The immune system is one of the most complex, and nuanced biological systems that functions to keep the human race alive each and every day. It is both specific and broad, lifelong, and short-term, inherited and acquired, all at the same time. While it defends against deadly threats such as bacteria and viruses, defects in the immune system can be just as fatal. The Immune System 101 articles describe how this contradictory system works and will summarize the variety of functions of the immune system, its importance, and its potential failings in six different articles.
1. The Human Immune System 101: Innate Immunity
2. The Human Immune System 101: Adaptive Immunity
3. The Human Immune System 101: Bacterial & Viral Defenses Against the Immune System
4. The Human Immune System 101: The Overactive Immune System
5. The Human Immune System 101: The Underactive Immune System
6. The Human Immune System 101: The Immune System and Cancer
The immune system is typically divided into two distinct types of immunity that work together to defend against organisms that cause diseases, also known as pathogens. These different arms of the immune system are known as innate and adaptive immunity. Each of these subsets of immunity can be divided further into humoral and cellular immunity, with the humoral section consisting of molecules circulating the bloodstream such as complement proteins (innate immunity) and antibodies (adaptive immunity), whereas cellular immunity consists of specific cells such as T cells (adaptive immunity) and neutrophils (innate immunity) that carry out specific immune functions.
Innate immune responses are typically rapid and can be triggered without the selective events that underlie adaptive immunity, which is characterized by antigen-specificity and immunological memory (Gasteiger, G., D’Osualdo, A., et al., 2016, p. 112).
Figure 1: A Variety of White Blood Cells. Jarun Ontakrai. (2020).
Cellular Innate Immunity
The innate immune system, also known as non-specific immunity, is activated within minutes of exposure to germs and recognizes pathogens through “highly conserved structures expressed by large groups of microbes or common biological consequences of infection” (Turvey, S. E., & Broide, D. H., 2010, p. 26). More simply put, distinct types of microbes express common groups of receptors that are specific to pathogens and therefore are not present in self-tissues. These are known as pathogen-associated molecular patterns (PAMPs) and are recognized by pattern recognition receptors (PRRs) present on the surface of innate immune cells as well as some cells that are not a part of the immune system. Additionally, innate immune cells can recognize damage-associated molecular patterns (DAMPs) that commonly occur as a result of infection or inflammation; these molecules may be released into the bloodstream and are recognized by white blood cells after cellular and tissue damage that is characteristic of infections and inflammation. (Turvey, S. E., & Broide, D. H., 2010, p. 24-26; Kawasaki, T., & Kawai, T., 2014, p. 1-2). After pathogen recognition occurs, the innate immune response is carried out by cellular or humoral-mediated responses (Turvey, S. E., & Broide, D. H., 2010, p. 25-26)
The cellular innate immune responses are conducted by a variety of different white blood cells such neutrophils, macrophages, natural killer cells, and dendritic cells, to name a few. The pathway in which the innate immune system is typically activated begins with a PRR, often one specific receptor known as a toll-like receptor (TLR) that is “expressed in innate immune cells such as dendritic cells and macrophages as well as non-immune cells such as fibroblast cells and epithelial cells” (Kawasaki, T., & Kawai, T., 2014, p. 1) and that recognizes specific PAMPs. There is a large array of PRRs that initiate the innate immune response through activation upon contact with PAMPs and trigger the release of inflammatory molecules known as cytokines, among a large array of other stimulants (Amulic, B., Cazalet, C., et al., 2012, p. 461-462). When released, cytokines cause the migration of more innate immune cells, such as neutrophils and macrophages, to the site of the infection (Gasteiger, G., D’Osualdo, A., et al., 2016, p. 112). This article uses neutrophils as an example of how cellular innate immunity functions.
Figure 2: Two Neutrophils Among Red Blood Cells. Ed Uthman. 2017.
