Insights into the immune system
Specific overactive immune cells play an important role in common autoimmune diseases such as rheumatoid arthritis. In collaboration with the FREEZE Biobank Freiburg, researchers have investigated this mechanism using biosamples from test persons with very rare immune defects. The insights gained could help to better target already approved therapies.
Researchers at the Medical Faculty of the University of Freiburg have found an important component in the development of common autoimmune diseases and chronic inflammations. For this purpose, they examined patients who did not suffer from one of these more widespread diseases, but those who had extremely rare genetic immunodeficiencies. The analysis of biosamples from these approximately 200 patients showed that certain gene alterations prevent the development of specific overactive immune cells. The discovery of these central mechanisms allows new insights into the development of immune cells that attack the body. Already approved therapies act on this previously unexplained molecular switch in the so-called B cells of the immune system. "Our findings can potentially help to develop more specific therapies for autoimmune diseases and to use existing therapies in a more targeted way," says Dr. Bärbel Keller, first author of the study at the Centre for Chronic Immunodeficiency at the University Medical Center Freiburg. The study was published in the renowned journal Science Immunology.
Several starting points for improved therapy
In chronic inflammatory autoimmune diseases such as rheumatoid arthritis or lupus erythematosus, a subform of activated B cells often accumulates in the blood of patients, which rarely occurs in healthy individuals. The Freiburg researchers have now shown that in people with specific genetic defects of the immune system, these overactive B cells of an excessive immune response do not accumulate. Laboratory tests confirmed the importance of these molecular building blocks for the immune response. "With this new knowledge, it is now possible to specifically search for inhibitors of these signalling pathways and thus slow down excessive immune reactions," said Prof. Dr. Klaus Warnatz, project leader at the Centre for Chronic Immunodeficiency and the Department of Rheumatology and Clinical Immunology at the University Medical Centre Freiburg.
In addition, the researchers were able to show that one of the central signalling pathways involves the messenger substance gamma interferon. Drugs known as JAK inhibitors, which are used for example in rheumatoid arthritis, are already able to interfere with its activity. "The increase in 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 must confirm this," says Keller.
Crucial gene defects extremely rare worldwide
The diseases of the patients studied are so rare that in some cases only two or three people are known to be affected worldwide. Therefore, the search for genetic changes was only possible in cooperation with a large number of international collaboration partners: "These rare patients with defined disorders of the immune system help us to understand fundamental mechanisms of the human immune system and thus to develop new therapeutic approaches," says Warnatz.
Special treasures: Biobanking of samples from rare diseases
To generate meaningful research results, the scientists needed suitable biospecimens such as blood and tissue. To achieve this, they worked closely with the FREEZE Biobank Freiburg, a partner biobank of the German Biobank Alliance (GBA) since 2019, where biospecimens are uniformly collected, processed and stored. The FREEZE Biobank was also responsible for the isolation of peripheral blood mononuclear cells - PBMCs for short - from part of the samples studied, which were made available for the immunological analyses. "The results of this study are a great success and we are pleased to have made an important contribution to this as a biobank with our partners at the Centre for Chronic Immunodeficiency and the Clinic for Rheumatology and Clinical Immunology," says Prof. Dr. Alexandra Nieters, head of the FREEZE Biobank. "We are especially grateful to the sample donors whose really very special samples have helped to better understand disease mechanisms of much more common autoimmune diseases."
Source: An original version of this text appeared as a press release from the University Medical Centre Freiburg.
Photo credit: FREEZE Biobank
Baerbel Keller et al. The expansion of human T-bethighCD21low B cells is T cell dependent. Science Immunology 2021; Vol 6, Issue 64. DOI: 10.1126/sciimmunol.abh0891
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