April 23, 2020

A new study supported by the Lupus Research Alliance discovered a way that harmful immune responses in lupus and lupus nephritis could be stopped while protective immune responses, such as those to infection, are preserved.  The findings were published in the prestigious Journal of Immunology and add evidence to the value of a clinical trial being conducted by LRA’s affiliate Lupus Therapeutics in collaboration with the pharmaceutical company Bristol-Myers Squibb to look at the effectiveness of BMS-986165 as a potential treatment for lupus nephritis.

Researchers thought blocking a protein called STAT1 could be a treatment for autoimmune conditions, including lupus. However, without STAT1, immune responses are impaired and there is a greater risk of infection. Thus, therapies that would target the entire STAT1 molecule may predispose patients to dangerous, and even possibly deadly, infections. LRA-grantees Dr. Roberto Caricchio at Temple University and Dr. Ziaur S. M. Rahman at Penn State decided to use their grant to see if they could find a way to preserve immune responses that depend on STAT1 while putting the brakes on autoimmunity.

Changing the chemical structure of amino acids, individual building blocks that make up STAT1, could be one way to turn on or off certain functions for the whole protein. Adding chemical elements of phosphorous and oxygen that form a phosphoryl group to certain amino acids is an example of a chemical change. The process of adding a phosphoryl group is called phosphorylation. Phosphorylation is a key way that cells regulate protein activity.

Treatments for disease often work by stopping the action of an entire protein molecule. You may be familiar with belimumab (Benlysta), which targets a protein called soluble B lymphocyte stimulator (BLyS). When belimumab attaches to BLyS, it blocks the activity of BLyS, causing abnormal B cells that contribute to lupus to die off. Where a treatment blocking a whole molecule is akin to cutting off power to an entire house, blocking phosphorylation of an amino acid is more like flipping a switch to turn off a single light in one room.

Once phosphorylated, STAT1 becomes a regulator called a transcription factor meaning that it tells the cell to turn on certain genes. These genes might be helpful, such as those that respond to infection, or harmful when things go awry to cause autoimmunity. STAT1 molecule has two amino acids that can be phosphorylated: tyrosine-701 and serine-727. While the role of tyrosine-701 is well-studied, the role of serine-727 was not until this publication.

To uncover the role of phosphorylation of serine-727 in SLE, lupus nephritis, and response to pathogens, Dr. Rahman’s laboratory developed a mouse model in which the STAT1 serine-727 is replaced with the amino acid alanine. Alanine cannot be phosphorylated but the rest of the STAT1 molecule, including tyrosine-701, is unaltered. This helped the researchers figure out which processes require phosphorylation of serine-727 and which do not.

Role in autoimmunity

Dr Rahman and his team studied what would happen if serine-727 couldn’t be phosphorylated in mouse models of lupus and lupus nephritis. They found fewer autoimmune cells and fewer autoantibody responses in both mouse models The mice also had fewer damaging deposits of autoantibodies bound to self-proteins, or immune complexes, in the kidney so there was less inflammation.

The researchers concluded that phosphorylation of STAT1 serine-727 is important in development of lupus as well as in lupus-related kidney damage.

Role in the immune response

Next, the researchers looked at whether mice needed phosphorylation of serine-727 for the immune system to attack a pathogen. They found that B cell responses to infections were unchanged. B cells were still able to produce antibodies targeted to viruses. They concluded that there does not appear to be a significant role for phosphorylation of serine-727 in response to pathogens.

A new therapeutic target

These findings are important because they indicate STAT1 has different and distinct roles in autoimmunity and immune response to pathogens. Thus, there is potential to develop a targeted therapy that prevents the phosphorylation of serine-727 in STAT1. This may eliminate B cells that are reacting to the body without affecting a person’s ability to fight off an infection.

Future research seeks to identify the specific enzyme, called a kinase, which is responsible for adding a phosphoryl group to serine-727. From there, a kinase inhibitor could be developed as a future treatment. This approach is already showing promise in lupus and lupus nephritis. Lupus Therapeutics is working with Bristol-Myers Squibb to study one kinase inhibitor, BMS-986165, as a possible treatment for lupus nephritis.