Once recruited to the site of infection, neutrophils—one of the most important cells of the innate cellular immune response—employ a variety of tactics to begin clearing pathogens, however only three will be described in this article: degranulation, phagocytosis, and neutrophil extracellular traps (NETs). First off, it is essential to understand the function of granules, which are “specialty storage organelles” within neutrophils, contain enzymes known as lysozymes, “are brimming with anti-microbial compounds, and function as a primary repository for the molecular weaponry of neutrophils” (Amulic, B., Cazalet, C., et al., 2012, p. 465-466). During the process of degranulation, a granule’s membrane fuses with the neutrophil’s cell membrane, releasing the antimicrobial enzymes to the site of inflammation or infection, creating an “environment inhospitable to invading pathogen” (Amulic, B., Cazalet, C., et al., 2012, p. 466).
Next, phagocytosis-mediated pathogen removal is a key component of how neutrophils work to clear infectious materials. To begin the process, PRRs on the surface of neutrophils bind to PAMPs on the surface of a pathogen. The cell membrane engulfs the microbe, pinching off in certain areas to create a phagosome that contains the pathogen. Once internalized, the process of killing the microbe is similar to degranulation in that the phagosome fuses with the granule, creating what is often referred to as a phagolysosome, where the granules’ antimicrobial properties act upon the pathogen (Amulic, B., Cazalet, C., et al., 2012, p. 466). The process of phagocytosis occurs in other innate immune cells such as macrophages and monocytes (Gasteiger, G., D’Osualdo, et al., 2016, p. 112-115).
Finally, upon contact with pathogens, neutrophils can form extracellular traps through a process known as NETosis. The formation of these traps requires that neutrophils undergo cell death and release “decondensed chromatin into the extracellular space” (Amulic, B., Cazalet, C., et al., 2012, p. 471). Chromatin fibers house genetic material and histone proteins which keep the DNA condensed; in the case of NETs, these fibers uncoil after histone degradation and are released into the extracellular matrix where the pathogens are located. Antimicrobial enzymes such as myeloperoxidase (MPO) and neutrophil elastase (NE) that reside within lysozymes enter the cytoplasm and nucleus during cell death, and are responsible for this histone degradation, causing chromatin to uncoil, thus contributing to NET formation. One formed, NETs contain these antimicrobial enzymes and are able to ensnare and inactive pathogens (Amulic, B., Cazalet, C., et al., 2012, p. 471-472).
Figure 3: Functions of a Neutrophil. Barbara Gierlikowska, Albert Stachura, et al. 2021.
Humoral Innate Immunity
While the cellular innate immune response relies on specialized cells to recognize and destroy pathogens, the humoral immune system is dependent on “soluble pattern recognition molecules (PRMs) that recognize PAMPs and initiate the immune response in coordination with the cellular arm, therefore acting as functional ancestors of antibodies” (Inforzato, A., Bottazzi, B., et al., 2016, p. 1). These PRMs include proteins involved in the complement cascade, naturally occurring antibodies (Nab), and pentraxins, among a whole host of others.
The complement system consists of an array of thirty-five different complement proteins that are activated through three different cascade pathways: alternate, classical, and lectin-pathways (Degn, S. E., & Thiel, S., 2013, p. 182). Each of these cascade pathways converges on the C3 protein, the most common of the complement proteins found in the bloodstream, and creates (Sarma, J. V., & Ward, P. A., 2010, p. 227). NAb recognizes pathogens through PAMPs and activates both the classical and lectin pathways, while the alternate pathway is triggered by the presence of bacterial carbohydrates, lipids, and proteins (Shishido, S. N., Varahan, S., et al., 2012, p. 143-144). Each pathway ends with the terminal pathway and the formation of a membrane attack complex (MAC) from a collection of complement proteins which forms a pore in the pathogen’s cell membrane or wall that cause the invading cell to swell with water and, ultimately, bursts (Shishido, S. N., Varahan, S., et al., 2012, p. 144).
Figure 4: Membrane Attack Complex Formation. Andrade, Fabiana & Lidani, et al. 2017.
