Measles, rubella, chickenpox – some diseases you get only once in a lifetime. Most of these diseases we do not have to go through today, a needle prick with a vaccine is enough and we are protected against it – we are immune. How does this protection of the immune system work, which we call immunological memory? And what has this memory to do with rheumatism and other chronic inflammatory diseases?
Memory cells – immune cells that "remember" pathogens
We are always and everywhere surrounded by bacteria, fungi and viruses. Nevertheless, we are not permanently ill. We owe this to our immune system. It can remember pathogens and protect us from a new infection. Behind this so-called immunological memory is the complex communication of different "memory cells". These memory cells remain in the body for years after the disease has subsided and store all the information about the defended pathogen like a database. In case of a new infection, the germ is fought immediately. We often don’t notice this effective defense response – we are immune to the pathogen. Immunological memory is one of the most impressive features of our immune system. A lifetime of expanding the database. The success of vaccinations is also based on immunological memory.
Disease-causing memory cells – this is why rheumatism becomes chronic
The immunological memory works because the immune system can distinguish foreign pathogens from its own tissue: The body’s own structures are normally recognized as such by the cells of the immune system and ignored. However, if this recognition mechanism fails, endogenous structures are falsely identified as foreign bodies by the immune system. The system gets out of joint and the "tolerance" to its own tissue breaks down. As a natural defense reaction, the body wants to eliminate the "intruder" with an inflammation and begins a protracted battle against itself. Serious diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis or multiple sclerosis may be the result.
Once the body has begun the fight against its own tissue, such as joint cartilage or nerve cells, the memory cells also begin to work – just as in the case of an infection. However, the "foreign body" that triggers the inflammation cannot be eliminated. This activates the memory cells again and again. The immunological memory database is being expanded – with memory cells that make people sick. They drive the inflammation like an engine – the disease becomes chronic. Affected persons must take medications for the rest of their lives that inhibit this immune reaction, but also have undesirable side effects.
DRFZ researchers study the survival of plasma cells in artificial survival niches in cell culture. (Dr. Marta Ferreira Gomes)
Plasma cells (green) lie surrounded by connective tissue cells, well protected in their survival niches in the bone marrow.
© Carolin Ulbricht / Anja Hauser AG Immundynamics DRFZ/Charite-Universitatsmedizin Berlin
The DRFZ on the campus of the Charite in Berlin Mitte
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Curing rheumatism – how the DRFZ paves the way
A clinical observation has had a decisive influence on the research strategy of the DRFZ: If the immune system is destroyed with chemotherapy and then rebuilt from the body’s own stem cells, the rheumatic inflammation disappears permanently. The affected persons are cured. However, the treatment, called "immune reset", is very risky and is only carried out in rare exceptional cases. The patients have no protection against any pathogens for a long time after the treatment. Apparently, not only do the disease-causing memory cells disappear, but the entire immunological memory database is erased. The immune reset is evidence that the memory cells of the immune system play a crucial role in chronic inflammatory autoimmune diseases.
At the DRFZ, ways are being sought to eliminate as selectively as possible only the disease-causing memory cells in order to cure inflammatory diseases permanently. Only the memory for the disease should be erased, while the protective immune system remains intact. A prerequisite for this ambitious project is a detailed knowledge of the biology of the different types of memory cells and their role in chronic inflammatory diseases:
- What role do the disease-causing cells play in the course of the disease??
- How do the disease-causing memory cells differ from the protective ones??
- Which factors are important for survival and communication between cells??
- Which of these factors might be suitable for therapeutic intervention?
In recent years, the ever better understanding of the life of the disease-causing cells has already led to the discovery of new therapeutic targets in and on the cells. These can be molecules on the surface of the cells, nutrients that the cells need to survive, or messenger substances that the cells need to communicate. Ultimately, the goal is to prevent the survival of disease-causing cells.
