Blocking Immune Molecule IL-21 May Be Target as MPO-AAV Therapy
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.
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.
About the Author