In addition to complementing proteins, pentraxins play a crucial role in the clearance of pathogens. In fact, after binding to pathogens, pentraxins play a crucial role in activating the complement pathways for the eventual removal of the pathogen by macrophages or MACs. Pentraxins, such as C-reactive proteins (CRPs), are a type of PRM that mark inflammation, infections, and tissue damage. Through binding to bacteria and other pathogen membranes, pentraxins mark these harmful organisms for clearance by macrophages, thereby working directly with the cellular arm of the innate immune system (Shishido, S. N., Varahan, S., et al., 2012, p. 144). These PRMs are a critical component of the immune system, interacting with both humoral and cellular components of the innate immune system to protect against deadly threats.
Overall, the innate immune system functions rapidly after pathogen exposure to alert the body of potential threats and directly eliminate them. While the humoral arm creates molecules to patrol the bloodstream for signs of danger, the cellular arm metaphorically watches for those signals, and together they clear infected areas. Recognizing these pathogens is an art that the immune system must master, as failure to do so may result in more harm than good; not only do the two sections of the innate immune system work together to keep a person healthy, but they also work with the much more specific leg of the immune system that employs very particular methods of pattern recognition: adaptive immunity.
Amulic, B., Cazalet, C., Hayes, G. L., Metzler, K. D. & Zychlinsky, A. (2012). Neutrophil Function: From Mechanisms to Disease. Annual Review of Immunology, 30 (1), 459–489. https://doi.org/10.1146/annurev-immunol-020711-074942
Degn, S. E. & Thiel, S. (2013). Humoral Pattern Recognition and the Complement System. Scandinavian Journal of Immunology, 78 (2), 181–193. https://doi.org/10.1111/sji.12070
Gasteiger, G., D’Osualdo, A., Schubert, D. A., Weber, A., Bruscia, E. M. & Hartl, D. (2016). Cellular Innate Immunity: An Old Game with New Players. Journal of Innate Immunity, 9 (2), 111–125. https://doi.org/10.1159/000453397
Inforzato, A., Bottazzi, B., Garlanda, C., Valentino, S. & Mantovani, A. (2011). Pentraxins in Humoral Innate Immunity. Advances in Experimental Medicine and Biology, 1–20. https://doi.org/10.1007/978-1-4614-0106-3_1
Kawasaki, T. & Kawai, T. (2014). Toll-Like Receptor Signaling Pathways. Frontiers in Immunology, 5. https://doi.org/10.3389/fimmu.2014.00461
Sarma, J. V. & Ward, P. A. (2010). The Complement System. Cell and Tissue Research, 343 (1), 227–235. https://doi.org/10.1007/s00441-010-1034-0
Shishido, S. N., Varahan, S., Yuan, K. Li, X. & Fleming, S. D. (2012). Humoral innate immune response and disease. Clinical Immunology, 144 (2), 142–158. https://doi.org/10.1016/j.clim.2012.06.002
Turvey, S. E. & Broide, D. H. (2010). Innate Immunity. Journal of Allergy and Clinical Immunology, 125(2), S24–S32. https://doi.org/10.1016/j.jaci.2009.07.016
Cover Image: Spano, C. (2020). How SARS-COV-2 Kills. [Illustration]. Retrieved from: https://www.economist.com/briefing/2020/06/06/how-sars-cov-2-causes-disease-and-death-in-covid-19
Figure 1: Ontakrai, J. (2020). White Blood Cells in Peripheral Blood Smear. [Image]. Retrieved from https://www.news-medical.net/news/20200519/Does-COVID-19-infect-peripheral-blood-cells.aspx
Figure 2: Uthman, E. (2017). Hypersegmented Neutrophils. [Image]. Retrieved fromhttps://www.flickr.com/photos/euthman/36831145373
Figure 3: Gierlikowska, B., Stachura, A., Gierlikowski, W. & Demkow, U. (2021). The Killing Mechanisms of Neutrophils; Phagocytosis, Degranulation, and Extracellular Traps Release. [Illustration]. Retrieved from https://www.frontiersin.org/articles/10.3389/fphar.2021.666732/full#B126
Figure 4: Fabiana, A. Lidani, K., Catarino, S., Messias-Reason, I. (2017). Serine Proteases in the Lectin Pathway of the Complement System. [Illustration]. Retrieved from https://link.springer.com/chapter/10.1007/978-981-10-2513-6_18