The immune system acts as both a powerful sword that helps to destroy foreign invaders, as well as a mighty shield that protects the body against harm. However, this system can backfire when the immune system’s weapons are used not on invading pathogens but itself. This condition is the cause of autoimmune diseases, which refer to when the immune system mistakenly attacks the body’s cells and parts. Examples include Type 1 Diabetes, in which the body mistakenly damages the pancreas, and lupus, where the body attacks normal healthy tissue. These conditions require long term treatment through a variety of methods including drug use. We are honored to have Professor Jo Cambridge, Professorial Research Associate at University College London (UCL), share her research concerning b-cells and autoimmune disease treatment with us.
Professor Jo Cambridge has greatly contributed to the field of immunology. Some of her notable work includes being part of a team from Rayne Institute and University College London who first applied the use of B cell depleting agents (based on Rituximab) for autoimmune diseases. She continues to work on several projects involving B cell biology and the treatment of autoimmune diseases like Lupus, Rheumatoid Arthritis, Thrombotic thrombocytopenic purpura (TTP) and others using Rituximab. Professor Cambridge continues to extend her research concerning B-cells in patients with Chronic Fatigue Syndrome, observing how their energy demand changes as well as their metabolic responses.
Autoimmune disease links with B-Cells:
Immunology, which revolves around the study of the immune system, is a field that requires much passion from the individual, due to the extensive research involved. For Professor Cambridge, her interest lay with B-Cells and their role in autoimmune disease. Back in the 1990’s, Professor Cambridge disagreed with the public consensus that autoimmune disease was caused by T-cells. Her studies in muscle disease in children found that there was no muscle antigen targeting problem with the T-cells, leading her to hypothesize that immune complexes drove disease, which must thus involve the B-cells, which were responsible for antibody production.
During this time, her colleague Professor Jo Edwards had been working to treat patients with rheumatoid arthritis, who too believed that T-cells were not the problem. Rheumatoid arthritis is a disease of the joints that can also affect other tissues all over the body (a sort of systemic disease). At the time, it was theorised that the T-cells were attacking something specific within the joint. However, Prof Edwards noted that there were no special antigenic markers on the joints that were not present elsewhere. Thus the question was raised: how did the T-cells target the joint?
After reading a multitude of older research papers, Professor Edwards focused on the pathology of the patients and, with Professor Cambridge, created a list regarding the mysterious phenomenons that occurred. These included the peculiar systemic nature of the disease as well as the bizarre presence of rheumatoid factors –which are autoantibodies directed against antibodies and also antibodies that are directed against post-translational modifications to proteins. The antigens recognised by these autoantibodies were not targeted to the joint. Other papers revealed that patients with rheumatoid arthritis had immune complexes, which refer to antibodies linked to antigens that are common in all humans. Immune complexes cause macrophages to produce cytokines, which are proteins which can cause a wide range of symptoms such as headaches, increase in temperature, and, if produced in the joint, causes them to ache. For patients with rheumatoid arthritis, the excess in cytokine production causes continual pain in their joints.
These immune complexes are formed naturally upon infection from a virus, when B-cells create antibodies specific to the pathogen. However, before the antibody response gets established, due to the small number of antibodies, only small immune complexes form. These, in small quantities, are not visible to the complement proteins present in the blood that aim to rid the body of such small complexes. Thus, another method involving the usage of FC receptors, which bind to the FC region of the antibody within immune complexes, assists with the process of clearing them. The researchers thought that if such small immune complexes could be continuously formed due to the presence of autoantibodies in Rheumatoid arthritis, tiny immune complexes would be constantly formed but were not being removed in a ‘safe’ way. Based on these observations, Professor Cambridge and Dr. Edwards theorised that the small immune complexes within patients with rheumatoid arthritis were cleared by activatory FcG receptors. Following their analysis of human tissue, they found that these receptors were present on the macrophages in all tissues affected by rheumatoid arthritis. The macrophages present on the joint lining all had a particular FcG receptor that specialised in dealing with small immune complexes. These receptors were constitutively expressed on the joint macrophages, and were less common in other areas of the body.
Upon attempts to mimic the binding of FcG receptors and the small immune complexes, it was found that crosslinking these particular FcG produced tumor necrosis factor (TNF) molecules. TNF is produced by macrophages in the joint as well as other tissues and is the main driver of rheumatoid arthritis by causing inflammation and aches. Previous trials attempted to alleviate the aches via the usage of Anti-T-cell drugs (based on the aforementioned theories) to little effect. Consequently, however, TNF inhibitor drugs were developed and are used as the most common mode of treatment, but these are not able to be used in many types of patients, including previous cancer patients and those with infections.
In order to overcome this hurdle, Professor Cambridge set about finding another drug that could be used to treat rheumatoid arthritis. Both Professor Edwards and herself believed that another method to attack rheumatoid arthritis would be through killing B-cells, as B-cells are in charge of producing antibodies. In order to produce these autoantibodies, B-cells with the same specificity of surface receptors must be continuously produced by a process called clonal expansion. In autoimmune diseases, the B-cell receptor is deceived into giving itself its own signal, causing it to continuously make autoantibodies that attack the body’s own tissues. Thus, finding a drug that could kill the B-cells would prevent the production of these autoantibodies that attacked the body’s tissues, and thus help mitigate the effects of rheumatoid arthritis.
Introducing- Rituximab:
For this, Professor Cambridge and Edwards turned to Rituximab. Rituximab was the first anticancer drug that helped to attack Non-Hodgkin lymphoma, and is composed of engineered mouse/human antibodies that kill the B-cell via antigen CD20 in both lymphoma B-cells and normal B-cells. It helped to kill cancer cells within a year's treatment, greatly increasing the patient’s survival period. There were initial worries that the drug would cause immune deficiencies, but studies found that patients did not get many more infections as much of an adult’s immunity is based on long-lasting plasma cells that were unaffected by Rituximab, due to their absence of antigen CD20.
