Max-Delbrück-Centrum für Molekulare Medizin (MDC)

Researchers reveal how cells accelerate changes to their identity, a process known as cell fate conversion. The study has implications for cancer research as the disease often arises from errors in cell fate decisions. The study could eventually lead to new methods of accelerating or manipulating the molecular mechanisms involved in the formation of cancer. Researchers at the Centre for Genomic Regulation (CRG) in Barcelona and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association in Berlin reveal how cells accelerate changes to their identity, a process known as cell fate conversion. The study, published today in the journal eLife, has implications for cancer research as the disease often arises from errors in cell fate decisions. The study could eventually lead to new methods of accelerating or manipulating the molecular mechanisms involved in the formation of cancer. Central to the study is C/EBPα (CCAAT/enhancer-binding protein alpha), a protein that orchestrates the conversion of B lymphocytes to macrophages, another type of immune cell. C/EBPα is a transcription factor, a type of protein which binds to specific DNA sequences in the regulatory regions of genes to influence the rate of transcription, the first step that leads to the activation or silencing of protein expression. Transcription factors play a vital role in the transformation of one cell type to another during differentiation and development, as well as in the growth and function of cells. Like many other proteins, C/EBPα is modified by enzymes, for example through the addition of a methyl group to specific amino acids. These modifications can have significant effects on interactions of the protein. The researchers found that when one specific arginine residue of C/EBPα is left unmethylated, it greatly accelerates the conversion process of B lymphocytes to macrophages. The study also found that the methylation of this specific arginine residue is mediated by the enzyme Carm1. Previous research has shown that Carm1-deficient mice are resistant to induced forms of acute myeloid leukaemia. The researchers hypothesise that the mechanisms they uncover in the present study can explain why: the unmethylated version of C/EBPα is a stronger inducer of macrophage differentiation compared to its methylated counterpart. As macrophages are a non-dividing cell type, this could prevent the formation of cancer cells. The researchers made the discovery while screening for C/EBPα mutants which affect the efficiency of cell fate conversion using human and mouse models. The location of the critical amino acid within C/EBPα was found when the authors tested a mutant form called C/EBPαR35A. This mutant dramatically accelerated the speed by which B cells could be turned into macrophages. To induce a cell conversion, C/EBPα works by interacting with another transcription factor called PU.1, which itself is essential for the development of immune cells and is already expressed in B cells. C/EBPαR35A had a much higher interaction affinity with PU.1, increasing the speed by which the combination of the two proteins silence the genes associated with B cells and activate the genes associated with macrophages. The methylation of C/EBPα is an example of an epigenetic mechanism. These are mechanisms which modify how the genome -- the instruction manual inside every cell of the human body -- is read. "Drugs that affect epigenetic mechanisms as described in the present study may indeed alter the function of transcription factors and correct cells that went astray, such as seen in cancer and leukaemia," says Dr. Achim Leutz, senior author from the Max-Delbrück-Center. "In this novel mechanism PU.1 is triggered by C/EBPα to switch from a B cell regulator into a macrophage regulator, an elegant 'on-off' mechanism that ensures the faithful formation of a mature cell type, avoiding the formation of 'confused' cells often seen in blood cancers. Therefore, drugs might be found that target this mechanism to correct such defects" adds Dr. Leutz. According to the authors of the study, much remains unknown about what determines the speed and directionality of cell fate decisions and their new work suggests that the two processes are two sides of the same coin. For instance, how do stem cells sequentially transform into the many different types of cells in the body? Better understanding how cells change their identity and how to manipulate the process might have applications from regenerative medicine to improving the efficacy of drugs against cancer. The research was led by a joint collaboration between the Centre for Genomic Regulation in Barcelona, the Max Delbrück Center for Molecular Medicine in Berlin and the University of Pennsylvania in Philadelphia. The study was funded by the Spanish Ministry of Economy, Industry and Competitiveness, the Catalan Agency of Research and Universities, a 4D-Genome European Research Council Synergy grant, by funds from the Max-Delbrueck-Center, and the United States National Institute of Health.

