The immune system deserves credit. For all the times we forget to wash our hands or ignore the five-second rule, our immune system is there to bail us out, never expecting an ounce of appreciation. For all the times bacteria and viruses tried to get ahead in the evolutionary arms race, the immune system continues responds with brilliant advancements in their processes. For all the magic that our immune systems performs on a minute-by-minute basis, however, there is a chink in the proverbial armor of the immune system: autoimmunity. Autoimmune diseases occur when the body’s natural line of defense identifies a naturally-occurring substance as a threat, whether that be a beneficial bacteria that lives in our intestine or even our own tissues, and proceeds to mount an immune response.
The seriousness of autoimmunity begs the question of how it comes to rise in the first place. Our bodies have evolved to develop an arsenal of lymphocytes, or cells that regulate the immune system, that are specific to specific types of pathogen that we could encounter, whether that be bacteria, virus or fungi (Rosenblum et al., 2015). T-cells are a type of lymphocyte that can either have a killer function against these antigens, or in the case that the object of encounter isn’t dangerous, a tolerance to them. Ultimately, the fundamental basis of autoimmune disease is the presence of T-cells that mistakenly react to our own tissues as they would with pathogens and perform their effector function of killing (Smith et al., 1999).
As one may expect, when autoimmunity arises, the immune system will perform its usual function as if it were fighting a foreign invader. One of the key players in the immune system’s pathogen sensing are DCs. Although they shouldn't be confused with the comic book universe, DCs, or dendritic cells, do play a superhero function in the context of our immune system. They patrol the outskirts of our body (such as the skin, mucous and intestines) on the hunt for anything out-of-the-ordinary and process them in such a way that the immune system will recognize them as something that needs to be taken care of. DCs are truly the bridge between our innate immunity, which regulates the broad, immediate responses we mount against invading bacteria and viruses, and our adaptive immunity, which may take longer to initiate but is more specific to whatever pathogen we are fighting.
Figurably, DC function is also crucial within the context of autoimmunity. In non-autoimmune conditions, DCs can present non-harmful antigen, or processed pieces of a bigger protein, to a T cell to make T cells tolerant to that protein (Ganguly et al., 2013). After DCs process an antigen, they migrate to the nearest T-cell “base” at a nearby lymph node, and present that antigen to them while releasing releasing pro-inflammatory chemicals called cytokines (Ganguly et al., 2013). Ultimately, many of the symptoms of autoimmunity diseases are the same as within normal diseases, such as chronic inflammation to tissues which could prove lethal (Janeway et al., 2001).
As dendritic cells can be powerful positive regulators of autoimmunity, they are also the target of immunotherapies against autoimmune diseases. Therapies often target regulators of DC function to dampen this pro-autoimmune effect. One of these regulators is a group of proteins called arrestins, which regulate survival and motility in pro-inflammatory cells like macrophages. In a recent study published in the Journal of Immunology, researchers identified a specific arrestin, B-arrestin 2, as a regulator of DC migration. Their research aim was to learn about the protein to determine how it affected autoimmunity, and their results were very telling.
First, the researchers found that B-Arrestin 2 is in some way incorporated with limiting the mobility of dendritic cells. They were able to prove this by finding that mouse bone marrow dendritic cells with mutated B-Arrestin proteins showed both more molecular markers signifying DC maturation as well as allowed for more DC migration to draining LNs. They even saw a physiological result in mice as a result of the mutated DCs in the shape of ear swelling! Keeping in mind that one of the ways to prevent inflammation from autoimmunity is to tamper down the migration of DCs to the lymph nodes, the fact that mutant B-Arrestin allows for increased motility suggests its important regulation.
Not only does nullifying the function of B-Arrestin 2 allow for increased maturation rates and motility of DCs, but it also causes the release of chemicals that encourage T cells to facilitate B-cells to activate against a given antigen. The researchers also went on to identify molecules that interact with B-Arrestin 2 and even chart the pathway that B-Arrestin 2-deficient DCs migrate to the lymph nodes to activate T-cells. Not only does having deficient B-Arrestin 2 prevent its own function, but there are an additional 2500 genes that were expressed differently in the mutated DCs in mice!
Perhaps the most functionally important finding was the fact that mice with DC cells lacking B-Arrestin 2 had worse cases of EAE, or Experimental autoimmune encephalomyelitis. For mice with the mutation, there was a significantly higher clinical score (marking severity of the disease), more infiltration of cells into the spinal cord and demyelination which harms nerve tissue. Another autoimmune disease called SLE (lupus) shows that B-Arrestin 2 deficiency in DCs causes a buildup of different subtypes of DCs in the lymph nodes, a dangerous place for build-up given their ability to prime T-cells against self-tissue for disease developments. Images below show (A) the increased clinical severity, (C/E) increased T-cell accumulation of B-Arrestin 2-deficient mice. The bar chart shows deficient mice in black and the functional mice in white, a clear discrepancy in the amount of cells infiltrating the spinal cord.
The plethora of ways that these authors were able to see the effects of B-arrestin 2-deficiency in DCs in mice open up a world of opportunities in the fight against autoimmune diseases. When the arrestin proteins are knocked out, migration and maturation of DCs allow for T-cells that usually perform inflammatory and killing functions against pathogens actually do so against self-tissue. While it remains to be seen if human dendritic cells behave in similar ways that mouse DCs do, given that mice have proven to be a successful model organisms is promising for the development of immunotherapies. Potential therapy can perhaps restore proper function of arrestin and arrestin-related proteins in DCs, or even introduce DCs with high expression of arrestin into inflammatory sites in autoimmune patients.
Given how impeccable our immune system usually responds, it makes sense that in the rare cases that something goes awry, it has drastic effects. The autoimmunity treatment industry is estimated to be $45.54B by 2022 (PR News Wire) and is one of the top 10 leading causes of death in female children and women due to its sex-hormonal dependence (American Autoimmune Association\). Especially when it comes to key players like dendritic cells, the identification of proteins that could potentially limit symptomology in autoimmunity could have wide-reaching advantages for patients and families affected everywhere.
Works cited:
- Ganguly D, Haak S, Sisirak V, Reizis B. The role of dendritic cells in autoimmunity. Nat Rev Immunol. 2013;13(8):566-77.
- Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. Autoimmune responses are directed against self antigens. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27155/
- Rosenblum MD, Remedios KA, Abbas AK. Mechanisms of human autoimmunity. J Clin Invest. 2015;125(6):2228-33.
- Yingying Cai, Cuixia Yang, Xiaohan Yu, Jie Qian, Min Dai, Yan Wang, Chaoyan Qin, Weiming Lai, ShuaiChen, Tingting Wang, Jinfeng Zhou, Ningjia Ma, Yue Zhang, Ru Zhang, Nan Shen, Xin Xie, Changsheng Du. Deficiency of β-Arrestin 2 in Dendritic Cells Contributes to Autoimmune Diseases. The Journal of Immunology December 12, 2018, ji1800261; DOI: 10.4049/jimmunol.1800261
- Smith, D A and D R Germolec. “Introduction to immunology and autoimmunity” Environmental health perspectives vol. 107 Suppl 5,Suppl 5 (1999): 661-5.
- Wang L, Wang F‐S, Gershwin ME (Research Center for Biological Therapy, the Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China; and Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA). Human autoimmune diseases: a comprehensive update. (Review).J Intern Med 2015; 278: 369–395.
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