The Secret of rheumatoid arthritis
Researchers at Stanford University Medical School, working under the guidance of Professor Cornelia Weyand, managed to cope with inflammatory joint injuries in rheumatoid arthritis in mice that had previously been implanted with human synovial tissue.
Rheumatoid arthritis is one of the most common autoimmune diseases affecting approximately 1% of the human population. One of its manifestations is the defeat of the synovial membrane – the soft tissue lining the surface of the joints and acting as a lubricant that prevents the bones from rubbing against each other. While the development of osteoarthritis is caused by age-related wear of the joints, rheumatoid arthritis develops with a chronic attack of the body's own immune cells on the cells of the synovial membrane. The inflammatory nature of rheumatoid arthritis also leads to systemic problems. For example, it doubles the risk of developing heart disease.
Existing medications alleviate the symptoms, but do not cure the disease, since for this it is necessary to normalize the behavior of the immune cells causing it. The reason why these cells begin to attack their own body continues to be a mystery today.
The authors managed to get closer to solving it. They found that the trigger mechanism for the development of rheumatoid arthritis is a violation of the metabolism of immune cells – T helper cells - which begin to redirect their resources from energy synthesis to the production of a whole army of pro-inflammatory daughter cells. This army leaves the lymph nodes and goes to the synovial membrane, where it settles and begins to release pro-inflammatory signals that attract other very aggressive immune cells to the joint. As a result, inflammation develops in the synovial membrane and it begins to break down, which is the hallmark of rheumatoid arthritis.
In their earlier work, the researchers identified differences between the T-helpers of patients with rheumatoid arthritis and healthy people. The former, for example, are characterized by small reserves of ATP molecules (adenosine triphosphate), which is the intracellular energy "currency" used by the cell for all metabolic processes. However, instead of directing their main source of energy – glucose – to the production of ATP, such cells spend it on the synthesis of various materials, including proteins, nucleic acids and membranes, which are later used to produce new T cells that contribute to further damage.
Normally, this should not happen. Like all other cells, T-lymphocytes have an enzyme AMP-dependent kinase (AMPK), a regulatory molecule that regulates the ratio of ATP and its two main decay products. If the concentration of decay products exceeds the concentration of ATP, AMP-dependent kinase stops the process of building a new cell and redirects glucose to the mitochondria, where ATP synthesis occurs.
The results of a new study shed light on the reasons why AMP-dependent kinase does not cope with its functions in T-helpers of patients with rheumatoid arthritis. To redirect glucose traffic from biosynthesis to energy production, AMP-dependent kinase must first be activated. This activation results from the attachment of a small chemical group to an enzyme molecule, which can only occur on the surface of membrane vesicles known as lysosomes.
Lysosomes have a reputation as cellular "cleaners", as they are usually filled with cellular debris undergoing a recycling process. However, their functions are not limited to this. The membrane surface of lysosomes is dotted with a variety of receptors, channels, enzymes and other proteins. Only after attachment to the surface of the lysosome and embedding in a large protein supercomplex, the AMP-dependent kinase is activated and acquires the ability to redirect the glucose flow in the right direction.
As part of the work, the authors identified 155 blood samples from patients with rheumatoid arthritis, the same number of blood samples from healthy people, as well as a small number of blood samples from people with other autoimmune diseases. They isolated T-helpers from all the samples, analyzed them and found a number of striking differences.
The T-helpers of all three groups of participants had the same amount of AMP-dependent kinase. However, the enzyme molecules in the cells of patients with rheumatoid arthritis were not activated and did not attach to the surface of lysosomes. Myristic acid molecules were also found much less frequently at their end sites.
In addition, T-helpers of patients with rheumatoid arthritis had significantly reduced levels of the enzyme N-myristoyltransferase-1 (NMT1), whose function is to attach myristic acid to the end sites of AMP-dependent kinase molecules. The end sections modified in this way act as "anchors" that attach the AMP-dependent kinase molecule to the surface of the lysosome. Increased levels of N-myristoyltransferase-1 in T-helpers of patients with rheumatoid arthritis using laboratory methods suppressed the secretion of proinflammatory cytokines by these cells. When injected into mice with implanted human synovial tissue, unmodified T-helpers of patients with rheumatoid arthritis caused great damage to this tissue. At the same time, the same cells with pre-elevated levels of N-myristoyltransferase-1 caused significantly less damage.
The experimental drug A769662, which causes the activation of AMP-dependent kinase molecules not only attached to the surface of lysosomes, but even floating freely in the cytoplasm, demonstrated the ability to suppress the pro-inflammatory activity of T-helpers and their desire to infiltrate and damage human synovial tissue not only in in vitro experiments, but in a mouse model.
The authors hope that in the near future they will be able to test this drug or its derivative in a clinical trial involving patients with rheumatoid arthritis.
Article by Zhenke Wen et al. N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation published in the journal Nature Immunology.
Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on Stanford University School of Medicine: Scientists identify reversible molecular defect underlying rheumatoid arthritis.