Preclinical Study Links CD59 Deficiency to Demyelination and Conduction Blocks

Dror Mevorach, MD

A 2023 study showed that nodes of Ranvier in the human peripheral nervous system (PNS) lack the protective complement regulator CD59, leaving them vulnerable to complement attack, while myelin, protected by CD59 and CD55 but not CD46 or CD35, remains susceptible to complement-mediated damage in conditions like autoinflammatory Guillain-Barré syndrome (GBS) linked to CD59 deficiency.

The nodes of Ranvier are small gaps in the myelin sheath that insulates axons and in the nervous system, playing a critical role in the rapid transmission of electrical signals along myelinated nerves. Published in the Journal of Neuroinflammation, the study aimed to determine the localization and possible role of membrane-bound complement regulators, including CD59, in the PNS of mice and humans. To do so, investigators used a CD59-deficient patient, along with wild-type (WT) and CD59a-deficient mice.

Led by Dror Mevorach, MD, a professor of medicine and head of the Immunology-Rheumatology Institution at Hadassah Ein Karem Medical Center, the study showed that CD59a-deficient mice displayed normal peripheral nerve morphology but developed myelin abnormalities as they got older. Electron microscopy (EM) analysis of 19-month-old animals revealed abnormalities in both genotypes, including the appearance of conspicuous axoplasmatic organelles that were often present in the paranodal region. These axoplasmatic organelles were more frequently detected in knockout (KO) compared with WT mice, with an average of 41.5 in KO mice vs 17.8 in WT mice (n = 5; P = .01).

Additional analyses of KO nerves revealed areas that contained mitochondria and dense bodies, as well as some neurofilaments that had lost their normal orientation and formed disorganized bodies. Overall, these results may indicate that CD59a nerves are more sensitive to nerve damage and degeneration, suggesting a protective role for CD59 in the PNS.

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To test whether the observations made in the mouse nerves apply to humans, the study authors also examined paraffin-embedded sections of sural nerve biopsied from a CD59-deficient patient between GBS episodes. Mevorach et al showed that CD59 protein was not detected with IHC staining in patient cross sections but was seen in cross sections from healthy control subjects. Nerve fibers appeared normal, without evidence of active axonal or myelin damage. There were no apparent excess of endoneurial cells or collagen.

In this specific analysis, EM revealed occasional thin myelin sheaths relative to axonal diameter with a relatively high g ratio of up to 0.8 um compared with 0.5-0.7 um seen in healthy axons, which was suggestive of segmental demyelination/remyelination. EM also showed a normal myelin sheath lamellar structure, with no signs of active axonal or myelin damage, macrophages, or abnormalities in axons or Schwann cells. These findings suggested that CD59-deficient patients undergo demyelination followed by remyelination, resulting in a thinner myelin layer.

In terms of other membrane-bound complement regulatory proteins, CD55 was not present in compact myelin in mouse peripheral nerve teased fibers and was expressed in SLI. In longitudinal human sural nerve sections, CD55 was localized in areas that correspond to exon fibers and compact myelin. All together, this suggests that CD55 is localized in myelin and blood vessels in human peripheral nerves, whereas in mice, CD59 localization is seen in compact myelin but CD55 is localized in SLI of the noncompact myelin compartment.

In human sural nerve cross sections, CD46 was localized in endothelial blood vessels of the epineurium and endoneurium, and partially in the perineurium, while CD35 was absent. In mice, the complement regulator Crry, a functional analog of human CD55 and CD46, was found in paranodal areas and compact myelin, whereas in humans, CD59 and CD55 are expressed in myelin, and CD59, CD55, and CD46 are present in blood vessels. These species-specific differences in complement regulator localization help explain why CD59 deficiency leads to GBS in humans but not in mice, where Crry may compensate for its absence.

REFERENCE
1. Karbian N, Eshed-Eisenback Y, Zeiback M, et al. Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system. Journal of Neuroinflammation. 2023;245:20. doi:10.1186/s12974-023-02920-9