), PNP caused by monoclonal gammopathy

of unknown significance (MGUS) (n=5), idiopathic PNP (n=10) and five

normal controls by immunohistochemistry. Biopsies of either ten

patients with diabetic and vasculitic PNP served as positive

controls.

RESULTS: CML, RAGE and NF-kappaBp65 were found in co-localization in

epineurial vessels in PNP owing to vitamin B12 deficiency, diabetes

and vasculitis and in the perineurium in diabetic PNP, vasculitic

PNP and in some cases in CIDP and vitamin B12 deficiency. Only

diabetic subjects demonstrated co-expression of the three antigens

in endoneurial vessels. Increased CML, RAGE and NF-kappaBp65

expression was detected in endoneurial and epineurial mononuclear

cells in CIDP and in vasculitic PNP. Additionally, RAGE expression

in Schwann cells was significantly increased in diabetic PNP.

DISCUSSION: These data suggest that activation of the RAGE pathway

might contribute to the pathogenesis of CIDP, PNP owing to vitamin

B12 deficiency, diabetes and vasculitis, whereas it does not seem to

be involved in the pathogenesis of PNP owing to alcohol, MGUS, CMT I

or II and idiopathic PNP.