Targeted destruction of disease-causing memory plasma cells – a new method
A cell type that plays a crucial role in many autoimmune diseases was discovered by researchers at the DRFZ 25 years ago: the long-lived disease-causing memory plasma cell. Well protected, they survive for decades in so-called "survival niches" in the bone marrow and other tissues. Here, they are kept alive by connective tissue cells and continuously release so-called auto-antibodies against the body’s own tissue into the bloodstream. These drive inflammation and thus disease. Current therapies can alleviate symptoms, but they do not reach the actual culprit – the disease-causing memory plasma cell in its niche. This explains why the disease flares up again immediately after medication is discontinued.
The DRFZ researchers, together with colleagues at Charite, have now developed a technology that detects and destroys plasma cells – and only those that produce very specific antibodies. If only the disease-causing memory plasma cells can be eliminated without affecting the protective ones, this could revolutionize the treatment of chronic autoimmune diseases. This technology has already been patented and successfully tested in animal models. It is now being further developed for use on humans.
Selective elimination of disease-causing plasma cells – animation of our new technology
Graphics and animation: Design meets science, Daniela Leitner
Another approach to eradicating disease-causing memory plasma cells is to interfere with their communication with connective tissue cells. The DRFZ researchers are artificially rebuilding the "survival niches" for this purpose. In these cell cultures, they are studying which substances the memory plasma cells need to survive. They have already been able to show that vital contact with connective tissue cells apparently triggers a specific signaling pathway in plasma cells. It makes the cells resistant to stress and lack of food, and also to conventional treatment of chronic inflammation. If this signaling pathway is interrupted, the memory plasma cells die off. This could be another way to truly cure chronic diseases caused by autoantibodies in the future.
Deprive the inflammation of fuel: switch off disease-causing T cells
In addition to memory plasma cells, so-called disease-causing memory T helper cells have long been a focus of the DRFZ. These cells are found in the inflamed tissues of autoimmune diseases, for example in the joints of rheumatoid arthritis sufferers. Finding the cells that cause disease is like looking for a needle in a haystack: Although they play a crucial role in the disease process, there are often only a few of them among millions of other cells. In addition, their function is always dependent on their interaction with their environment.
The DRFZ uses a very recent method of genetic engineering to accurately study many cells at once: the Single cell sequencing. In contrast to other methods, this not only provides information about the structure of the cell, but above all clues about its function. Every cell in the body, including an immune cell, carries the entirety of our genetic information, about 25.000 genes, in itself. However, only a fraction of this is active, and this is cell specific. It is precisely this activity that determines whether a cell transports oxygen as a red blood cell, for example, or drives inflammation in the joint of a rheumatism patient as a disease-causing memory T cell.
Using single-cell sequencing, researchers from the DRFZ, together with colleagues from the Charite, have studied memory T helper cells from the joints of children and adolescents suffering from rheumatism. Based on gene activity, they were able to divide the cells into previously unknown subgroups. Some of them inhibit inflammation, others further drive inflammation. It is precisely these cells that must now be eliminated in order to stop the inflammatory process in the joints.
Pioneering work at the DRFZ: Switching off gene switches – preventing inflammation
The DRFZ scientists use a new strategy to specifically influence the activity of the disease-causing cells. They use small molecules that penetrate the cell’s interior into the cell nucleus and link to specific sites on the genetic material, so-called "gene switches. In simple terms, this means that genes can be switched on or off. These tiny molecules, called oligonucleotides, can therefore specifically influence cell function.
In an animal model for inflammatory bowel disease, the DRFZ has already succeeded in specifically killing disease-causing memory T cells with this method. The protective memory T cells retained. The treatment was successful: the inflammation of the intestine became significantly weaker. This principle is now to be transferred to other diseases. The goal is to develop therapeutic oligonucleotides for human use that disrupt the machinery of inflammation in chronic autoimmune diseases.
The projects described here represent only a part of the work of the DRFZ on the subject of immunological memory. Other areas of focus include analyses of memory B cells and cells of the innate immune system. You can find more detailed information in the profiles of the research groups conducting research on immunological memory.