Proteins Linked to Neuromyelitis Optica Increase MG Disease Severity, Mouse Model Shows

José Lopes, PhD avatar

by José Lopes, PhD |

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Proteins associated with the development of neuromyelitis optica (NMO) were found to aggravate the severity of myasthenia gravis (MG) in a mouse model, which could explain why patients with one disorder are more susceptible to the other condition.

Findings were reported in the study, “NMO-IgG and AQP4 Peptide Can Induce Aggravation of EAMG and Immune-Mediated Muscle Weakness,” appearing in the Journal of Immunology Research.

MG is an autoimmune condition caused by the production of antibodies against acetylcholine receptors (AchRs) at the neuromuscular junction, the site where nerves and muscle cells communicate.

NMO, a central nervous system disorder that primarily affects the optic nerve and the spinal cord, is caused by autoantibodies against the protein aquaporin 4 (AQP4) mediate NMO. These AQP4 antibodies (AQP4-Ab or NMO–IgG) lead to demyelination — the loss of the protective layer of nerve fibers, called myelin — and neuronal injury in NMO, which may also involve mild muscle disease.

Both MG and NMO are linked with other organ-specific and systemic autoimmune disorders. Accordingly, research shows that MG patients are at greater risk of having NMO.

The researchers aimed to create an animal model for both NMO and MG. They used the experimental autoimmune MG (EAMG) mouse model, given AChRs from the Torpedo californica electric ray, as well as NMO-IgG and an AQP4-derived peptide to induce MG and NMO.

Injection of either NMO-IgG or AQP4 peptide to both EAMG and healthy mice led to increased susceptibility to fatigue and aggravation of experimental MG symptoms. This was shown through increased muscle weakness, impaired response to repetitive nerve stimulation, increased neuromuscular jitter — which reflects irregular neuromuscular transmission — and disrupted immune responses.

Specifically, the scientists observed increased levels of MCP-1, IP-10, and CXCR3 proteins, which supports a key role for peripheral immune response in muscle weakness of EAMG mice, they said.

The observed exacerbation of MG in mice injected with either AQP4 peptide or NMO-IgG may be due to a systemic and/or local immune response, the authors suggested. The increased levels of the pro-inflammatory molecule IL-6 — which contributes to both NMO and MG — supports the relevance of a systemic immune response, they believe.

According to the researchers, the aggravated disease severity in mice with this approach “can explain exacerbation or increased susceptibility of patients with one autoimmune disease to develop additional autoimmune syndrome.”

“Our approach of inducing a second autoimmune disease in mice that already developed one autoimmune syndrome can have clinical and pathophysiological relevance,” they said.