Study: MuSK-Specific Antibodies Do Not Explain Variation in Serum IgG4 Levels in People With MuSK MG

People with muscle-specific kinase (MuSK) myasthenia gravis (MG) have slightly elevated levels of serum immunoglobulin G4 (IgG4), but the phenomenon does not appear to be the result of a predisposition to generate IgG4 responses, according to a new study.

The investigators said it thus remains unclear which immunological mechanisms lead to the apparent increase in IgG4 production in these patients. The study was published in the Journal of Neuroimmunology.

Corresponding author Maartje G. Huijbers, PhD, of the Leiden University Medical Center, in the Netherlands, and colleagues, noted that MG is an antibody-mediated autoimmune disease that in most cases involves antibodies interfering with receptors for acetylcholine at the neuromuscular junction. However, in some patients, the disease is caused by antibodies to other proteins, including MuSK.

The antigen-specific antibodies in antibody-mediated autoimmune diseases are often from a specific subclass of immunoglobulin G, of which there are 4, Huijbers and colleagues said.

“The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies,” they wrote.

However, MuSK MG is categorized as an IgG4 autoimmune disease, since the majority of pathogenic autoantibodies are of IgG subclass 4. That finding was surprising, the authors noted, given that IgG4 has anti-inflammatory characteristics. Yet, repeated studies have confirmed the observation.

“The predominant mechanism appears to be functional blocking of its antigen rather than antigenic modulation or complement activation common to IgG1-3 autoimmune diseases,” they wrote. “However, why these diseases are dominated by IgG4 autoantibody responses is unknown.”

Previous studies have found altered serum IgG levels in autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Huijbers and colleagues thus wondered whether people with MuSK MG might also have a general predisposition to generate IgG4 responses.

In order to find out, the investigators used nephelometric and turbidimetric assays to quantify serum immunoglobulin isotypes and IgG subclasses in patients with MuSK MG and AChR MG. The samples came from databases and biobanks in 5 countries, and were all from patients who either had never taken immunosuppressive treatment or who had been off the therapy for at least one year prior to the sample date. The investigators also compared serum IgG levels in the participants to those of healthy patients.

The results showed that both the patients with MuSK MG and those with AChR MG had higher levels of absolute serum IgG1, compared to healthy controls. Those with MuSK MG—but not those with AChR MG—had significantly higher levels of IgG4, though in most cases patients’ IgG4 serum levels still fell within the normal range.

The investigators said a correlation analysis suggested that MuSK-specific antibodies alone do not appear to explain the variation in IgG4 levels in these patients. Rather, they said it appears that patients with MuSK MG may have a more active antibody response in general.

“However, since circulating IgG4 levels fall within the normal range for most MuSK MG patients, it is unlikely that a predisposition to ubiquitously generate IgG4 responses causes the dominance of IgG4 antibodies targeting MuSK,” they wrote.

The authors said more research is needed to better understand IgG4-autoimmune diseases, but they also noted that such research is challenging in MG, because the research relies on patients who have not received treatment with immunosuppressive therapy.

Reference

Vergoossen DLE, Ruiter AM, Keene KR, et al. Enrichment of serum IgG4 in MuSK myasthenia gravis patients. J Neuroimmunol. 2022;373:577978. doi:10.1016/j.jneuroim.2022.577978