New Hope for Lupus: Understanding How Immune Cells Go Wrong

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Systemic lupus erythematosus(SLE), or lupus, is a tricky illness that affects people in different ways. Some might have mild symptoms, like skin rashes or joint pain, while others experience much more serious, life-threatening problems. It's a disease where the body's immune system, which usually fights off infections, attacks its own tissues and organs. Scientists have been working hard to understand what goes wrong in lupus and how to help people who have it.

One of the things that makes lupus complicated is that many different things can contribute to it, including a person's genes and how their immune system works. It's also known that a protein called interferon (IFN) is often activated in lupus patients. While blocking interferon has been tried as a treatment, it doesn't work for everyone. This has led researchers to look deeper into the immune system to figure out other players involved in the disease.

Red blood cells and immune-responses

Recent research has uncovered that a specific type of red blood cell, one that still contains mitochondria (Mito+ RBCs), may be a key trigger for immune responses in lupus. Mitochondria are like tiny powerhouses inside cells, and they contain their own DNA and RNA. In people with lupus, these Mito+ red blood cells can be targeted by the immune system. When immune cells called monocytes encounter these targeted red blood cells, they start producing both interferon and another protein called interleukin-1b (IL-1b).

This is a significant finding because it shows that these immune cells, monocytes, can produce two key inflammatory proteins together. The production of interferon depends on the monocyte sensing mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA) from the red blood cells. This sets off a chain of reactions inside the monocyte.

A new way of releasing IL-1b

The research also discovered that IL-1b production is unusual in these monocytes. Normally, IL-1b is released from cells through a process called pyroptosis, which is a type of cell death. This process relies on a protein called gasdermin D (GSDMD). But in these lupus monocytes, the release of IL-1b happens without cell death and is not dependent on GSDMD.

Instead, it's been found that another protein called MxA plays a crucial role. MxA is produced when a cell is exposed to interferon. The scientists found that MxA helps to package the IL-1b into special compartments inside the cell, allowing it to be released. This is a new way of understanding how IL-1b is released and is independent of cell death pathways.

What happens in lupus patients?

To confirm these findings, researchers looked at blood samples from people with active lupus. They found that a specific type of monocyte, which expresses both IL-1b and MxA, was more common in those with active disease. They also noticed that the amount of these monocytes correlated with the severity of the lupus symptoms. This suggests that these monocytes are actively involved in the disease process.

Furthermore, they observed that in lupus patients with active disease, these monocytes were seen to have engulfed red blood cells. This process, called erythrophagocytosis, is another way to identify the monocytes associated with lupus. Some of these monocytes also had markers of erythrophagocytosis and were found to be producing both interferon and IL-1b.

Key points from the research:

  • Mito+ RBCs trigger immune responses: Red blood cells with mitochondria can activate monocytes, leading to the production of interferon and IL-1b.
  • Unusual IL-1b secretion: IL-1b is released without cell death, relying on the protein MxA.
  • Monocytes in active lupus: A specific type of monocyte that produces IL-1b and MxA is more common in people with active lupus.
  • Erythrophagocytosis: Monocytes that have engulfed red blood cells are also seen to express interferon and IL-1b.

Looking ahead

These findings offer valuable insights into the complex mechanisms that drive lupus. They suggest that targeting the MxA protein, or the processes that lead to its activation, could be a way to control the inflammatory responses in lupus. Also, figuring out how Mito+ red blood cells trigger these events is another key area for potential new treatments. Further research is needed to confirm if this pathway could be a target for new therapies for lupus and whether it can be used to track disease progression in patients.

This research highlights how a detailed look at specific immune cells and their interactions can uncover new pathways in the development of diseases like lupus. By better understanding these processes, scientists and clinicians can work to develop more effective and personalized treatments.

 

Journal information: Type I IFN drives unconventional IL-1β secretion in lupus monocytes. Immunity (2024).  https://doi.org/10.1016/j.immuni.2024.09.004

Additional information: https://www.cell.com/immunity/home

Location: Oxford, UK

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