Recognition of crystalline structures by the immune system – Part 2 (revised)

• Applicant: Dr. Konstantin Neumann
• Subject Area: Immunology ; Biochemistry ; Rheumatology ; Toxicology, Laboratory Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506243736

Our immune system is designed to protect us from infections with pathogens. To do this, the immune system must recognize these organisms and distinguish them from our own tissue. The immune system has developed recognition molecules that recognize conserved structures (or patterns) in pathogens. One recognition molecule recognizes for example lipopolysaccharides, which are found in the cell wall of many bacteria, while others recognize the genome of viruses inside our cells like the double-stranded RNA of the virus that causes COVID-19. The immune system also recognizes damage caused by a pathogen or for other reasons. The activation of the immune system by pathogens or damage usually leads to inflammation, which is mostly also responsible for the symptoms of the infection. Due to their development, humans have a higher concentration of uric acid in their bodies than other living beings. Uric acid can crystallize in the joints and then lead to painful inflammation. In this disease, known as gout, the inflammation is indistinguishable from inflammation caused by pathogens like bacteria, which must be considered when making a diagnosis. The joint is often punctured to see if there are uric acid crystals or bacteria in it. Since the immune response to crystals is so similar to that to bacteria, both should be detected in a similar way. We have shown in previous work that the immune system does indeed recognize crystals with recognition molecules that also recognize bacteria. We were able to show that the well-known C-reactive protein (CRP) recognizes gout crystals and activates part of the immune system, the so-called complement system. We have also discovered two immune receptors on immune cells that recognize gout crystals. However, one of them inhibited the immune response to the crystals. The immune system thus seems to recognize the crystals, but wants to prevent an excessive response. We have thus shown that gout crystals are recognized by the immune system in much the same way as pathogens. In this project, we now aim to clarify how other crystals are recognized by the immune system. Distinct crystals can form in joints and kidneys, cholesterol crystals promote atherosclerosis, and crystals even form in infectious diseases (like the heme crystals in malaria). Are these crystals also recognized by specific recognition molecules, if so by which ones? What immune responses do they trigger? The answers to these questions can give us insights into how the immune system responds to threats, while it attempts to launch the right type of immune response even when no pathogen is directly recognized. Our work could also point to ways to influence immune response to crystals in a more targeted manner.

• DFG Programme: Research Grants