The in-depth study of autoimmune diseases and new technologies will help researchers identify innovative therapeutic perspectives. From CAR-T cell therapies to chemokines: Prof. Mariagrazia Uguccioni, researcher and director of the Chemokines and Immunity Laboratory at the Institute for Research in Biomedicine (IRB) in Bellinzona (affiliated with USI), and Dr Veronica Martini, postdoc assistant in the same laboratory, tackle these topics in a contribution produced in collaboration with laRegione.
The human immune system is a marvel of biological defence that, like a grand orchestra composed of different instruments, requires coordinated action to ensure a harmonious performance. Only by respecting timing and intensity can this complex system preserve the body’s balance and health. Within this orchestra are cells belonging to the so-called innate immunity, which act as the first line of defence, ready to respond immediately to any threat with a rapid, yet non-selective, response. Once these "first responders" have contained the problem, other cells of the adaptive immune system come into play-T and B lymphocytes-which help broaden the response, ensuring the perfect execution of the score: the elimination of the cause of the damage and its repair. Although slower to react, they possess an "ironclad memory" and can recognise previously encountered adversaries, thereby developing the ability to respond faster and more effectively to a subsequent attack.
When the body’s defence mechanisms transform from best ally to worst enemy, autoimmune and autoinflammatory diseases develop. These are two distinct categories that share a fundamental dysfunction of the immune system. However, at the beginning of the 20th century, there was general scepticism regarding the immune system’s ability to attack one’s own organism; so much so that the German physician and scientist Paul Ehrlich (Nobel Prize in Medicine, 1908) formulated the theory of "horror autotoxicus," suggesting that our immune system would only ever react against foreign structures. This theory was later overturned in the 1950s, thanks to studies identifying the first antinuclear autoantibodies and the "rheumatoid factor." A fundamental contribution was also made by the Swiss scientist Peter Miescher, who was among the first to advocate for the efficacy of targeted therapeutic combinations aimed at blocking immune functions altered in autoimmunity.
These pathologies are not as rare as one might think. In Europe and North America, nearly 1 in 15 people is affected by an autoimmune disease, with a steady 10% growth in the population over recent decades. Among the most common autoimmune diseases in Switzerland are rheumatoid arthritis, affecting approximately 85,000 people, followed by systemic lupus erythematosus and chronic inflammatory bowel diseases. While rheumatoid arthritis primarily affects the joints, lupus targets various organs and systems, including the skin, kidneys, lungs, and nervous system. We must also not forget conditions affecting the joints, like arthritis and ankylosing spondylitis. What connects these seemingly diverse conditions?
When the body’s protection systems fail
Immune tolerance-the system’s ability to distinguish "self" from "non-self"--breaks down in all’autoimmune diseases. Before entering action, adaptive immune cells must pass through a "central training school." During this period, lymphocytes that erroneously identify parts of their own body as adversaries are destroyed, a mechanism known as central tolerance. This system is not perfect; some cells may pass the central tolerance "test" yet still recognise certain "self" molecules. This is where peripheral tolerance comes into play: a "patrolling system" led by regulatory T cells that can suppress their autoreactive counterparts. The study of the molecules identifying these regulatory lymphocytes earned Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi the Nobel Prize in Medicine in 2025, in recognition of the pioneering work that inspired generations of researchers to study immune regulation. During the development of autoimmune diseases, certain factors challenge and break this complex network of tolerance.
Risk factors for autoimmune and inflammatory diseases
Several conditions predispose individuals to autoimmune diseases and contribute to the breakdown of the tolerance network. A primary risk factor is the genetic background: having family members affected by autoimmune diseases unfortunately increases the risk. Certain variations in genes expressed by immune cells can predispose an individual to uncontrolled immune responses. Secondly, environmental triggers such as viral infections, exposure to toxins, chemicals, or smoking can provoke or worsen autoimmune reactions. Gender is another significant factor: the incidence of autoimmune diseases is three times higher in women than in men, likely due to hormonal influences and differences in immune system behaviour. Equally important, diet and the microbiota can promote the development and flare-ups of autoimmune diseases. Indeed, many microorganisms in our microbiota have co-evolved with humans and perform beneficial functions, including promoting immune system development.
A further level of complexity is provided by epigenetics-heritable changes not linked to the DNA sequence itself: the body’s ability to alter gene expression, "switching them on or off" based on environmental factors. Since epigenetic modifications can influence the expression of immune-related genes, such as those involved in tolerance, they contribute to the susceptibility and progression of autoimmunity. The presence of numerous factors means that initial manifestations generally occur in adulthood and that, within the same family, some members may develop the disease while others do not.
Autoinflammatory diseases often have a single primary cause: DNA mutations that lead to an overactive innate immune system, resulting in recurrent episodes of inflammation. Some of these are caused by a mutation in a single gene, such as Familial Mediterranean Fever or TNF receptor-associated periodic syndrome (TRAPS), while others involve multiple mutations. These conditions are usually hereditary and can manifest themselves early in life, with flare-ups triggered by environmental or other factors that are still being studied.
Pharmacological treatments: different strategies for common enemies
Just as the causes of autoimmune diseases are manifold, the manifestations of the same disease can vary. Someone with ankylosing spondylitis may have chronic lower back pain, but some individuals also simultaneously suffer from eye inflammation, psoriasis, or intestinal inflammation. Therapeutic treatments must therefore address all these symptoms of the same disease. Current therapies focus on treating symptoms associated with the excessive immune response using anti-inflammatories and immunosuppressants. In recent years, drugs that inhibit specific inflammatory mediators, such as cytokines, have been developed. Despite this variety, approximately 40% of patients do not have a complete response to therapy. Their hope, therefore, lies in new therapeutic approaches that cannot ignore precision medicine, which can adapt therapies to each patient’s immune profile. A new therapeutic frontier is CAR-T cell therapy: an emerging treatment for lupus that involves engineering a patient’s T lymphocytes to target and eliminate harmful B lymphocytes specifically. Early clinical trials have shown promising results, with several patients achieving drug-free remission lasting up to three years after a single infusion.
The future of therapy is rooted in today’s research
Our laboratory, which has been operating at the Institute for Research in Biomedicine since its opening in 2000, studies chemokines, molecules that guide the positioning of immune cells within our body, and how these can influence the different nuances and manifestations of autoimmune diseases. Our research began long ago, with the studies that led Marco Baggiolini, then director of the prestigious Theodor Kocher Institute in Bern, to describe the first chemokine in 1987 and subsequently to understand the importance of these molecules both in physiology and in inflammatory, infectious or tumour diseases. Our intensive research, inspired by these initial studies and supported over the years by the Swiss National Science Foundation, the European Commission and countless other philanthropic funding sources, has enabled us to understand how we might interfere with the activity of a chemokine, which finds a favourable environment in rheumatoid arthritis to keep the inflammatory process alive. These studies have required years of patience and active collaboration with doctors and colleagues at the IRB, who have helped better characterise the interactions between molecules and develop a strategy to identify new, targeted anti-inflammatory drugs. We will not stop there: we already have new indications that cancer cells also benefit from these interactions.
We have always believed that analysing the "microenvironment"--the surroundings in which cells are embedded-will provide the right answers to treat the different manifestations of inflammatory or neoplastic diseases with precision. The passing of the torch to new generations of passionate researchers will allow for the continuous advancement of knowledge, without which the development of drugs would be impossible.
produced by the Institute for Research in Biomedicine (IRB) in Bellinzona, affiliated with USI, on its 25th anniversary, in collaboration with laRegione .
