Autoimmunity: Why does your body attack your own cells?

By MingMing Yang

Our immune system is complex and vital for our survival. Unlike other body systems, it is pervasive, spreading throughout our body involving many kinds of cells, organs, and tissues (The immune system: Cells, tissues, function, and disease., 2018). In normal conditions, it recognizes invading pathogens and damaged cells in our body, mounting an immune response, mostly carried out by white blood cells called lymphocytes, recognizing and eliminating foreign antigens, preventing them from further invading our body. However, this tightly regulated process could sometimes go wrong, in which our immune system mistakenly take our own body cells as foreign and trigger an immune response against our own body tissues, producing autoimmune disorders (Autoimmunity | biology, n.d.). Unlike autoinflammation, where the innate immune system directly causes tissue inflammation due to dysregulated secretion of pro-inflammatory cytokines, autoimmunity involves the inaccurate activation of the adaptive immune system, which produces autoantibodies that destroy our own cells (Doria et al., 2012).

To better understand autoimmunity, the concept of ‘self-tolerance’ has to be first introduced. It is an important mechanism for the immune system to recognise ‘self’ from ‘non-self’, and only mount appropriate immune responses when encountering foreign substances. During the differentiation and maturation of T cells and B cells in the thymus and the bone marrow respectively, a process called V(D)J recombination occurs. This assembles antibody genes from three separate gene segments, creating huge diversity in these antibodies expressed on the surface of B or T cells (B cell receptor (BCR) and T cell receptor (TCR) respectively), or a secreted form produced by B cells called immunoglobulin (Ig). A significant portion of antibodies generated via this random process bind to one or more self-antigens, which is potentially dangerous. This is when mechanisms, collectively called central tolerance, that prevent the maturation of these self-responsive lymphocytes come in place. This involves clonal deletion which causes apoptosis of autoreactive lymphocytes, and clonal anergy, which lead to functional elimination of these cells via down-regulation of responsiveness. When B cells further undergo affinity maturation and somatic hypermutation in peripheral tissues after maturation, peripheral tolerance comes in to ensure that no self-reactive antibodies are produced during these changes in the BCR. This is done by a lack of T cell help in self-reactive B cells, in which T cells that recognise the MHC Class II-presented antigen will not be able to detect B cells with self-antigen present on MHC Class II as a result of successful T cell tolerance, leading to a loss of survival signal for those B cells(Goodnow et al., 2005; Smith & Germolec, 1999). However, when tolerance is broken and these elimination processes fail, autoimmune disease is produced.

Autoimmune diseases are believed to arise from both genetic and environmental factors, with a hypothesis that polymorphisms in various genes result in defective regulation for lymphocyte activation, and environmental factors initiate or augment activation of self-reactive lymphocytes that have escaped control and could react against self-components (Rosenblum, Remedios & Abbas, 2015). It is divided into two classes: organ specific, in which antibodies react to self-antigens localized in a specific tissue; and systemic, characterized by reactivity against a specific antigen or antigens spread throughout various tissues in the body (Smith & Germolec, 1999). 

In organ-specific autoimmune diseases, Th1 cytokines such as IL-2 and IFN-y are said to predominate, and the effector responses tend to occur via cell-mediated immune responses including killing by cytotoxic T cells through the release of cytokines, or through directing IgG and IgM antibodies toward cell-surface antigens, triggering Fc receptor-mediated killing (Smith & Germolec, 1999). An example of this is Type 1 diabetes, characterized by autoimmune response against pancreatic β cells, leading to reduced or ceased insulin production. It is generally said to be a T cell-mediated autoimmune disease, which induces autoantibodies circulating to various islet cell antigens followed by the destruction of pancreatic β cells. Thus, anti-islet autoantibodies are used as a predictive marker for the development of the disease (Kawasaki, 2014). 

Systemic autoimmune disorders are distinguished by elevated levels of Th2 cytokines such as IL-4, IL-5, and IL-10, the widespread circulation of autoantibodies and immune complex deposition, opsonization with antibody, and cell damage via complement-mediated lysis (Smith & Germolec, 1999). For example, systemic lupus erythematosus (SLE) is a chronic autoimmune connective tissue disorder that can affect any part of the body, associating with diverse abnormalities of the skin, kidney, and haematological and musculoskeletal systems. It is characterized by multisystem microvascular inflammation with the generation of numerous autoantibodies, in particular, antinuclear antibodies (ANA). Affecting the immune system, SLE reduces the ability of the body to prevent and fight infection. Moreover, many of the drugs used to treat SLE also suppress the function of the immune system, further reducing the ability of it to fight infection (COJOCARU et al., 2011).

As autoimmunity is resulted from a disruption of balance within the immune system, traditional treatments have relied on immunosuppressive medications that dampen immune responses globally in order to alleviate symptoms. Attempts to correct specific deficits are also made in organ-specific autoimmune diseases. Although these drug treatments show promising results and are highly effective for many patients, long-term treatments with high doses are often required to maintain disease control. This leaves the patient susceptible to life-threatening opportunistic infections and long-term risk of malignancy due to having suppressed immune systems. In addition, the benefits of many of these drugs are counterbalanced by their toxicity and serious side effects (Rosenblum et al., 2012). Therefore, researchers are trying to develop more sustainable ways in treating autoimmunity. 

Costimulatory blockade is one of the attractive potential treatments for autoimmune diseases. Since costimulatory signal provided by antigen-presenting cells is crucial for T cell activation, specifically blocking this pathway aimed to render self-reactive T cells anergic and attenuate the overall autoimmune response. Using cytotoxic T lymphocyte–associated antigen 4 (CTLA-4)–Ig for this approach, which directly prevents costimulation mediated by CD28, has by far shown the greatest success. Treatment with CTLA-4–Ig was shown to be effective in both rheumatoid arthritis and psoriatic arthritis and has recently shown promise in treating type 1 diabetes (Rosenblum et al., 2012).

Another exciting approach in treating autoimmune diseases is regulatory T cell (Treg) therapy. Tregs are a subset of CD4+ T cells that express high levels of the interleukin-2 (IL-2) receptor α chain CD25, and the transcription factor Foxp3. It is shown to suppress pathogenic immune responses directed at self-antigens. Hence, being able to isolate, activate and expand these cells ex vivo to high numbers, and adoptively transfer them to patients with autoimmune disease might be an option to suppress and potentially cure the ongoing autoimmune response (Rosenblum et al., 2012). A clinical trial using this approach in patients with new-onset Type 1 diabetes obtained optimistic results, in which eight out of twelve patients met remission criteria for reduced insulin supplementation and one patient became insulin independent after the trail, and no severe adverse effects were observed (Kumar et al., 2019; Marek-Trzonkowska et al., 2014).

The water that bears the boat is the same that swallows it up. This summarizes our immune system in autoimmunity. Though effective cures for these mysterious conditions are not yet found, our understanding to these disorders is ever increasing. With ongoing effort in research that are providing encouraging results, we can remain hopeful that new therapies for autoimmune diseases can be developed in the near future.


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Rosenblum, M. D., Gratz, I. K., Paw, J. S. & Abbas, A. K. (2012) Treating Human Autoimmunity: Current Practice and Future Prospects. Science Translational Medicine. 4 (125), 125sr1. Available from: Available from: doi: 10.1126/scitranslmed.3003504. [Accessed Feb 16, 2021]. 

Rosenblum, M. D., Remedios, K. A. & Abbas, A. K. (2015) Mechanisms of human autoimmunity. The Journal of Clinical Investigation. 125 (6), 2228-2233. Available from: Available from: doi: 10.1172/JCI78088. 

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