Overactive immune system pathway may help drive GPA: Study
Researchers identify it as potential therapeutic target
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Certain T-cells may show excessive activity in a signaling pathway called STAT3-PIM1 in people with granulomatosis with polyangiitis (GPA) who test positive for antibodies against proteinase 3 (PR3-GPA), according to a new study.
Researchers aimed to identify unique activity patterns in T-cells containing the CD4 protein marker (CD4+ T-cells), a group of immune cells that help drive inflammation in PR3-GPA and other types of ANCA-associated vasculitis. The research team hypothesized that STAT3-PIM1 signaling might contribute to the development of the condition. They also observed that a subset of cells, called effector memory T-cells, continued to exhibit excessive signaling even during remission.
“Collectively, these findings implicate the STAT3-PIM1 axis as a mediator of CD4+ T-cell-driven inflammation in PR3-GPA and highlight this pathway as a potential therapeutic target,” researchers wrote.
The study, “Single-cell multiomics reveals activation of the STAT3–PIM1 axis in T-cell subsets in proteinase 3-ANCA–positive granulomatosis with polyangiitis,” was published in Annals of the Rheumatic Diseases.
Detailed characterization of CD4+ T cells in PR3-GPA is still limited
In ANCA vasculitis, self-reactive antibodies trigger misguided immune attacks that can cause inflammation and damage to small blood vessels, leading to a wide array of symptoms throughout the body.
GPA is a type of ANCA vasculitis that often involves vessels in the lungs, kidneys, and upper respiratory tract. For most people with GPA, the disease-causing antibodies target a protein called PR3.
Although studies have shown a higher frequency of activated CD4+ T cells in people with GPA compared with healthy individuals, detailed characterization of these cells in PR3-GPA remains limited.
“In this study, we aimed to characterise the molecular signatures of CD4+ T cells in PR3-GPA during both active disease and remission,” the researchers wrote.
To do this, they examined T-cells from people with active PR3-GPA, meaning they had ongoing symptoms. The team compared these to T-cells from people in PR3-GPA remission (disease under control) and from control participants.
Compared with controls, participants with active PR3-GPA showed higher gene activity in the STAT3-PIM1 signaling pathway, which helps activate CD4+ T-cells. Overly active genes included STAT3, PIM1, and SOCS3.
Notably, effector memory T-cells, specialized T-cells that defend against previously encountered invaders, continued to have elevated PIM1 activity in disease remission. This was not the case for other types of CD4+ T-cells. Effector memory T-cells also didn’t show elevated SOCS3 or STAT3 activity.
“This aligns with prior reports of persistent T-cell activation during remission, suggesting that sustained PIM1 expression may reflect ongoing immune activity,” the researchers wrote.
Elevated signaling observed across 4 key components of the pathway
Supporting these findings, kidney tissue from a separate group of people with PR3-GPA also showed higher STAT3 and PIM gene activity in regions with inflammation.
To further probe the relationship between STAT3-PIM1 signaling and active PR3-GPA disease, the team analyzed participants’ blood for inflammatory molecules called cytokines.
Blood levels of cytokines, predominantly those involved in regulating PIM1 gene activity, were higher in participants with active PR3-GPA than in controls. Some differences were also observed between active disease and remission, including a cytokine called IL-6.
This provided evidence for elevated signaling across four key components of the signaling pathway — IL-6, STAT3, PIM1, and SOCS3.
“From a translational perspective, several therapeutic strategies could be considered to target this signalling axis,” the team wrote. These could include Pim inhibitors, which target the proteins produced by PIM1 and related genes.
The researchers exposed T-cells from each participant group to two types of Pim inhibitors. In active disease participants, both Pim inhibitors reduced the proportion of CD4+ T-cells that were activated. In both active disease and remission participants, the Pim inhibitors also decreased the rate of T-cell growth.
This finding supports the theory that Pim inhibition may suppress PR3-GPA disease activity and control inflammation. However, the researchers stressed that further studies are needed to understand the molecular underpinnings of this disease.
“Our data do not indicate that this pathway is exclusively responsible, and other cytokines and signalling pathways … may also contribute,” they wrote.
Future studies could also continue to investigate STAT3-PIM1 signaling as a therapeutic target. They could also dig deeper into the potential significance of STAT3-PM1 during remission.
“Longitudinal studies are warranted to determine whether PIM1 may serve as a biomarker of immune persistence or relapse risk,” the team wrote.
