Immune Checkpoint Molecules May Serve as Markers of AAV Activity
Blood levels of two proteins particularly high in patients with active disease
Blood levels of the soluble forms of CD28 and TIM-3 — two receptor proteins involved in the regulation of immune responses — are significantly associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) activity, a study showed.
The levels of these so-called immune checkpoint molecules were increased in people with active AAV relative to healthy controls and showed a reduction after immunosuppressive treatment.
In addition, the blood levels of other soluble immune checkpoint molecules were found to be altered in patients compared with healthy controls, supporting that an aberrant production may relate to AAV.
“Our results provide new insights into [immune checkpoint molecules’] potential [in disease-related immune] roles in AAV and offer novel biomarkers of disease activity in AAV,” the researchers wrote.
The study, “Soluble immune checkpoint molecules in patients with anti-neutrophil cytoplasmic antibody‐associated vasculitis,” was published in Scientific Reports.
Significantly higher blood levels of checkpoint molecules with active AAV
AAV is an autoimmune disease in which the immune system produces abnormal antibodies that target the body’s healthy cells and tissues. They excessively activate the immune system, causing inflammation and damage to small and medium-sized blood vessels.
Immune checkpoint molecules play a decisive role in maintaining the balance between immune stimulation and suppression. As such, dysregulation of this balance may disrupt immune self-tolerance and contribute to the development of autoimmunity.
Immune self-tolerance refers to the immune system’s ability to recognize the body’s healthy cells and tissues as “self,” and not mount immune attacks against them.
Immune checkpoint molecules exist in a membrane-bound form, at the surface of immune cells, or in a soluble form, circulating through the blood. While the roles of soluble immune checkpoint molecules remain mostly unclear, they have been found at abnormal levels in autoimmune diseases such as lupus.
“However, there has been no study clarifying the levels of the production of soluble forms of immune checkpoint molecules and determining their clinical roles in AAV patients to date,” the researchers, with Yonsei University College of Medicine in Seoul, South Korea, noted.
They investigated these soluble molecules as potential markers of AAV activity, comparing their levels in 56 people with an active and inactive AAV state — that before and after treatment — and 40 healthy adults, serving as controls.
Patients (26 women and 20 men) had a median age of 64.5 years. At study’s start, nearly two-thirds (73.2%) had been newly diagnosed with AAV, while 26.8% had relapsed after previous treatment.
They were given immunosuppressant therapies used to manage AAV, most commonly glucocorticoids, cyclophosphamide, and/or azathioprine.
Disease activity was assessed with the Birmingham Vasculitis Activity Score (BVAS), whose scores range from 0 to 63 with higher scores indicating greater disease activity.
At study’s start, when patients had active disease, they had a median BVAS score of 12, and that score dropped to 4 after treatment (inactive disease). The median time between patients’ active and inactive states was 13.5 months.
Eight of the 14 soluble immune checkpoint molecules measured, including soluble CD28 (sCD28) and TIM-3 (sTIM-3), were found at significantly higher levels in active AAV patients compared with healthy controls, while sCTLA-4 was found at significantly lower levels.
In addition, four of the eight soluble immune checkpoints found at significantly higher levels in patients with active disease — sCD28, sCD80, sTIM-3, and sCD27 — showed a significant reduction after treatment (inactive disease).
These results suggest these molecules may be have a role as surrogate markers or predictors of therapy benefit in AAV.
In addition, higher blood levels of sCD28, sTIM-3, and sPD-L1 significantly associated with higher BVAS scores and higher levels of blood markers of active disease.
“In conclusion, we demonstrated altered concentrations of [blood] soluble checkpoint molecules in patients with AAV, as well as a positive correlation between [blood] sCD28 and sTim-3 concentrations and disease activity,” the researchers wrote.
“sCD28 and sTIM-3 may act as surrogate markers of AAV disease activity,” they added.
Notably, these results are consistent with those of previous studies, where sCD28 and sTIM-3 concentrations were increased in people with lupus and related to disease activity.
“Based on these findings, we expected that soluble immune checkpoint molecules would be clinically useful if they could predict disease relapse or treatment failure,” the team wrote, adding that they may also help to understand the mechanisms behind AAV.
Further studies with people of other ethnicities are needed to confirm these findings, the scientists wrote. Future research should also focus on the mechanisms behind the altered levels of these soluble immune checkpoint molecules, and on whether previous treatment may have affected their levels.