Brain Advance Access originally published online on May 16, 2008
Brain 2008 131(7):1926-1939; doi:10.1093/brain/awn074
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Structural requirements of anti-GD1a antibodies determine their target specificity
1Department of Neurology, Johns Hopkins University, Baltimore, MD, USA, 2Department of Neurology, The Second Teaching Hospital, Hebei Medical University, Shijiazhuang, People's Republic of China, 3Department of Biophysics and Biophysical Chemistry and 4Department of Pharmacology, Johns Hopkins University, Baltimore, MD, USA
Correspondence to: Dr Kazim Sheikh, Department of Neurology, Johns Hopkins Hospital, 600 N. Wolfe St., 509 Pathology Building, Baltimore, MD, 21287, USA E-mail: ksheik{at}jhmi.edu
The acute motor axonal neuropathy (AMAN) variant of Guillain–Barré syndrome (GBS) is associated with anti-GD1a and anti-GM1 IgG antibodies. The basis of preferential motor nerve injury in this disease is not clear, however, because biochemical studies demonstrate that sensory and motor nerves express similar quantities of GD1a and GM1 gangliosides. To elucidate the pathophysiology of AMAN, we have developed several monoclonal antibodies (mAbs) with GD1a reactivity and reported that one mAb, GD1a-1, preferentially stained motor axons in human and rodent nerves. To understand the basis of this preferential motor axon staining, several derivatives of GD1a were generated by various chemical modifications of N-acetylneuraminic (sialic) acid residues (GD1a NeuAc 1-amide, GD1a NeuAc ethyl ester, GD1a NeuAc 1-alcohol, GD1a NeuAc 1-methyl ester, GD1a NeuAc 7-alcohol, GD1a NeuAc 7-aldehyde) on this ganglioside. Binding of anti-GD1a mAbs and AMAN sera with anti-GD1a Abs to these derivatives was examined. Our results indicate that mAbs with selective motor axon staining had a distinct pattern of reactivity with GD1a-derivatives compared to mAbs that stain both motor and sensory axons. The fine specificity of the anti-GD1a antibodies determines their motor selectivity, which was validated by cloning a new mAb (GD1a-E6) with a chemical and immunocytochemical binding pattern similar to that of GD1a-1 but with two orders of magnitude higher affinity. Control studies indicate that selective binding of mAbs to motor nerves is not due to differences in antibody affinity or ceramide structural specificity. Since GD1a-reactive mAb with preferential motor axon staining showed similar binding to sensory- and motor nerve-derived GD1a in a solid phase assay, we generated computer models of GD1a based on binding patterns of different GD1a-reactive mAbs to different GD1a-derivatives. These modelling studies suggest that critical GD1a epitopes recognized by mAbs are differentially expressed in motor and sensory nerves. The GD1a-derivative binding patterns of AMAN sera resembled those with motor-specific mAbs. On the basis of these findings we postulate that both the fine specificity and ganglioside orientation/exposure in the tissues contribute to target recognition by anti-ganglioside antibodies and this observation provides one explanation for preferential motor axon injury in AMAN.
Key Words: acute motor axonal neuropathy; anti-ganglioside antibodies; gangliosides; Guillain–Barré syndrome; immune neuropathies
Abbreviations: Ab, antibody; Abs, antibodies; AMAN, acute motor axonal neuropathy; DRG, dorsal root ganglion; ELISA, enzyme linked immunosorbent assay; GBS, Guillain–Barré syndrome; IgG, immunoglobulin G; mAb, monoclonal Ab; MoS, motor-specific; NeuAc, N-acetylneuraminic acid; NoS, nonselective; PBS, phosphate-buffered saline; TLC, thin layer chromatography; 3D, three-dimensional
Received April 20, 2007. Revised February 14, 2008. Accepted March 26, 2008.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Kaida, T. Ariga, and R. K Yu Antiganglioside antibodies and their pathophysiological effects on Guillain-Barre syndrome and related disorders--A review Glycobiology, July 1, 2009; 19(7): 676 - 692. [Abstract] [Full Text] [PDF]
|
|