Regulatory T cells ensure that immune responses happen in a controlled way. But eating too much salt weakens these cells' energy supply, thus rendering them dysfunctional for a while. This may have implications for autoimmunity. Regulatory T cells ensure that immune responses happen in a controlled way. But eating too much salt weakens these cells' energy supply, thus rendering them dysfunctional for a while. This may have implications for autoimmunity, an international team -- including Dominik Müller -- reports in Cell Metabolism. Eating too much salt, which is common in many Western societies, is not only bad for our blood pressure and cardiovascular system -- it could also adversely impact the immune system. An international research team, coordinated by scientists at the VIB Center for Inflammation Research and Hasselt University in Belgium as well as the Max Delbrück Center in Germany, is now reporting in "Cell Metabolism" that salt can disrupt key immune regulators called regulatory T cells by impairing their energy metabolism. The findings may provide new avenues for exploring the development of autoimmune and cardiovascular diseases. A few years ago, research by teams led by Professor Dominik Müller at the Max Delbrück Center for Molecular Medicine and the Experimental and Clinical Research Center, a joint institution of Charité -- Universitätsmedizin Berlin and Max Delbrück Center (ECRC) in Berlin, Germany and Professor Markus Kleinewietfeld at the VIB Center for Inflammation Research and Hasselt University in Belgium, as well as by colleagues of theirs, revealed that too much salt in our diet can negatively affect the metabolism and energy balance in certain types of innate immune cells called monocytes and macrophages and stop them from working properly. They further showed that salt triggers malfunctions in the mitochondria, the power plants of our cells. Inspired by these findings, the research groups wondered whether excessive salt intake might also create a similar problem in adaptive immune cells like regulatory T cells. Important immune regulators Regulatory T cells, also known as Tregs, are an essential part of the adaptive immune system. They are responsible for maintaining the balance between normal function and unwanted excessive inflammation. Tregs are sometimes referred to as the "immune police" because they keep bad guys like autoreactive immune cells at bay and ensure that immune responses happen in a controlled way without harming the host organism. Scientists believe that the deregulation of Tregs is linked to the development of autoimmune diseases like multiple sclerosis. Recent research has identified problems in mitochondrial function of Tregs from patients with autoimmunity, yet the contributing factors remain elusive. "Considering our previous findings of salt affecting mitochondrial function of monocytes and macrophages as well as the new observations on mitochondria in Tregs from autoimmune patients, we were wondering if sodium might elicit similar issues in Tregs of healthy volunteers," says Müller, who co-heads the Hypertension-Mediated End-Organ Damage Lab at the Max Delbrück Center and the ECRC. Previous research has also shown that excess salt could impact Treg function by inducing an autoimmune-like phenotype. In other words, too much salt makes the Treg cells look like those involved in autoimmune conditions. However, exactly how sodium impairs Treg function had not yet been uncovered. Salt interferes with mitochondrial function of Tregs The new international study led by Kleinewietfeld and Müller and first-authored by Dr. Beatriz Côrte-Real and Dr. Ibrahim Hamad -- both of whom work at the VIB Center for Inflammation Research and Hasselt University in Belgium -- has now discovered that sodium disrupts Treg function by altering cellular metabolism through interference with mitochondrial energy generation. This mitochondrial problem seems to be the initial step in how salt modifies Treg function, leading to changes in gene expression that showed similarities to those of dysfunctional Tregs in autoimmune conditions. Even a short-term disruption of mitochondrial function had long-lasting consequences for the fitness and immune-regulating capacity of Tregs in various experimental models. The new findings suggest that sodium may be a factor that could contribute to Treg dysfunction, potentially playing a role in different diseases, although this needs to be confirmed in further studies. "The better understanding of factors and underlying molecular mechanisms contributing to Treg dysfunction in autoimmunity is an important question in the field. Since Tregs also play a role in diseases such as cancer or cardiovascular disease, the further exploration of such sodium-elicited effects may offer novel strategies for altering Treg function in different types of diseases," says Kleinewietfeld, who heads the VIB Laboratory for Translational Immunomodulation. "However, future studies are needed to understand the molecular mechanisms in more detail and to clarify their potential relationship to disease."

-- Data being presented at the European Academy of Neurology Congress demonstrates consistent reductions in NMOSD attacks and disability scores across populations -- DUBLIN--(BUSINESS WIRE)-- Horizon Therapeutics plc (Nasdaq: HZNP) today announced new findings from a post hoc analysis of the N-MOmentum Phase 3 pivotal trial of UPLIZNA supporting the medicine’s efficacy in Europeans living with NMOSD. These data are being presented during the 8th Congress of the European Academy of Neurology (EAN), June 25-28 in Vienna. UPLIZNA received marketing authorization from the European Commission (EC) on April 25, 2022 and is the first and only targeted CD19+ B-cell-depleting monotherapy proven to reduce attacks in adult patients with NMOSD who are anti-aquaporin-4 immunoglobulin G seropositive (AQP4-IgG+). This post hoc analysis compared attack rates, disability-related outcomes and safety among 50 trial participants from the European Union (EU) (including participants from Bulgaria, Czech Republic, Estonia, Germany, Hungary and Poland) versus 163 non-EU participants. “People living with NMOSD in Europe need novel treatment options that have been shown to reduce attacks that can cause irreversible and debilitating