Activation of terminal components of complement in patients with Guillain-Barré syndrome and other demyelinating neuropathies.

Abstract

In the present study, the role of antiperipheral nerve myelin antibody (anti-PNM Ab) in demyelination by generating the terminal attack complex (C5b-9) of complement was explored in patients with Guillain-Barre syndrome (GBS) and other demyelinating neuropathies. The presence in serum of SC5b-9, an inactive C5b-9 containing S protein, was assessed quantitatively by enzyme-linked immunosorbent assay using an antibody (Ab) to neoantigens expressed on C9 when complexed with C5b-8 or after tubular polymerization. SC5b-9 was detected in all 19 GBS, four patients with paraprotein-associated neuropathy and five of six patients with chronic recurrent polyneuritis. No SC5b-9 was detected in 10 normal controls. Kinetic studies from six GBS patients showed the highest values of SC5b-9 on the 3rd to 5th d of admission; in contrast, the anti-PNM Ab were highest on the day of admission. Anti-PNM Ab fell rapidly to very low levels by the 15th to 20th d. SC5b-9 declined with similar kinetics to undetectable levels by the 30th d. Levels of Ab and SC5b-9 did not quantitatively correlate with soluble immune complexes in these patients' serum. Membrane-bound C5b-9 was also detected by immunohistochemistry in the peripheral nerves from a GBS patient. These results, which show a relationship between levels of complement-fixing anti-PNM Ab and the tissue-damaging C5b-9 complex, suggest that peripheral nerve myelin may serve as the target for Ab-mediated complement attack.

Crystal Structure of C5b-6 Suggests Structural Basis for Priming Assembly of the Membrane Attack Complex

“…A large number of other complement-mediated disorders are known, and in many situations indications were found for the importance of the MAC. They include inflammation caused by trauma (49), rheumatoid arthritis (50), macular degeneration (51,52), hemolytic anemias (53,54), nephritis (55,56), and demyelinating neuropathies such as multiple sclerosis and Guillain-Barré syndrome (57,58). In rodent models, MAC formation increased the severity of rheumatoid arthritis, whereas a CD59 derivative decreased it (59,60).…”

High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments.

“…The increased C3 uptake in active phase of DM, but not in the chronic form or the controls, suggests that the high rate of complement activation may be responsible for the formation of a large number of activated early components. Whether C3 uptake is also increased in other complement-mediated neuromuscular diseases, such as Guillain-Barre syndrome (33) or myasthenia gravis where IVIG is also effective (23,34), is not known.…”

Overexpression of GD1a Ganglioside Sensitizes Motor Nerve Terminals to Anti-GD1a Antibody-Mediated Injury in a Model of Acute Motor Axonal Neuropathy

“…Antibody binding to target membranes results in complement activation with membrane attack complex (MAC) pore formation (Koski et al, 1987;Acosta et al, 1996). Our studies on antidisialosyl ganglioside Ab binding to presynaptic NMJ gangliosides indicate that uncontrolled calcium influx through MAC pores triggers massive neurotransmitter release with electrophysiological failure and calpain-mediated disintegration of the presynaptic axon Bullens et al, 2000;O'Hanlon et al, 2001O'Hanlon et al, , 2003Halstead et al, 2004).…”