The role of ABCs in lupus: insights for developing precision therapies

The immune system is a complex network of cells and molecules that work together to protect the body from foreign invaders, such as bacteria and viruses. One important component of this system is B cells, which produce antibodies that can recognise and neutralise these threats. However, in autoimmune disorders like lupus, B cells mistakenly attack the body’s own tissues, leading to chronic inflammation and damage to organs such as the kidneys, lungs, and skin.

A distinctive characteristic of lupus is the presence of high levels of autoantibodies, which bind to the body’s own DNA or RNA. This leads to constant activation of the immune system, causing ongoing inflammation and tissue damage. Existing therapies that target B cells can be effective in some lupus patients, but they also compromise the immune system’s ability to fight infections, highlighting the need for more targeted approaches.

Researchers from the University of Pittsburgh, US, have now identified a specific type of B cell, called age-associated B cells or ABCs, as a key driver of lupus. The team showed that targeting these cells in a mouse model reduced the severity of the disease, suggesting a potential avenue for new therapies.

In the study published in the Journal of Experimental Medicine, the researchers found that ABCs were particularly prone to producing autoantibodies and promoting inflammation in lupus. By targeting these cells specifically, they were able to reduce the levels of autoantibodies and decrease disease severity in mice. While more research is needed to determine whether this approach will be effective in humans, the findings suggest that targeting ABCs could be a promising strategy for treating lupus without compromising the immune system’s ability to fight infections.

“A hallmark of lupus is high levels of autoantibodies that bind to a patient’s own DNA or RNA,” said lead author Dr Kevin Nickerson, Research Assistant professor in Pitt’s Department of Immunology.
“Because these genetic materials are never eliminated from the body, the immune system is continually reactivated, leading to inflammation that, over time, causes a great deal of damage to the patient’s body.”

According to Nickerson, existing therapies that broadly target B cells can be effective in some lupus patients, but because they also impair B cells that produce infection-fighting antibodies, these treatments can compromise immunity, suggesting a need for more narrowly focused approaches.

Nickerson, senior author Dr Mark Shlomchik and their team set out to better understand the role of ABCs in lupus. Nickerson explains the study’s findings and what they could mean for the future of lupus treatments.

What are age-associated B cells?

Age-associated B cells, or ABCs, are a sub-category of B cell that were first identified as being more frequent in older individuals than younger individuals. It quickly became apparent to researchers that these cells are also found in greater numbers in patients with certain autoimmune diseases, including lupus, and during certain chronic infections such as malaria and HIV. These and other findings led researchers to propose that ABCs are a type of immune memory cell that form during some types of chronic inflammatory immune responses. They might accumulate very slowly over a healthy individual’s entire lifetime, or much more rapidly in a younger patient with lupus.

What motivated this study?

Previous research had shown that higher numbers of ABCs in a lupus patient’s blood often correlated with the severity of their symptoms, particularly lupus nephritis (kidney disease). ABCs were thought to be autoimmune memory B cells that develop into cells that make lupus autoantibodies. In this study, we set out to test whether ABCs were indeed a driver of lupus disease. Using a pre-clinical mouse model of lupus, we examined ABCs in great detail, studied their relationship to other types of B cells and genetically depleted these cells right after they are formed to see what effect they have on disease.

What were your main findings?

Our most important finding was that reducing the number of ABCs by eliminating them as soon as form slowed or reduced disease progression in the kidneys in mice, directly demonstrating that ABCs drive disease in this lupus model.  We also found that ABCs are a more diverse subset of B cells than previously known, which could suggest that they have different functions or that multiple pathways are involved in their formation.

We also demonstrated that ABCs are indeed a direct precursor to the cells that make lupus autoantibodies. Although they resemble anti-pathogen memory B cells in some respects, they seem to undergo continual cycles of reactivation, proliferation and differentiation. This makes sense because the DNA and RNA to which they respond are always present, so they ca not fully enter a resting state, unlike the memory response in B cells that recognise pathogens, which are eventually eliminated.

What are the implications of these findings and what do they tell you about potential therapies for lupus?

Several lupus therapeutics in the clinic today aim to reduce B cell numbers by directly killing them or by blocking the factors necessary for their survival. However, these currently available therapies are nonspecific, meaning that they affect all B cells, whether those B cells are autoreactive or directed against pathogens. While depleting all B cells prevents lupus progression and organ damage, it significantly impairs a patient’s ability to respond to infections.

If ABCs are the pathogenic population of B cells in lupus, as our study suggests, then narrowly targeted therapies that focus on eliminating these “bad” cells, while sparing “good” B cells, could be beneficial. To do this, we need a more complete understanding of ABCs and where they come from to help design the best approaches. Our study contributes to this understanding.

What are the next steps for this research?

An important unresolved question is what makes ABCs so pathogenic? And how are they actually promoting disease? One part of that could be their role in making autoantibodies, but we have reason to believe that ABCs could also activate the T cell arm of the immune system in lupus. Autoreactive T cells, when activated, infiltrate organs and tissues from the bloodstream, causing injury by damaging cells and disrupting normal organ function. We want to know if ABCs are directly promoting this pathogenic process and if they are also found within the inflamed tissues at the sites of damage.  In addition, we want to develop methods to deplete ABCs during ongoing disease in a pre-clinical model to determine if and how that could slow down or treat disease.