Role of Epigenetics in Immunity and Immune Response to Vaccination

Necip Ozan Tiryakioglu

Necip Ozan Tiryakioglu will always be remembered for his hardworking, scientific seriousness, and productivity. We would like to extend our condolences to his family, lovers, and the scientific community.

The Immune System

An effective immune system is the result of interaction and interplay between the innate immune system and the adaptive immune system.

Innate immunity functions as general resistance, which provides continuous but non-specific protection against pathogens. This general resistance involves natural protections such as skin, low gastric pH, lysozyme, mucus, cilia, and the natural microflora. The innate immune system does not provide a specific and reinforced response to repeated pathogen exposure and is therefore described as not having “long term memory” (Turvey and Broide 2010).

Additional components of innate immunity include interferons and collagen-containing C-type lectins (collectins). Interferons are categorized as Type I and Type II. Type I interferons are synthesized by host cells in response to viral infection and give rise to increased antiviral activity in neighboring cells (De Andrea et al. 2002). Collagen-containing C-type lectins on the other hand are present in serum and on mucosal surfaces. Collectins act by binding to membrane oligosaccharides or lipids of microorganisms. This binding may cause a direct elimination of the micro-organisms by membrane destabilization or result in an indirect response such as facilitating the phagocytosis of infectious microorganisms by cell aggregation (Atochina-Vasserman 2012). The innate immune system also has three complement pathways classified as the classical pathway, the properdin pathway, and the lectin pathway. The classical pathway is induced by the binding of immunoglobulin M (IgM) or some immunoglobulin G (IgG) antibodies to the surface antigens of microorganisms. The other complement pathways, the properdin, and the lectin pathways do not require antibody binding for activation. Instead they are induced by the accumulation of certain membrane-binding proteins on microbial membranes. The combinatory action of these three pathways is called the complement cascade which triggers three important functions of the immune system: 1) phagocytosis, 2) inflammation, and 3) rupturing of bacterial cell walls (Rus, Cudrici, and Niculescu 2005).

Another crucial part of innate immunity is the pattern recognition receptors (PPRs), which are produced by innate immune system cells and function as molecular detectors for certain pathogen-associated molecules. The first group of molecules recognized by PPRs are pathogen-associated molecular patterns (PAMPs) (Amarante-Mendes et al. 2018; Akira, Uematsu, and Takeuchi 2006). PAMPs are not found naturally in mammalian cells and comprise of molecules which are necessary for microbial survival. The second group of molecules recognized by PPRs are the damage-associated molecular patterns (DAMPs). DAMPs are molecules released by host cells upon cell damage (Rajaee, Barnett, and Cheadle 2018). PPRs cooperate with each other to initiate expression of certain genes, triggering cellular immune responses to eliminate pathogens. They also induce the release of inflammatory cytokines (Takeda, Kaisho, and Akira 2003). The final components of innate immunity are mononuclear phagocytes and granulocytic cells. These cells also establish the link between innate and adaptive immunity. Mononuclear phagocytes are produced by bone marrow and can later differentiate into monocytes. Differentiated monocytes later migrate in tissues and further differentiate into macrophages or dendritic cells (Hume et al. 2002). Dendritic cells are crucial for the link between the innate and adaptive immune systems (Hoebe, Janssen, and Beutler 2004). Granulocytes are categorized as neutrophils, eosinophils, basophils, and mast cells (Breedveld et al. 2017). Neutrophils are the most numerous and active of phagocytic cells. Eosinophils show less phagocytic activity and are more specialized against parasites. Basophil constitutes approximately 1% of circulating leukocytes (Stone, Prussin, and Metcalfe 2010). They are particularly prominent in allergic reactions and release histamine among other molecules when they receive damage (Siracusa et al. 2013). Mast cells reside in tissues and contain relatively high amounts of histamine and heparin which are released upon their activation (Rivera et al. 2008). A fully functional immune system and therefore an effective immune response relies on the interaction between the innate and adaptive immune systems. Innate immunity functions as a quick response and may in some cases be able to eliminate the pathogen by itself. In other cases, the activation of the adaptive immune system by the innate immune system is required to eliminate the pathogen. The main functional difference between these systems is the response time. The first encounter with a certain pathogen evokes a quick response from the innate immune system and a slower but more systemic response from the adaptive system. The adaptive immune system adapts to antigens from pathogens or vaccination over repeated exposure, hence its name, and provides a more rapid response with each exposure due to its “memory” (Nicholson 2016). The two types of adaptive immunity are antibody-mediated immunity and cell-mediated immunity. The В cells and antibodies constitute the antibody-mediated immunity while the T cells compose cell-mediated immunity (Janeway et al. 2001). The antibody-mediated immunity, also called as humoral immunity, functions via activated В cells and antibodies. В cells originate from bone marrow and express В cell receptors which bind specific antigens and induce a response. Since these antigens do not require T cell activation to activate В cells, they are called T-independent antigens. Bacterial polysaccharides and lipopolysaccharides are such T-independent antigens and can induce antibody production by В cell without the help of T cells (Janeway et al. 2001). The activation of В cells without T-helper cells induce a weaker response in comparison to the activation with T-helper cells (Kurosaki, Kometani, and Ise 2015; McHeyzer-Williams et al. 2012). The response induced via T-helper cells is more effective, especially in terms of long-term immune memory, which is the main goal of vaccine-induced immunizations (Goldsby et al. 2003). The binding of antigens to В cell receptors and the release of cytokines from T cells stimulate the maturation of В cells, leading to more specific antibody production. Mature В cells later produce clones which produce IgM. IgM is the foremost antibody produced after a first-time encounter with a specific antigen (Capolunghi et al. 2013). Further downstream in the immune response the production of antibodies shifts to IgGs from IgMs. This event is called immunoglobulin class switching or isotype switching (Market and Papavasiliou 2003). IgG is the main antibody type in circulation and more effective at antibody neutralization. These features make IgGs crucial for vaccine immunization. The production of memory cells and IgGs facilitates a quicker and widespread response for the future encounters with the pathogen.

The second type of adaptive immunity is cell-mediated immunity. Cell-mediated immunity functions via T cells which are released into circulation following their maturation in the thymus. T cells are categorized as CD4+ cells and CD8+ cells according to the type of T cell receptor (TCR) they express. The helperT cells express CD4 receptors while cytotoxic T cells express CD8 TCR (Margolick, Markham, and Scott 2006). There are two types of helper T cells, Thl and Th2. Thl cells are involved in cell-mediated immunity and Th2 cells are involved in antibody-mediated immunity (O’Garra and Arai 2000). In contrast to В cells, T cells require antigen processing by antigen-presenting cells for antigen recognition. Following activation and clonal expansion, memory T cells are produced to induce a rapid immune response for subsequent infections (Pennock et al. 2013). Following their formation, memory T cells can provide immunity for approximately ten years (Hammarlund et al. 2003).

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