2 Pro-inflammatory T-cell Subsets Linked to Disease Severity in Study

Blood levels of two pro-inflammatory subsets of immune T-cells are abnormally low in people with myasthenia gravis (MG) who have antibodies against the acetylcholine receptor (AChR), a study shows.

The reduced levels of these cells were associated with their retention in a patient’s thymus — whose removal is a common MG therapeutic approach — supporting the organ’s role in disease-related abnormal immune attacks.

Notably, lower frequencies of both T-cell subsets were associated with high disease burden, and their numbers were restored in patients who underwent thymus removal surgery, highlighting their potential as biomarkers of disease severity.

These findings shed light on the underlying mechanisms of MG and suggest new potential biomarkers and therapeutic targets for the disorder. Larger studies are needed to confirm these results and to evaluate whether these immune changes are also observed in MG patients without anti-AChR antibodies, the researchers noted.

The study, “Single-cell profiling of myasthenia gravis identifies a pathogenic T cell signature,” was published in the journal Acta Neuropathologica and conducted by a team of researchers in Switzerland and the U.K.

In MG, the immune system produces self-reactive antibodies that mistakenly attack proteins involved in the communication between nerve cells and muscle cells, leading to muscle weakness and fatigue. AChR, which facilitates this communication, is the most frequent target in MG.

Despite their central role in MG, “AChR antibody levels do not correlate well with disease severity or treatment responses, highlighting our lack of knowledge of the underlying mechanisms of the disease,” the researchers wrote.

“There is clear evidence of the key role of the thymus in inducing and maintaining MG, and several studies have implicated specific [T-cell] populations besides antibody-producing B cells,” they added.

An organ critical to immune response, the thymus is thought to be the place where cells that drive MG-associated abnormal immune attacks reside and grow. As such, its surgical removal — a procedure called thymectomy — is a standard strategy for these patients, and was previously associated with durable benefits in the Phase 3 MGTX trial (NCT00294658).

“However, a comprehensive unbiased analysis of the immune cells involved in both the thymus and periphery [circulating blood] of MG patients is lacking,” the team wrote.

To address this knowledge gap, the researchers used state-of-the art cellular and molecular analysis technology, in combination with machine learning tools, to analyze immune cell subsets in blood and thymus samples from 38 MG patients who were positive for anti-AChR antibodies and 21 age- and sex-matched healthy individuals.

Machine learning is a type of artificial intelligence that uses algorithms to analyze data, learn from its analyses, and then make predictions.

By creating a comprehensive immune map of both groups, the team was able to identify two dysregulated subsets of circulating memory T helper (Th) cells: ThCD103 and ThGM.

Memory immune cells are long-lived cells, crucial to the immune system “remembering” microbes or foreign particles that the body was previously exposed to. In case of re-exposure, these cells quickly raise a highly specific immune response against the threat, or in the case of autoimmune diseases, molecules naturally present in the body.

These pro-inflammatory cells were found at low frequencies in the blood of all MG patients, but this reduction was particularly pronounced in those with higher disease burden. This highlighted a link between these cells — particularly ThCD103 cells producing the pro-inflammatory molecule TNF — and disease severity.

In contrast, the levels of anti-AChR antibodies in the blood — the routine blood biomarker for MG diagnosis — were not associated with disease severity.

The researchers then speculated the low number of these cells in the bloodstream of MG patients might be due to their retention in the inflamed thymus, which is known to harbor high numbers of self-reactive T-cells and antibody-producing B-cells.

Analysis of thymus samples revealed higher frequencies of ThCD103 and ThGM cells, as well as memory B-cells, in the diseased thymus, compared with healthy thymus, “supporting the concept of a well-defined local inflammatory process underlying autoimmunity in MG,” the researchers wrote.

Notably, ThCD103 cells were found at B-cell-rich regions of MG thymi, supporting the involvement of thymus-resident memory Th cells in the B-cell-driven abnormal attacks in MG. ThCD103 cells have been previously associated with poor outcomes or disease worsening in other chronic inflammatory conditions.

Further analyses showed that “both signature Th subsets rebounded in the blood of MG patients after surgical thymus removal, indicative of their role as cellular markers of disease activity,” the team wrote.

In addition, their blood levels were effectively reduced by long-term immunosuppression driven by treatment with azathioprine in MG patients.

These findings highlighted that “thymectomy abrogates the retention of inflammatory cells in the thymus thereby increasing signature Th cells in the blood, whereas azathioprine halts cell [growth] and triggers [cell death]” in immune cells, the researchers wrote.

As such, combining these approaches “removes [disease-associated] cells in the thymus and decreases Th signature cells in the circulation,” they added, noting that their combination was previously shown to promote a favorable clinical response, compared with thymectomy alone.

Overall, these findings suggest that therapeutic interventions targeting ThCD103 and ThGM cells may be beneficial in MG patients. The team noted that such a potential treatment, called etrolizumab, is currently in Phase 3 trials of ulcerative colitis, a type of inflammatory bowel disease.