Lupus Study Points to Faulty Immune Signaling, Leading to Lack of Regulatory B-cells, as Driver of Inflammation

Lupus Study Points to Faulty Immune Signaling, Leading to Lack of Regulatory B-cells, as Driver of Inflammation
regulatory B-cells

The excessive inflammatory response that is characteristic of systemic lupus erythematosus (SLE) has now been shown by scientists at University College London to be caused by altered signaling between different kinds of immune cells — leading to a lack of production of regulatory B-cells to control immune responses.

The team studied three different immune cells that normally affect each other’s function: antibody-producing B-cells, contributing with lupus autoantibodies; plasmacytoid dendritic cells that produce IFN-α, a molecule stimulating B-cells; and regulatory B-cells that suppress excessive immune responses. Researchers isolated the cells from lupus patients’ blood and studied cell signaling in the laboratory.

Researchers were previously not aware of the signals that drive the production of the regulatory cells. In healthy individuals, immature B-cells grow into regulatory B-cells when stimulated by IFN-α. The regulatory cells then work to limit IFN-α production by releasing other factors. This study revealed that in lupus, plasmacytoid dendritic cells promote the production of antibody producing cells but fail to induce the production of regulatory cells.

“Our study shows for the first time that the overproduction of IFN-a by hyperactivated plasmacytoid dendritic cells in lupus patients is the consequence of the lack of suppressive regulatory B cells,” the study’s senior author, Claudia Mauri, an immunologist at University College, said in a press release. “The uncontrolled production of IFN-α causes an increase of antibody-producing B cells and suppresses the division and appearance of regulatory B-cells.”

The study, A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus published in the journal Immunity, also identified a potential reason why some patients react well to rituximab while others do not. Rituximab, which works by depleting most of the circulating B-cells, has been used off-label for the treatment of lupus, but the varying results have confused researchers.

By studying the immune cells and gene expression from 200 lupus patients and 100 healthy individuals, the team noted that the response to rituximab was linked to IFN-α-related gene activity. “After treatment, newly formed B cells come back into circulation,” said Madhvi Menon, the study’s lead author and a postdoctoral fellow in Dr. Mauri’s lab. “Our study suggests that response to rituximab is determined by the presence or absence of an elevated IFN-α-related gene activity. Thus, only in patients that have a normal IIFN-α signature do the newly repopulated B cells successfully mature into regulatory B cells.”

This finding indicates that if rituximab treatment is considered, lupus patients should first be tested for this IFN-α-related gene signature. “This would be an important step towards personalized medicine for the treatment of lupus,” Dr. Mauri concluded.

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