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Using very rare immunodeficiency diseases, Freiburg researchers were able to elucidate a mechanism of common autoimmune diseases / Findings could help to use existing therapies in a more targeted manner

Researchers at the Faculty of Medicine - University of Freiburg have now discovered an important building block in the development of autoimmune diseases and chronic inflammation. As part of a global research network, they examined around 200 patients with various extremely rare genetic immunodeficiencies. They found that certain gene mutations prevent the development of specific overactive immune cells. The discovery of these central mechanisms provides new insights into the development of immune cells that attack the patient's own body. Already approved therapies act on this previously unexplained molecular switch in the so-called B-cell of the immune system. The study was published on October 8, 2021 in the renowned journal Science Immunology.

"Our findings can potentially help to develop more specific therapies for autoimmune diseases and to use existing therapies in a more targeted manner," says Dr. Bärbel Keller, first author of the study at the Center for Chronic Immunodeficiency at the Medical Center - University of Freiburg.

Several starting points for improved therapy

In chronic inflammatory autoimmune diseases such as rheumatoid arthritis or lupus erythematosus, a subtype of activated B cells accumulates in the blood of some of the affected patients, which rarely occurs in healthy people. The Freiburg researchers have now shown that these overactive B cells of an excessive immune response cannot accumulate in people who have specific genetic defects of the immune system. Laboratory tests have confirmed the importance of these molecular building blocks for the immune response. "With the new knowledge, it is now possible to search for inhibitors for these signaling pathways in a more targeted manner and thus slow down excessive immune reactions," says Prof. Dr. Klaus Warnatz, project leader at the Center for Chronic Immunodeficiency and the Department of Rheumatology and Clinical Immunology at the Medical Center - University of Freiburg.

The Freiburg researchers also showed that one of the central signaling pathways involves the messenger substance gamma interferon. Drugs known as JAK inhibitors, which are used to treat rheumatoid arthritis, for example, already interfere with its activity. "The proliferation of these activated B cells in the blood of patients with autoimmune diseases may help in diagnostics to identify patients who particularly benefit from JAK inhibitor therapy. Clinical studies need to confirm this," says Keller.

Critical genetic defects extremely rare worldwide

The diseases of the patients studied are so rare that in some cases only two or three affected individuals are known worldwide. This is why the search for genetic changes was only possible in collaboration with a large number of international collaboration partners: "These rare patients with defined immune system disorders help us to understand fundamental mechanisms of the human immune system and thus develop new therapeutic approaches," says Warnatz.

Original title of the study: The expansion of human T-bethighCD21low B cells is T cell dependent
DOI: 10.1126/sciimmunol.abh0891
Link to the study:https://www.science.org/doi/10.1126/sciimmunol.abh0891

Contact:
Prof. Dr. Klaus Warnatz
Center for Chronic Immunodeficiency - CCI and
Department of Rheumatology and Clinical Immunology
Medical Center - University of Freiburg
Phone: 0761 270-77640
Klaus.warnatz@uniklinik-freiburg.de