• IES Life Sciences

New LRA-Supported Study Provides Clue to Potential New Treatment Target

A new study supported by the Lupus Research Alliance discovered that molecules called type II interferons can trigger the immune system to over-produce the B cells that cause lupus inflammation. Type I interferons have already been shown to be very important in lupus which has led to exciting new drugs like anifrolumab in development for lupus.  Published in the prestigious Journal of Immunology, this work shows that blocking a different type of interferon may be another great drug target.

B cells are important members of the immune system. During infections, B cells release molecules known as antibodies to coat pathogens or microbes. This coating allows other immune cells to recognize and destroy the microbes without hurting the body. In lupus patients, however, an unknown process leads to the development of autoreactive B cells (B cells that target the body’s tissues and organs). Results of the study led by LRA-grantees Dr. Roberto Caricchio and Dr. Ziaur S. M. Rahman found that in a mouse model of lupus, genetic material causes immune cells to produce inflammation-causing substances. One of these substances, known as type II interferon, causes harmful B cells to multiply throughout the body. Ultimately, these B cells produce antibodies that damage the organs and lead to the development of lupus symptoms.

This study built on previous work by the authors linking the immune response to the body’s genetic material with an increase in the number of lupus-causing B cells. How this happens was unclear, but the researchers had an important clue. In human patients, the body’s genetic material can be recognized by other immune cells known as T cells. T cells identify genetic material using special sensors called toll-like receptors. One toll-like receptor, known as toll-like receptor 7 (TLR7) has been linked to lupus. When the body’s genetic material binds to TLR7, T cells responded by making inflammatory substances, particularly interferons. Many lupus patients have over-active TLR7, meaning that more interferons are present than normal. Because B cells (including harmful B cells) multiply when they are exposed to interferons, researchers concluded that TLR7 might cause lupus through the production of these extra interferons. However, there are many types of interferon molecules, so it was unclear which might be responsible.

Addressing this question, Dr. Rahman and his colleagues developed a mouse model in which TLR7 is over-active. To determine the impact of each interferon, the researchers used versions of the lupus mouse model that lacked a receptor for either Type I or Type II interferons.  This means the researchers could test, one at a time, how the disease changed with and without both types of interferon. To measure changes in the development of lupus, the number of harmful B cells and antibodies against the body were counted. The amount of tissue damage throughout the body was also measured. The researchers found that if you remove the Type I interferon receptor, the mice had less harmful B cells, antibodies and tissue damage. However, when they removed type II interferons the mice had almost no disease symptoms. This demonstrated that Type II interferon has a major role in the development of lupus symptoms in the mice.

These findings suggest that treatments that block type II interferon or TLR7 could lower the number of harmful B cells in lupus patients. If fewer harmful B cells were present, patients would be less likely to have symptoms or to develop complications such as lupus nephritis. It has been well proven that type I interferons are important in lupus.  These new results suggest that drugs that would target type II interferons, and potentially others, may also help patients with lupus.

- FEB 27 2020

Site: https://www.lupusresearch.org/new-lra-supported-study-provides-clue-to-potential-new-treatment-target/

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