Scientists identify potential blood-based biomarkers of IgG4-RD severity
Study researchers call for larger trials to validate their ability to track disease
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In a proof-of-concept study, a team of scientists in Spain has identified a range of blood markers related to immune responses that may help to track disease activity in people with IgG4-related disease (IgG4-RD).
“In this prospective longitudinal study of [untreated] patients with IgG4-RD, [statistical] models identified exploratory associations between clinical activity measures and selected [blood-based] immune signatures,” researchers wrote.
They emphasized, however, that “given the proof-of-concept design, the small sample size, and the absence of a control group, these findings should be interpreted as hypothesis-generating signals intended to inform future validation studies, rather than as established immune signatures.”
The study, “Proof-of-concept study: longitudinal immune biomarker signatures in treatment-naïve IgG4-related disease,” was published in Scientific Reports.
IgG4 antibodies are noy very useful in tracking IgG4-RD severity
IgG4-RD is an immune-mediated inflammatory disorder marked by the formation of abnormal clumps of immune cells — particularly B-cells producing a specific type of antibody called IgG4 — in tissues. These clumps can lead to inflammation and scarring.
Although IgG4-RD is defined by cells that make IgG4, levels of this type of antibody aren’t closely associated with disease severity. Indeed, many people with IgG4-RD have normal levels of IgG4 antibodies.
Because IgG4 antibodies themselves are not very useful as an objective measure to track IgG4-RD severity, the scientists wanted to explore whether other immune-related molecules might serve as better markers of disease activity.
To that end, they measured levels of several cytokines (immune signaling molecules) in blood samples from 10 people with IgG4-RD before they received any treatment and about a year after starting glucocorticoids, the standard first-line treatment for IgG4-RD.
The researchers then used statistical analyses to look for associations between these blood markers and markers of disease activity.
“Our aim was to explore whether circulating immunological signatures, including selected cytokines …, show longitudinal patterns and activity-associated signals that may complement conventional biomarkers in the monitoring of IgG4-RD,” the team wrote.
Levels of some cytokines fell after 1 year of treatment
Participants’ median age was 75.7 years, 70% were men, and most (60%) had disease involvement of the retroperitoneum — the area in the back of the abdomen where several tissues and organs are located, including the kidneys and the aorta (the largest blood vessel in the body).
Results showed that higher scores on the IgG4-RD Responder Index (RI), a measure of disease severity, were significantly associated with higher blood levels of several cytokines, including interferon-gamma (IFN-gamma), interleukin-10 (IL-10), IL-5, and IL-13.
Higher RI scores also showed significant associations with higher total levels of IgG antibodies (a broader antibody class that includes IgG4) and elevated counts of immune cells called eosinophils.
Several studies have linked IgG4-RD with an abnormal type 2 immune response, which involves eosinophils and other cells associated with allergic reactions and the fight of parasitic infections. Previous research suggested that high eosinophil counts can predict relapse risk in IgG4-RD.
Data at about a year after participants started glucocorticoids demonstrated significant reductions in the levels of IgG4, as well as IL-4 and IL-21.
IL-21 is a key cytokine supporting B-cell maturation and antibody production, “and its levels have been shown to correlate with [blood] IgG4 and disease activity in IgG4-RD,” the researchers wrote.
Also, IL-4 is known to drive type 2 immune responses, and “the decreases in IgG4 and IL-4 are directionally consistent with treatment-associated changes in [type 2 immunity pathways],” they added.
“Longitudinal decreases in IgG4, IL-4, and IL-21, together with … associations between RI and [IFN-gamma], IL-10, IL-5, IL-13, total IgG, and blood eosinophil count, suggest that immune-based profiles may provide information complementary to conventional [antibody tests],” the researchers wrote.
Because the analysis was limited to a small number of patients and was not adjusted for potential influencing factors, larger studies with adjusted analysis “are required to validate these candidate immune signatures and to determine whether they may contribute to multimodal monitoring of IgG4-RD,” they concluded.
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