FRANKFURT. For the first half of the twentieth century, autoimmune diseases were widely believed not to exist. This view was rooted in Paul Ehrlich’s concept of “horror autotoxicus” – the idea that the body possesses intrinsic mechanisms that prevent immune attacks against itself. It was not until the 1950s that several long-recognized disorders were identified as autoimmune diseases.
Autoimmune diseases arise when immune cells fail to distinguish between self and foreign structures and attack the body’s own tissues instead of invading pathogens. B cells that mistake the body’s own molecules for foreign antigens and produce antibodies against them are therefore not self-tolerant. According to the theory of clonal deletion, proposed during the same decade, all such self-reactive immune cells are normally eliminated in the bone marrow shortly after they are formed. Christopher Goodnow demonstrated that this is not the case.
Instead, the bone marrow releases a substantial proportion of these self-reactive B cells into the peripheral circulation while rendering them functionally inactive. In this anergic state, they circulate without producing autoantibodies. Under certain conditions, however, they can regain this ability – just as they can acquire the ability to eliminate bacteria and viruses. Anergic B cells therefore represent both a reserve force of the immune system and a potential source of autoimmune disease.
“By demonstrating the existence of clonal anergy, the laureate fundamentally challenged the black-and-white thinking that had long dominated classical immunology,” says the chairman of the Scientific Council, Thomas Boehm. “His work showed that the immune system must constantly balance the risk of autoimmunity with defensive readiness in order to function effectively. His discoveries on B-cell tolerance have profoundly advanced our understanding of how autoimmune diseases arise.”
What a New Technology Revealed About Self-Tolerance
Are self-reactive B cells really all eliminated before they can cause harm? By the mid-1980s, this question had become one of the central issues in immunology, as growing evidence challenged the concept of complete clonal deletion. In this context, Christopher Goodnow set out, as part of his doctoral thesis, to observe interactions between autoantigens and autoantibodies in vivo. To do so, he employed a technology that had only recently become established in immunology: the generation of transgenic mice. Working with an excellently strong research team, he developed a mouse strain carrying the gene for a chicken egg protein and another expressing a high-affinity antibody against that same protein. Crossing the two strains produced mice in which the egg protein acted as a self-antigen, encountering its corresponding antibodies within the animal’s blood vessels. As expected, these mice immediately stopped secreting the autoantibody from their B cells. The surprise was that the autoreactive B cells themselves remained in circulation. Their activity, however, had fallen twenty-fold. Rather than being eliminated, they had acquired self-tolerance through near-complete functional silencing. A dramatic shift in the ratio of two surface immunoglobulins served as the hallmark of this anergic state. The researchers also discovered that this silencing is reversible. It is maintained only in the continuous presence of self-antigens.
Why Anergic Immune Cells Are Essential
Young B cells are inherently “sticky”: they express a wide variety of receptors generated through billions of random genetic combinations. As a result, roughly two-thirds of all newly formed B cells are capable of binding to the body’s own tissues and producing autoantibodies. If the immune system eliminated all of these cells, it would leave a massive gap in its own defensive arsenal. Instead, it permanently removes only the most dangerous self-reactive B cells while placing the remainder into a dormant state. Because B cells can remodel their receptors through somatic hypermutation during an immune response, Goodnow proposed in 1991 that these dormant cells might later be converted into fully functional B cells capable of recognizing foreign antigens. It was only 25 years later that technological advances made it possible for Goodnow to demonstrate this visionary hypothesis experimentally, introducing the concept of “clonal redemption”.
What Cancer and Autoimmune Diseases Have in Common
Since the 1990s, Goodnow has also investigated the signaling pathways and immune checkpoints that normally prevent B cells from producing autoantibodies. “Only by understanding why most people do not develop autoimmune disease can we understand what goes wrong in those who do,” says Goodnow. In some countries, autoimmune diseases affect as many as ten percent of the population. This work established the laureate as one of the pioneers of the checkpoint concept in immune regulation. He showed that autoimmune diseases emerge when multiple immune checkpoints fail and uncovered striking parallels with cancer. In both cases, disease typically develops over many years through the stepwise circumvention of a series of molecular control mechanisms, driven primarily by spontaneous somatic mutations affecting these checkpoints. Clinically, the laureate’s discoveries have major implications for the development of personalized therapies for autoimmune diseases.
Christopher Goodnow , born in 1959, conducts research and teaches as head of the Immunogenomics Laboratory at the Garvan Institute of Medical Research and as a professor at the University of New South Wales in Sydney. https://www.garvan.org.au/people/researchers/christopher-goodnow
A photo of the award winner can be downloaded at www.paul-ehrlich-stiftung.de .
Detailed background information entitled “A Calculated Play with Fire” can be found here: https://www.uni-frankfurt.de/188991800 .
The prize will be awarded on March 14, 2027, 5 p.m. in Frankfurt’s Paulskirche by the Chairman of the Scientific Council of the Paul Ehrlich Foundation. We kindly ask that you take this into account when planning your schedule. Please do not hesitate to contact us with any questions.
The Paul Ehrlich and Ludwig Darmstaedter Prize is Germany’s most prestigious medical award. It is endowed with €120,000 and is traditionally presented on Paul Ehrlich’s birthday, March 14, at Frankfurt’s Paulskirche. The award honors scientists who have made outstanding contributions in the fields of research championed by Paul Ehrlich, particularly in immunology, cancer research, hematology, microbiology, and chemotherapy. The prize, which has been awarded since 1952, is funded by the Federal Ministry of Health, the Association of Research-Based Pharmaceutical Companies and earmarked through donations from the following companies, foundations, and institutions: Else Kröner-Fresenius Foundation, Sanofi-Aventis Deutschland GmbH, C.H. Boehringer Sohn AG & Co. KG, Biotest AG, Hans and Wolfgang Schleussner Foundation, Fresenius SE & Co. KGaA, F. Hoffmann-LaRoche Ltd., GSK GlaxoSmithKline GmbH & Co. KG, Grünenthal Group, Janssen-Cilag GmbH, Merck KGaA, Bayer AG, Georg von Holtzbrinck GmbH & Co. KG, and B. Metzler seel. Sohn & Co. AG. The award recipients are selected by the Scientific Council of the Paul Ehrlich Foundation. A list of the members of the Scientific Council is available on the Paul Ehrlich Foundation’s website.
The Paul Ehrlich Foundation is a legally dependent foundation administered in trust by the Association of Friends and Supporters of Goethe University. The honorary president of the foundation, established in 1929 by Hedwig Ehrlich, is Professor Dr. Katja Becker, President of the German Research Foundation (DFG), who also appoints the elected members of the Foundation Board and the Board of Trustees. The Chair of the Scientific Council of the Paul Ehrlich Foundation is Professor Dr. Thomas Boehm, Director Emeritus at the Max Planck Institute for Immunobiology and Epigenetics in Freiburg; the Chair of the Board of Trustees is Professor Dr. Jochen Maas. In his capacity as Chair of the Association of Friends and Supporters of Goethe University, Prof. Dr. Wilhelm Bender is also a member of the Board of Trustees of the Paul Ehrlich Foundation. The President of Goethe University is, by virtue of this office, also a member of the Board of Trustees.
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