Anti-GD1a antibodies from an acute motor axonal neuropathy patient selectively bind to motor nerve fiber nodes of Ranvier

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Abstract

Acute motor axonal neuropathy (AMAN) is associated with high titer anti-GD1a antibodies. We have found that very high titer IgG anti-GD1a antibodies (Ab) from one AMAN patient selectively bind to motor, but not sensory, nerve nodes of Ranvier. Binding is abolished by preadsorption with GD1a. Sera negative for Ab do not immunostain motor and sensory nerve roots. We have also found that botulinum toxin A (BTA), which binds to GD1a, stains both motor and sensory nerve nodes of Ranvier. Our results strongly support the pathogenetic role of anti-GD1a antibodies in AMAN. Why BTA also binds to sensory fibers still remains to be elucidated, although the different size of BTA and its specificity to other gangliosides present in sensory axons might represent important factors.

Introduction

GD1a is a disialo-ganglioside highly concentrated in nervous tissues. Its immuno-localization in the CNS, but not in the PNS, has been recently investigated using high-affinity IgG (Lunn et al., 2000). Although it is present in both human motor and sensory nerves, GD1a shows different migration patterns in extracts from motor and sensory roots and their axonal fractions (Ogawa-Goto et al., 1990) and a higher concentration in motor (4%) than sensory (1%) myelin from human roots. High titers of anti-GD1a antibodies have mainly been reported in patients with acute motor axonal neuropathy (AMAN) Yuki et al., 1992, Carpo et al., 1996, Lugaresi et al., 1997, Ho et al., 1999. In a recently published series of Japanese Guillain–Barré syndrome (GBS), anti-GD1a antibodies were present in 30% of 86 consecutive patients and anti-N-acetylgalactosaminyl-GD1a in 17%; antibodies showed a correlation with the axonal form of GBS and were frequently associated with Campylobacter jejuni (CJ) infection (Ogawara et al., 2000). The association of IgG anti-N-acetylgalactosaminyl GD1a antibodies with motor axonal GBS and CJ infection has also been recently reported in 33 retrospective cases of GBS (Kaida et al., 2000). In Europe, besides the first two AMAN cases we reported and associated with CJ enteritis (Lugaresi et al., 1997), the association of anti-GD1a antibodies to axonal GBS has been reported in two out of three Spanish patients from a series of 78 GBS patients (Gallardo et al., 2001), appearing rarer than in Japan. In the cases of AMAN associated with campylobacter enteritis we described, antibodies reacted to GD1a or possibly N-acetylgalactosaminyl-GD1a but not to other gangliosides (Lugaresi et al., 1997).

To elucidate the association between anti-GD1a antibodies and neuropathy with pure motor involvement, we studied the binding of our patient 2 serum (Lugaresi et al., 1997) to human ventral and dorsal roots by immuno-fluorescence microscopy. To better elucidate the actual target antigen of anti-GD1a antibodies on human roots, we also performed colocalization studies using botulinum toxin A (BTA). GD1a, together with GT1b, represents in fact the ligand for BTA Kitamura et al., 1980, Habermann et al., 1988, Marxen et al., 1991.

Section snippets

Human motor and sensory roots

Human motor and sensory roots were obtained at autopsy about 16 h post-mortem from a patient with no history of neuropathy. Roots were snap frozen in vials containing isopentane kept in liquid nitrogen and subsequently stored at −80 °C.

Human serum and antibody characterization

Serum from the AMAN patient with very high titer anti-GD1a IgG antibodies we previously described (patient 2) (Lugaresi et al., 1997) was stored at −80°C until use. Anti-GD1a antibody titers were determined through ELISA as previously described (Lugaresi et al.,

Immuno-staining with anti-GD1a antibodies

Serum positive for anti-GD1a antibodies strongly reacted with the nodal region of motor roots (Fig. 1A) but not of sensory roots. No binding was observed with control serum or with anti-GD1a serum preadsorbed with GD1a. Anti-GD1a antibodies eluted after adsorption showed the same labeling pattern of the anti-GD1a sera.

Staining with BTA

BTA bound to the nodal and paranodal region of both human motor and sensory roots (Fig. 1B, D).

Double staining with BTA and serum with anti-GD1a antibodies

BTA staining colocalized with anti-GD1a serum immuno-staining, binding to the nodal

Discussion

A pathogenetic role for anti-ganglioside antibodies in acute dysimmune neuropathies has been deemed probable Ho and Griffin, 1999, Lunn et al., 2000. The association of different anti-ganglioside antibodies to distinct neuropathies might be due to a different ganglioside composition and to a different exposition of the gangliosides in target tissues Dalakas and Quarles, 1996, Lugaresi et al., 1997, Kaida et al., 2000. Our results strongly support the pathogenetic role of anti-GD1a antibodies in

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