Due to Rituximab’s lower price (compared to TNF inhibitors) and ability to be used on patients regardless of previous cancer history and infections, it was chosen for Professor Edwards’ clinical study. In 1999, a study with five patients (that all were unable to receive treatment with TNF drugs due to the aforementioned reasons) was conducted. Patients were treated with five courses of Rituximab treatment. Though there was no sign of progress in the first month, the duo predicted that the lack of progression was due to the fact that antibodies had a half life of four weeks and thus more time would be needed to lower the antibody concentration. Lo and behold, after the first month, all patients slowly improved. Another trial involving 20-30 patients was also conducted by Professor Edwards and produced similar results. Though within this trial there were a few patients which expressed no change or improvements, these results were only present in patients which did not have autoantibodies in the first place. Thus, this confirmed the theory that rituximab could help rheumatoid arthritis patients with antibodies, and could possibly be extended to other autoimmune diseases.
During this time, a paper concerning the results of the study was written but was rejected by multiple scientific and medical journals. Eventually it was published in 2001 while other studies were carried out. In 2003, the drug company Roche finally started a clinical trial of Rituximab with a pool of over 160 patients. Tragically, the pair did not receive any funding from other establishments, companies, nor charities for their work. Nonetheless, the trial proved that Rituximab could be used to treat autoimmune diseases and is now used in around 750,000 patients worldwide. It is used as the first line of treatment in Brazil and, along with another anti-CD20 agent (Obinutuzumab), is one of the few licensed drugs used for lupus.
COVID-19 and Immune disease links:
Despite the potential havoc that the immune system can wreck on the body, it is still a crucial system that helps protect the body from disease. In order to effectively infect the body, many diseases have created mechanisms to prevent the activation of the immune system. In the case of COVID-19, upon its entry through the epithelium, it turns off the interferon pathway. The interferon pathway contains viral sensing proteins that can sense DNA/RNA production. If it senses the production of such proteins in the cytoplasm, the STING pathway will alert the cell to activate transcription factors to make interferons, proteins that stop viruses from entering neighbouring cells and also activate the immune system, thus halting the spread of disease. However, COVID-19 contains a protein that inhibits the anti-viral sensing pathway and thus prevents these protective mechanisms from kicking into action.
Apart from invading viruses and pathogens, the immune system can also be affected by outside stimuli. One such stimuli is stress, as increases in stress hormones are detected by receptors on immune cells, leading to a variety of responses. For example, a stress steroid hormone known as cortisol disrupts the cell’s typical processes like traveling through the lymphatic system to the bloodstream. Cortisol can also affect microbiomes in the gut, as it affects the gut’s ability to absorb food. Since the gut is the main source of the building blocks required for neurotransmitters, it is necessary to both eat properly and reduce cortisol levels to ensure optimal efficiency of bodily functions. High levels of cortisol are generated during long periods of stress and studying, and thus to reduce cortisol levels one must do some exercise and let out the accumulated burst of energy.
Some individuals may believe that they can “boost” and strengthen their immune systems by consuming vitamins. However, this is an inaccurate assumption given that vitamins do not directly trigger the immune system. Nonetheless, essential vitamins are used within the immune system for basic functions. For example, Vitamin D is important for macrophage functions as it is the main cofactor for oxidative killing. Thus, it is necessary for all individuals, including students, to get vitamin D from either an hour of exposure to the sun per day or consuming 1000 units of vitamin D. The lack of vitamin D has been proven to be important for combating COVID-19, as it has been found that the levels of vitamin D within an individual inversely correlated with the severity of disease. Consequently, large South-Asian populations suffer from COVID-19 more severely as their skin is developed to repel vitamin D.
Regardless, Professor Cambridge recommends that students get more exercise and spend more time in the sun in order to ensure their immune system is functioning at its optimal condition. Though this will be difficult for students, especially those who enter the medical field and enroll in medical school due to the intensive lessons involved.
Final advice:
Unlike the problem-based learning approach used by many Hong Kong Universities, UCL and many other universities in the United Kingdom prioritise building a good foundation of understanding concerning the scientific aspects of the field. In their first three years, students will mainly engage in non-patient-based learning which involves theory and lab work. Students will only face patients in their 4th year onwards, in which they will be taught in the wards in small groups. During this time, students will be able to circulate through different specialties at a relatively quick pace, allowing them to have a bit of experience in the different fields of medicine. The learning is mainly tutor-lead, with students often being encouraged to think through problems and issues rather than being quizzed on different concepts. This is as the answers in medicine are rarely obvious, requiring much reading, understanding and experience to recognise.
Upon one's analysis of diseases and illnesses, it is extremely important to study its pathology. This is due to the fact that a lack of knowledge in what is occurring in the affected tissue/blood/areas leads to an inability to understand the cause of the disease. Through intellectual thought and analysis, one must brainstorm possible ideas as to what is perpetuating the disease. Then, these ideas can be explored further through reading more studies and conducting trials, allowing another small piece of the puzzle that makes up the human body to be revealed.
Professor Cambridge helped to provide an in-depth explanation of her research on the immune system. Upon delving deeper into the nature of a single part of the immune system, B-cells, and a single drug, Rituximab, she was able to make new discoveries in the field. These discoveries in turn sparked further research into a multitude of different autoimmune diseases and possible new treatments. We hope that this article will help spark our readers interest in the field of immunology and passion for unraveling the many mysteries of the human body.
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