Knowledge & Functional Transformation in Immune System

ALL men by nature desire to know.

                                    -Aristotle, Metaphysics, Book I.

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      There is a biological defense system, which we call the immune system, in evolutionarily relatively more advanced organisms. Basically, the immune system is examined in living things as two separate sub-systems. The innate immune system has a fast and nonspecific defense mechanism, while the adaptive immune system generates a slow but pathogenic specific response. Adaptive immune system has unique immunological cells. One of them is B cells. B cells are factories of the adaptive system that synthesize antibodies and cytokines. Antibodies provide unique binding affinity to specific antigens secreted by pathogens¹. B cells are basically a white blood cell called the lymphocyte group and mature in the bone marrow. B cells are also included in the group of antigen presenting cells. The most important feature that distinguishes B cells from other adaptive immune system cells i.e. T cells and NK cells is the synthesis of B cell receptors (BCRs) on their cell surface. Basically, the maturation of B cells takes place in three stages; class switching, Somatic hypermutation, career decision². 

Figure 1. Class switching molecular mechanisms and different isotypes of antibodies. (https://www.immunology.org/)

• This class switching mechanism, which is described as class change recombination (CSR), is a biological phenomenon that changes the immunoglobulin production of a B cell from isotype, which is constantly synthesized (default), IgM to different isotopes, such as isotype IgG. During this process, the constant region portion of the antibody heavy chain is changed, but the variable region of the heavy chain remains the same. This can basically be said to not affect antigen specificity for such class change. Instead, the antibody activates different effector mechanisms while maintaining affinity for the same antigens. This allows broad range spectrum action for B cells.  As B cells mature, newly formed IgA, IgG, and IgE antibodies as a result of DNA cut-off in the IgM encoding genes provide different advantages in the immunological mechanisms for B cells. This mechanism was demonstrated in Figure 1. This class switching is mainly caused by T cell dependent and T cell independent mechanisms. In T cell-dependent activation, helper T cells activate class switching by secreting various interferon leukins (ILs) and binding to the CD40 receptor (via CD40L on Th cells) on the B cell surface³. T cell-dependent B cell activation was illustrated in Figure 2.

Figure 2.  T cell-dependent activation of B cells, CD40 and cytokines involve activation (wikipediacommon.com).

In this work, the advantages of changing the default IgM antibody to IgG and IgE antibodies in activated B cells will be discussed.

Class switching from IgM to IgG antibodies

• In activated B cells, the IgM antibody is known as the default isotype. Similar to the combination of five IgG antibodies in the form of a star ring, the IgM antibody performs a very basic task, such as activating the complement system during infection. By combining C3 protein complexes via IgM, it can neutralize many pathogens by activating the complement system in the early stages of infection. By cutting DNA out of the gene region encoding the IgM antibody, IgG isotypes are obtained. The Fc region of IgG antibodies was synthesized differently than IgM antibodies. Although antigen binding is the same in this newly formed isotype, it causes functional change in B cell. IgG antibodies can activate the complement system, just like IgM antibodies. But unlike IgM antibodies, it has introduced new functions such as opsonizing pathogens or activating NK cells during infection. For example, IgG1 antibodies, an IgG subtype, bind to the cell surface of the invaders and opsonize them against immune cells that can phagocytosis. Such cells have Fc receptors that can bind to the Fc regions of the respective IgG antibodies. For example, IgG3 antibodies, which have the highest affinity for Fc receptors in NK cells, bind NK cells to secrete cytotoxic molecules which cause pathogen elimination. The activation of NK cells by IgG subtype antibodies is called antibody-dependent cellular cytotoxicity (ADCC)⁴. These biological phenomena were shown in Figure 3.  As a result, thanks to the IgG class differentiation, B cells gained new functions such as opsonizing bacteria for phagocytic cells, providing pathogen elimination caused by NK cells such as ADCC, neutralizing toxins, activating virion proteases such as intracellular antibody-mediated proteolysis (by binding TRIM21).

Figure 3. Structure of IgG and antibody-dependent cellular cytotoxicity (ADCC) (https://www.immunology.org/). 

Class switching from IgM to IgE Antibodies

• Mast cells located just below our organs that take part in the physical barrier, such as mucosal layer or skin, are white blood cells containing granules which contain allergen-led molecules like histamine and heparin. These granules are released by mast cells to kill parasites in the organism (degranulation). For the activation of this process, IgE antibodies formed as a result of class switching mechanism are needed. Mast cells have receptors (i.e. FcεRI) that recognize the Fc regions of these newly switched IgE antibodies. The mast cells decorated with IgE antibodies scatter the granules out of the cell as a result of binding to two or more antigens antibody cross-linked. As a result of this event, parasitic infections such as helminths are prevented. Allergy and anaphylactic shock can be observed due to exposure to too many allergenic antigens and degranulation⁵. Ultimately, advantageous new functions such as preventing parasitic infections like helminths/hookworms, gaining resistance against venoms of snakes and honey bees and introducing the cancerous structure to the immune system were obtained through mast cells as a result of the IgE antibody class switching.

Figure 4. Structure of IgE & mechanism involved IgE-mediated mast cell degranulation (siciencedirect.com)

References

1 . Pieper, K., Grimbacher, B., & Eibel, H. (2013). B-cell biology and development. The Journal of allergy and clinical immunology, 131(4), 959–971. https://doi.org/10.1016/j.jaci.2013.01.046

2.      Methot, S. P., & Di Noia, J. M. (2017). Molecular Mechanisms of Somatic Hypermutation and Class Switch Recombination. Advances in immunology, 133, 37–87. https://doi.org/10.1016/bs.ai.2016.11.002

3.      Stavnezer J. (1996). Immunoglobulin class switching. Current opinion in immunology, 8(2), 199–205. https://doi.org/10.1016/s0952-7915(96)80058-6

4.      Valenzuela, N. M., & Schaub, S. (2018). The Biology of IgG Subclasses and Their Clinical Relevance to Transplantation. Transplantation, 102(1S Suppl 1), S7–S13. https://doi.org/10.1097/TP.0000000000001816

5.      Balbino, B., Conde, E., Marichal, T., Starkl, P., & Reber, L. L. (2018). Approaches to target IgE antibodies in allergic diseases. Pharmacology & therapeutics, 191, 50–64. https://doi.org/10.1016/j.pharmthera.2018.05.015

                                               MUSTAFA ÖZTÜRK, revised from Immunology Course Assignments