Tfh Cell Protein Fragments May Be Potential Biomarkers

Immune T follicular helper cells also may have therapeutic value

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Adults with myasthenia gravis (MG) have elevated levels of protein fragments released from T follicular helper (Tfh) cells — an immune cell type involved in the development of autoimmune conditions — in their bloodstream, a study reported.

According to researchers, these results suggest that molecules associated with Tfh cells participate in the development of MG and represent potential disease biomarkers or therapeutic targets.

The study, “Role of soluble forms of follicular helper T-cell membrane molecules in the pathogenesis of myasthenia gravis,” was published in the Journal of Neuroimmunology.

In MG, self-reactive antibodies, called autoantibodies, target and damage components of the neuromuscular junction — the place where nerve endings communicate with muscle cells. About 80% of MG patients have autoantibodies against the acetylcholine receptor (AChR), a key molecule in nerve-muscle communication.

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Tfh cells are a subset of immune T-cells found in secondary lymphoid organs, including the tonsils, spleen, and lymph nodes, that direct the function of antibody-producing B-cells. Tfh cells also are known to play an essential role in the development of autoimmune diseases, including MG, by influencing the production of autoantibodies.

Like all cells, Tfh cells have a characteristic pattern of proteins on their surface. Fragments of these proteins can detach from cell membranes and end up in the bloodstream as water-soluble molecules.

Although several studies have demonstrated a relationship between these water-soluble forms of cell membrane molecules and MG development, “no study has measured the serum levels of several soluble molecules simultaneously and analyzed their relationships,” the researchers wrote.

The research team, based at Chiba University in Japan, reviewed the medical records of 39 adults with generalized MG who tested positive for anti-AChR antibodies, of whom 23 (59%) were women. Among them, nine (23%) had early-onset MG, 21 (54%) had late-onset MG, and nine (23%) had a form of MG associated with a tumor in the thymus (thymoma).

Using participants’ stored blood samples collected before they started immunosuppressant treatment, the team measured the levels of several fragments of molecules found on Tfh cells, including PD-1, PD-L1, ICOS, ICOSLG, and CTLA4. Interleukin-21 (IL-21), an immune signaling protein released by Tfh cells to guide B-cell function, also was measured. Blood samples from 27 sex- and age-matched patients with non-inflammatory conditions were analyzed as controls.

More PD-1 fragments in the blood

Analyses revealed that MG patients had significantly more PD-1 fragments in their bloodstream compared with controls (median of 332 vs. 285 picograms per milliliter (pg/mL) of blood). Similar results were seen for IL-21 (median of 30.8 vs. 19.2 pg/mL). Levels of the other proteins tested did not differ between the two groups.

“IL-21 was increased in the MG group and could be a potential therapeutic target because of ability to activate Tfh,” the researchers noted.

Correlation analyses found significant relationships between PD-1 levels and those of IL-21, ICOSLG, CTLA4, and AChR antibodies, “suggesting that [PD-1] is a key player in the molecular interactions underlying MG,” the team wrote.

ICOS correlated with IL-21, AChR antibodies, and MG activities of daily living (MG-ADL) assessment scores, indicating its potential as a biomarker of disease activity, the team noted.

ICOSLG level was significantly higher in patients with late-onset MG than in those with early-onset disease (4.2 vs. 3.3 nanograms per milliliter (ng/mL) of blood), but there was no difference between late-onset patients and controls.

Blood samples were available for 12 patients following immunosuppressive treatment. During follow-up, median MG-ADL score dropped (improved) from 10 to 2, and median levels of anti-AChR antibodies fell from 40.5 to 11 nanomoles per liter (nmol/L) of blood.

Levels of PD-L1 and CTLA4 rose significantly after treatment. In contrast, PD-1 levels fell, but the difference was not statistically significant, and no correlation between PD-1 levels and treatment effectiveness was found. Treatment had no impact on the other Tfh cell proteins.

Because immune-suppressing treatments increased the numbers of anti-inflammatory T-regulatory cells, “our results may be due to an increase in CTLA4 expression on regulatory T cells,” the team wrote.

“Further analysis of their relationship with membrane-expressed molecules and T cell and B cell profiles is required to reveal the relationship between these soluble molecules, MG pathogenesis [development], and disease activity,” the team wrote.