Interactions between 2 immune cell types may drive IgG4-RD activity: Study
Newly identified immune-related axis could be a potential treatment target
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Interactions between two specific subsets of immune cells may contribute to disease activity in people with immunoglobulin G4-related disease (IgG4-RD), according to a new study.
Researchers speculated that this newly identified immune-related axis could be a potential target for new IgG4-RD treatments.
The study, “Extrafollicular [Tph2–CD11c-positive, CD21-negative] B cell interactions orchestrate immune dysregulation in IgG4-related disease,” was published in Allergology International.
Cause of IgG4-RD remains unclear
IgG4-RD is an immune disorder marked by the infiltration of immune cells into tissues, particularly plasma cells that produce IgG4, a type of antibody. This results in the formation of tumor-like lesions and tissue enlargement that can affect an organ’s function. However, the cause of IgG4-RD remains unclear.
There are many different types of immune cells, each with highly specialized jobs. Less than a decade ago, researchers identified a specific group of immune cells, T peripheral helper (Tph) cells, which can be further classified into several subtypes.
Tph cells have been shown to play key roles in activating immune B-cells, which can turn into plasma cells. Emerging data suggest that some Tph cell subtypes may be involved in immune-related diseases, but much remains unknown about this group of immune cells.
To explore the potential role of Tph cells in IgG4-RD, scientists in Japan analyzed immune cell levels in blood samples from 68 people with IgG4-RD and 31 people without the disease.
“We focused on Tph cell subsets to clarify their role in the [development] of IgG4-RD,” the researchers wrote.
IgG4-RD patients with higher Tph2 cell counts had more severe disease
Results showed that IgG4-RD patients generally had elevated Tph cell counts, as well as higher levels of Tph cells positive for markers of inflammatory activation. More granular analyses revealed that this increase was mainly driven by substantial increases in the number of a specific Tph cell subtype, Tph2.
Further analyses in the IgG4-RD group demonstrated that higher Tph2 counts were significantly associated with higher numbers of plasmablasts, short-lived antibody-producing versions of plasma cells, and higher levels of IgG4.
Blood levels of Tph2, as well as IgG4, strongly decreased following treatment with glucocorticoids, a class of anti-inflammatory medicines commonly used off-label to treat IgG4-RD.
IgG4-RD patients with higher Tph2 cell counts also had significantly more severe disease, as measured by the IgG4-RD Responder Index, more organs affected, and higher levels of biomarkers of T-cell activation.
“These findings suggest that circulating Tph2 cells are closely linked with key clinical parameters reflecting disease activity and [antibody] dysregulation in IgG4-RD,” the researchers wrote. “Thus, they may serve as potential biomarkers of disease burden.”
Tph2 cells are thought to interact specifically with age-associated B-cells, a subset of B-cells that expand with age, chronic infection, and autoimmunity. They are characterized by the presence of the CD11c protein and the absence of the CD21 protein on their surface.
We identified a distinct immunological axis in IgG4-RD characterized by the coordinated expansion of Tph2 cells and [age-associated B-cells]. This immunological axis may be a key driver of disease activity and a target for future therapies.
The researchers found that IgG4-RD patients had a significantly higher proportion of B-cells belonging to this specific subgroup, and higher levels of these age-associated B cells were significantly associated with a greater number of organs involved and higher levels of IgG4 and T-cell activation biomarkers.
“These results imply that [age-associated B-cells] are significantly associated with important immunological and clinical parameters in IgG4-RD and could contribute to the development of the disease,” the researchers wrote.
Additional analyses showed that higher blood counts of Tph2 cells were significantly associated with higher numbers of circulating age-associated B cells. And both of these cells were found at higher levels in affected tissue from IgG4-RD patients.
Based on these data, the researchers speculated that these two cell types may interact to help drive disease activity in IgG4-RD.
Further supporting this idea, the researchers found that the frequency of IgG4-producing B-cells was highest when they grew Tph cells and age-associated B-cells together. Milder effects were observed when Tph cells were grown with other types of B-cells, and when age-associated B-cells were grown with other types of T-cells.
“We identified a distinct immunological axis in IgG4-RD characterized by the coordinated expansion of Tph2 cells and [age-associated B-cells],” the researchers wrote. “This immunological axis may be a key driver of disease activity and a target for future therapies.”
