TRAF6, Tied to Inflammation in MG, at High Levels in Immune B-Cells

Protein level rise particularly noted in generalized MG and with disease activity

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Levels of the tumor necrosis factor receptor-associated factor 6 (TRAF6) protein in immune B-cells are higher than normal in people with myasthenia gravis (MG), and may be a useful biomarker of inflammation in MG, a study suggested.

The observed elevations were more pronounced among patients with generalized MG (gMG) than in those with ocular MG, particularly during periods of acute symptom worsening, during which they correlated with measures of disease severity. In a subset of MG patients followed pre- and post-treatment, TRAF6 levels declined with therapy.

Findings were detailed in the study “Expression of TRAF6 in peripheral blood B cells of patients with myasthenia gravis,” published in the journal BMC Neurology.

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The autoimmune attacks that characterize MG are known to be mediated by a class of immune cells called B-cells. These immune cells are responsible for producing the self-reactive antibodies that disrupt nerve-muscle communication in MG.

TRAF6 is involved in signaling pathways that promote inflammation in the body. It acts to trigger certain inflammatory molecules that can then boost B-cell activation. TRAF6 has been found at higher than normal levels in the blood of people with MG and other autoimmune conditions, including systemic lupus erythematosus and rheumatoid arthritis.

TRAF6 blood levels climb during acute MG attacks

Data also suggest that the source of this increased TRAF6 in MG patients are peripheral blood mononuclear cells, a term which encompasses a number of different immune cells, including B-cells.

Researchers in China aimed to investigate whether TRAF6 levels were specifically altered in the B-cells of MG patients relative to a control, or comparison, group of healthy people, and whether these levels linked with MG type and severity.

A total of 89 MG patients — 44 males and 45 females, with a mean age of 58.3 — were recruited from the Tianjin Medical University General Hospital between November 2020 and October 2021. An additional 43 controls, matched for age and sex to the MG group, were included in the analysis.

Of the total patient group, 38 had ocular MG, a disease type typically localized to the muscles controlling eye and eyelid movements. The other 51 had gMG, generally considered a more severe disease form affecting muscle groups throughout the body.

At study entry, 47 patients had achieved a minimal manifestation state (MMS), or the near-absence of symptoms following MG treatment with steroids, immunoglobulins, and/or immunosuppressants, the study noted. The other 42 patients were experiencing acute attacks and had not yet been given immunosuppressive therapy.

Overall, MG patients had a higher proportion of B-cells expressing, or producing, TRAF6 compared with healthy controls. This included a higher overall proportion of B-cells, but also of memory B-cells — those that have been trained to launch an immune response against what it perceives to be a threat.

These observed differences were greater among the 51 gMG patients compared with the ocular MG group.

Similarly, among the 42 patients with acute disease activity, TRAF6 levels were higher in those with gMG than ocular MG. These levels were also significantly higher in gMG patients during an acute attack than in gMG patients with MMS.

No differences were evident between gMG and ocular MG patients who had achieved MMS. However, blood levels of TRAF6 were elevated in all MG patients, regardless of disease type, relative to healthy people.

TRAF6 levels were also evaluated in the 11 patients followed before and after immunosuppressive treatment for an acute attack. It was observed that this protein’s blood levels fell significantly in both B-cell populations after treatment.

Since this observation was made in a limited patient group, researchers noted that “whether the effect of immunosuppressive therapy on TRAF6 is directly related to MG regression will require further study.”

Increasing TRAF6 levels in both types of B-cells positively correlated with disease severity, as measured by the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale, and held for both ocular MG and gMG patients experiencing an acute attack.

Study findings suggest that TRAF6 “may be a useful biomarker of disease subtype,” and “an indicator for predicting disease severity,” the researchers wrote.

They also noted that TRAF6 could potentially be leveraged as a marker of inflammation and treatment effectiveness in MG patients, and may itself be “a potential therapeutic target in MG.”