damage, such as vision loss and paralysis,” said Friedemann Paul, M.D., study author and head, Clinical Neuroimmunology Research Group, NeuroCure Clinical Research Center, and head, Clinical and Experimental Neuroimmunology, Experimental and Clinical Research Center, Charité–Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medine, Berlin, Germany. “With UPLIZNA, physicians have a treatment option that can be given twice a year after initial dosing to help prevent NMOSD attacks by specifically targeting CD19 B-cells, which play a central role in the pathogenesis of the disease.” Key analysis findings:1 Participants in the EU who were treated with UPLIZNA experienced fewer attacks (12.5%) compared to those treated with placebo (30%), sharing similar results with non-EU participants receiving UPLIZNA (10.7%) or placebo (45.2%). No significant differences in Expanded Disability Status Scale (EDSS) worsening were found between participants in the EU (15%) versus non-EU participants (14.9%). Fewer NMOSD-related hospitalisations were reported among those receiving UPLIZNA compared to those treated with placebo (mean, EU: 1.0 vs 2.0; non-EU: 1.0 vs 1.33). “The UPLIZNA pivotal trial is the largest in NMOSD and clearly demonstrates the merits of targeting CD19 B-cells, including plasmablasts and plasma cells, to provide broad, deep and durable B-cell depletion,” said Karl Boegl, M.D. Ph.D., executive director, EMEA regional medical affairs lead, Horizon. “We believe these data provide treating physicians with greater certainty that a targeted monotherapy like UPLIZNA can be a valuable option for the treatment of NMOSD patients in Europe.” About Neuromyelitis Optica Spectrum Disorder (NMOSD) NMOSD is a unifying term for neuromyelitis optica (NMO) and related syndromes. NMOSD is a rare, severe, relapsing, neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord, brain and brain stem.2,3 Approximately 80% of all patients with NMOSD test positive for anti-AQP4 antibodies.4 AQP4-IgG binds primarily to astrocytes in the central nervous system and triggers an escalating immune response that results in lesion formation and astrocyte death.5 Anti-AQP4 autoantibodies are produced by plasmablasts and some plasma cells. These B-cell populations are central to NMOSD disease pathogenesis, and a large proportion of these cells express CD19.6 Depletion of these CD19+ B-cells is thought to remove an important contributor to inflammation, lesion formation and astrocyte damage. Clinically, this damage presents as an NMOSD attack, which can involve the optic nerve, spinal cord and brain.5,7 Loss of vision, paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain and respiratory failure can all be manifestations of the disease.8 Each NMOSD attack can lead to further cumulative damage and disability.9,10 NMOSD occurs more commonly in women and may be more common in individuals of African and Asian descent.11,12 About UPLIZNA For information about UPLIZNA for Europe, please view the Summary of Product Safety Characteristics. About Horizon Horizon is a global biotechnology company focused on the discovery, development and commercialization of medicines that address critical needs for people impacted by rare, autoimmune and severe inflammatory diseases. Our pipeline is purposeful: We apply scientific expertise and courage to bring clinically meaningful therapies to patients. We believe science and compassion must work together to transform lives. For more information on how we go to incredible lengths to impact lives, visit and follow us on Twitter, LinkedIn, Instagram and Facebook. Forward-Looking Statements This press release contains forward-looking statements, including statements regarding the potential benefits of UPLIZNA in treating patients with NMOSD. These forward-looking statements are based on management’s expectations and assumptions as of the date of this press release and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include, but are not limited to, risks regarding whether future data analyses or clinical evidence will be consistent with the analyses from the N-MOmentum clinical trial or Horizon’s expectations. For a further description of these and other risks facing Horizon, please see the risk factors described in Horizon’s filings with the United States Securities and Exchange Commission, including those factors discussed under the caption “Risk Factors” in those filings. Forward-looking statements speak only as of the date of this press release and Horizon undertakes no obligation to update or revise these statements, except as may be required by law. References Paul F, Aktas O, Marignier R, Boegl K. Efficacy of inebilizumab in the European Union subpopulation of the N-MOmentum Trial. Poster presented at: 8th Congress of the European Academy of Neurology (EAN); June 25-28, 2022; Vienna, Austria. Ajmera MR, Boscoe A, Mauskopf J, Candrilli SD, Levy M. Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. J Neurol Sci. 2018;384:96-103. What is NMO? Guthyjacksonfoundation.org. Accessed April 15, 2021. Layman’s Guide to NMO. Sumairafoundation.org. Accessed April 25, 2021. Liu Y, et al. A tract-based diffusion study of cerebral white matter in neuromyelitis optica reveals widespread pathological alterations. Mult Scler. 2011;18(7):1013-1021. Chihara N, et al. Interleukin 6 signaling promotes anti-aquaporin-4 autoantibody production from plasmablasts in neuromyelitis optica. PNAS. 2011;108(9):3701-3706. Duan T, Smith AJ, Verkamn AS. Complement-independent bystander injury in AQP4-IgG seropositive neuromyelitis optica produced by antibody dependent cellular cytotoxicity. Acta Neuropathologica Comm. 2019;7(112). Beekman J, et al. Neuromyelitis optica spectrum disorder: patient experience and quality of life. Neural Neuroimmunol Neuroinflamm. 2019;6(4):e580. Kimbrough DJ, et al. Treatment of neuromyelitis optica: review and recommendations. Mult Scler Relat Disord. 2012;1(4):180-187. Baranello RJ, Avasarala, JR. Neuromyelitis optica spectrum disorders with and without aquaporin 4 antibody: Characterization, differential diagnosis, and recent advances. J Neuro Ther. 2015;1(1):9-14. Wingerchuk DM. Neuromyelitis optica: effect of gender. J Neurol Sci. 2009;286(1-2):18-23. Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol. 2016;79(5):775-783.