Blocking Immune Molecule IL-21 May Be Target as MPO-AAV Therapy

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Levels of the immune signaling molecule interleukin-21 (IL-21) and the cells that produce the protein were elevated in the blood of people with ANCA-associated vasculitis (AAV) with myeloperoxidase (MPO) antibodies, a study found.

IL-21 levels also were linked to higher MPO levels and disease activity, suggesting its direct involvement in disease progression, researchers said.

“Blocking IL-21 activity may represent a novel potential target for the future treatment of MPO-AAV,” the researchers wrote, noting that “the level of IL-21 in the patient group was significantly higher than that in the healthy control group.”

The study, “Elevated Level of Serum Interleukin-21 and Its Influence on Disease Activity in Anti-Neutrophil Cytoplasmic Antibodies Against Myeloperoxidase-Associated Vasculitis,” was published in the Journal of Interferon & Cytokine Research

AAV is caused by self-reactive autoantibodies called ANCAs — anti-neutrophil cytoplasmic autoantibodies — that lead to aberrant immune responses in the body. Simply put, such autoantibodies mistakenly target the body’s own tissues or organs.

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There are different types of ANCAs that contribute to AAV, most commonly MPO or proteinase 3 (PR3), with each leading to distinct disease manifestations.

AAV associated with MPO (MPO–AAV)  is the most common AAV type in China and other East Asian countries, predominantly affecting middle-aged or elderly people. This AAV type can rapidly progress to cause severe, life-threatening complications.

Interleukin-21, commonly called IL-21, is a multifunctional immune system molecule that has been proposed as a biomarker of disease activity in AAV; its presence in the bloodstream has been linked to more active AAV symptoms. Produced by certain subsets of immune cells, IL-21 helps to enhance their development and increase autoantibody production.

But whether IL-21 plays a specific role in MPO-AAV was not previously known.

Now, researchers examined IL-21 levels in 42 people with MPO-AAV. All were seen at a clinic in China between March 2017 and February 2o2o. A group of 42 healthy people, comprised of 22 women and 20 men, served as controls.

The vasculitis patients — 24 women and 18 men — had a mean age of 65.9, while the mean age of the healthy controls was 63.07.

Among the patients, 41 had a diagnosis of microscopic polyangiitis (MPA), which is more commonly associated with MPO antibodies. One person had granulomatosis with polyangiitis (GPA), a condition usually marked by PR3-ANCAs.

Kidneys (88%), lungs (88%), and joints (83.3%) were the organs and tissues primarily affected by AAV. The patients had a mean disease duration of three months, and none had ever been treated with glucocorticoids or immunosuppressive agents.

Blood samples were analyzed for the presence of interleukin-21 and biomarkers of follicular helper T-cells (Tfh), a subset of immune cells that predominately produce IL-21 and are known to play a role in autoimmunity.

Significantly higher levels of IL-21 and Tfh cells were found in the patients’ blood as compared with the healthy controls. Patient Tfh cells also contained more ICOS and PD-1 proteins than those of the healthy people. ICOS is a protein that increases interleukin-21 production in Tfh cells, and serves as a biomarker of Tfh activation. In contrast, PD-1 regulates some Tfh activities, and serves as a biomarker of Tfh suppression.

Further analyses revealed the ratio of ICOS to PD-1 was higher in patients compared with healthy people, suggesting an imbalance in Tfh activation in the context of AAV.

Among patients, IL-21 levels were positively correlated with some clinical features. Specifically, higher interleukin-21 levels were linked to more Tfh cells, more ICOS and PD-1, and higher MPO levels.

Further, increased levels of the molecule were associated with elevations in c-reactive protein, an inflammatory marker, and erythrocyte sedimentation rate, another indicator of inflammation. Scores on the Birmingham Vasculitis Activity Scale (BVAS) — a measure of disease activity — were similarly linked to IL-21 elevations.

Statistical analyses also showed that IL-21 was independently associated with both MPO levels and BVAS scores.

“We speculate that the increased level of IL-21 in patients with MPO-AAV may promote Tfh activity,” the researchers wrote, adding that the Tfh cells may in turn promote the maturation of B-cells. B-cells are an immune cell type that produces MPO-ANCAs, thus leading to increased disease activity.

“IL-21 might also affect MPO-ANCA levels and disease activity through other mechanisms. Thus, further research into such potential mechanisms should be explored,” the team wrote.