Investigating the potential cellular effects of C-reactive protein

The biological function of the C-reactive protein, CRP, has long been unidentified. Investigators at LiU have discovered that this protein has a useful function in the inflammatory disease systemic lupus erythematosus or SLE. According to the research, this is only true for one of CRP’s two forms.

Investigating the potential cellular effects of C-reactive protein
Christopher Sjöwall. Image Credit: Magnus Johansson

Most people would have had a CRP blood test on multiple occasions. This is a routine health care test that is used to identify infection or systemic inflammation in the body. The level of C-reactive protein, or CRP for short, is evaluated.

CRP is an ancient protein and similar proteins can be found in all animals, even in primitive organisms. When a protein has been so well preserved throughout evolution, this usually means that it has an important function. CRP is used a lot in clinical care as a marker of ongoing inflammation, but few have studied its biological effects.”

Christopher Sjöwall, Senior Associate Professor, Department of Biomedical and Clinical Sciences, Linköping University

Christopher Sjöwall is also a consultant at Reumatologiska kliniken (Rheumatology Clinic) in Östergötland.

The body attacks itself

Christopher Sjöwall has spent several years studying the chronic inflammatory disease systemic lupus erythematosus, or SLE. To put it simply, this is a disease in which the body’s immune system begins to react to one’s own body, also known as an autoimmune disease.

One such reaction is the creation of antibodies that target endogenous constituents, known as autoantibodies. However, when inflammatory activity in the body is high in SLE patients, CRP levels are lower than anticipated. Previous research on animals with Lupus-prone disease has shown that adding CRP may result in milder disease and lower autoantibody levels, implying that CRP may also play a beneficial role in human SLE, though the reason for this is unknown.

A signaling protein known as type I interferon is a key player in SLE. Interferon is generally a vital part of the body’s defense against infections. Interferon levels rise quickly in the first hours after infection and slow it down by, for example, making virus replication more difficult. Interferon levels should gradually decrease. However, in some diseases, such as SLE, the interferon stays in the system for too long, causing damage.

We have shown a mechanism that is likely quite important, where the relative lack of CRP in SLE patients with high disease activity leads to high interferon activity.”

Christopher Sjöwall, Senior Associate Professor, Department of Biomedical and Clinical Sciences, Linköping University

The researchers investigated the effect of CRP and SLE-specific immune complexes formed by autoantibodies reacting with dead cell material on interferon and other signaling proteins in their research.

Researchers investigated what occurred when serum from SLE patients with differing levels of CRP was mixed with healthy cells. They discovered that when CRP levels were low, there was more interferon than when they were high, which they interpret as CRP contributing to a reduction in an interferon response.

A matter of shape

It was also discovered that the shape of CRP is significant, which the Linköping researchers were the first to demonstrate. The protein is made up of five identical units (pentamer shape) that can split and work independently (monomer shape). The scientists found that only the pentamer shape CRP decreases interferon activity.

The finding that the pentamer shape of CRP can suppress the immune response is interesting also in the context of other diseases, such as various virus diseases.”

Marie Larsson, Professor, Virology, Linköping University

These observations pave the way for future research into medicines to decrease immune complexes and high interferon levels. However, because interferon is important in the body’s defense against infections, treating SLE and similar diseases is a constant balancing act, and more investigation is necessary to find optimal treatment strategies.

Source:
Journal reference:

Svanberg, C., et al. (2023) Conformational state of C-reactive protein is critical for reducing immune complex-triggered type I interferon response: Implications for pathogenic mechanisms in autoimmune diseases imprinted by type I interferon gene dysregulation. Journal of Autoimmunity. doi.org/10.1016/j.jaut.2023.102998.

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