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Accompanying video lecture on Drbeen.com: https://members.drbeen.com/view/overview-innate-and-acquired-arm-1/rkhSjfCd2lW
Introduction to The Immune System
Our immune system is a major organ system in our body that helps defend against the microorganisms trying to invade us. A majority of the patients presenting to a hospital with a complaint of fever have an underlying infection. This infection may have been caused by bacteria, viruses, fungi or parasites.
Some patients suffer from decreased immunity (e.g. HIV/AIDS), therefore they are more susceptible to infections. Other patients may have over-activation or mistargeting of their immune system which results in their immune system attacking their own tissues causing damage to their bodies resulting in autoimmune disorders. In yet other cases, the immune system may misidentify a non-harmful substance as being harmful and start an allergic response against it.
Functions of the immune system start at the surfaces of the body where mechanical barriers act as the first line of defense. Our skin is multilayered and keratinized. This structure prevents the entry of bacteria, fungi, and viruses from entering deeper tissues. The superficial layers of keratinization and dead cells are protective as well. Pathogens get stuck in these layers and are removed when these layers are shed. Mucous membranes of the conjunctiva, gastrointestinal tract, respiratory system, urogenital and reproductive system have surfaces with secretions covering the epithelium. The moist surfaces have chemical substances and enzymes that can attach with pathogens and prevent these pathogens from entering the deeper tissues. Cilia are also present on some of the surfaces, pathogens can become stuck on these ciliary surfaces. In these situations, pathogens are removed as the cilia propel and move the pathogens to the exit. Also of interest is that on these mucosal surfaces, there are proteins called defensins that can identify a foreign pathogen and create holes in the membrane of the pathogen to destroy it before it enters our body and harms us.
Figure: Some of our defensive structures that make up our immune system.
Our body is also inhabited by many non-pathogenic bacteria and fungi, which are called normal flora. They are present in the gut, throat, vagina, and pulmonary surfaces. They occupy the receptors that are potential attachment sites for pathogens. Thus the presence of normal flora protects us from infections. Sometimes the use of broad-spectrum antibiotics wipes out normal flora, and pathogens attain an opportunity to attach to the mucosal surface and invade that area to enter.
Another important protective mechanism is the acidic environment of the stomach and vagina. The enzymes of pathogens require an optimum pH for their function. When a pathogen enters the acidic environment of the stomach or vagina, its body becomes coagulated by the acids.
Injury to the mechanical barriers is a risk factor for infections. For example, if the skin is breached, as, in surgery or trauma, the chances of infections are increased. If the acidic environment of the stomach is altered, such as when we take proton pump inhibitors, the chances of certain infections increase.
A stronger strain of bacteria may also increase the chance of infection.
Figure: two important cells that take part in the immune system. We will study more cells in the next sections.
Our body reacts with the pathogen after the pathogen has penetrated the physical barrier. The body has dendritic cells, and macrophages, which are large cells that can engulf bacteria. These cells are present across the body, mostly under the skin and mucosal surfaces. The cells recognize, capture, and then breakdown these foreign invaders (pathogens.)
Macrophages, also known as phagocytes contain phagosomes and endosomes that are filled with digestive enzymes that break down the phagocytized bacteria. After the breakdown of these pathogens, macrophages and dendritic cells present parts of these pathogens (called antigens) on their surface with the help of certain proteins (i.e. MHC-II). Thus, these cells are known as antigen-presenting cells (APCs.) After presenting antigens on their surface for the immune system to recognize, the cells also secrete interleukins. Interleukins act as chemotactic agents (attracting agents) for the cells of the immune system. This results in more immune cells to arrive at the site of infection and help fight it.
Macrophages can release IL-1, IL-6, IL-8, IL-12, tumor necrosis factor (TNF), and many other chemicals. Macrophages, also take these pathogens and move towards the lymph nodes, where, because of the interleukins, they interact with more immune cells called lymphocytes.
Types of Immune Mechanisms
The immune system can be divided into two arms; innate arm and the adaptive arm of the immune system.
Innate immunity is the nonspecific defense mechanism that occurs immediately or within hours of an antigen’s appearance on (skin/mucous membranes), or in the body. This response is elicited by the chemical properties of the antigen.
Adaptive immunity refers to an antigen-specific immune response. The antigen is first processed and recognized. After this, the adaptive immune system activates and creates an army of its immune cells that are able to attack this specific antigen. Adaptive immunity also results in the formation of specialized memory-cells which can help rapidly launch an immune response to similar antigens invading our bodies in the future.
A HIGH-LEVEL VIEW OF THE IMMUNE SYSTEM ACTIVITY
Phagocytosis (eating), or pinocytosis (drinking) of debris or a pathogen by neutrophils, macrophages, or dendritic cells constitutes the innate arm of the immune system.
Macrophages phagocytose, process, and present an antigen using their MHC-2 proteins. Macrophages also release interleukin-12 (IL-12). IL-12 is responsible to activate the acquired arm of the immune system. IL-12 does so by signaling lymphocytes to be activated. Lymphocytes belong to the acquired arm of the immune system. Interestingly, after activation, lymphocytes secrete interferon-gamma (IFN-Ɣ). Interferon-gamma, in turn, activates macrophages (innate arm). Hence, both arms of the immune system amplify each other’s actions. But, remember, it is the innate arm of the immune system that becomes activate first in response to a harmful entity. It then activates the acquired arm. And, after this, both arms continue to amplify each other.
Figure: IL-12 IFN-gamma axis.
There are two types of lymphocytes in the acquired arm of the immune system: T lymphocytes are trained in thymus, and B lymphocytes are matured in the bone marrow. A T-cell is initially trained as a naïve T cell in the Thymus and then it moves to reside in a lymph node. On its surface, a naïve T cell contains receptors for IL-12 and IL-4. Under the influence of IL-12, a naïve T cell becomes a helper-1 T cell (TH-1 cell.) This TH-1 cell starts releasing two proteins: IL-2 and IFN-Ɣ.
To recap, the innate arm cells (macrophages) are producing IL-12 to activate the acquired arm, and in turn, the acquired arm cells (TH-1) are releasing IFN-Ɣ that activates the macrophages. This is called IL-12-IFN-Ɣ axis. (IL12 from the macrophage, and IFN-Ɣ from the T-helper cells.) This axis is the mechanism by which activated acquired immune system amplifies the activity of macrophages (innate immune system cell,) since IFN-Ɣ further activates macrophages. Thus innate arm and the acquired arm of the immune system trigger and amplify each other.
IL-2 also acts via an autocrine mechanism on the TH-1 cell itself. (Autocrine stimulation means that the cell that is stimulated by the substance is the cell that actually produced the substance.)
Cytotoxic T-cells are another type of T lymphocyte. Some pathogens, like viruses, enter cells and try to evade the immune system. The function of cytotoxic T cells is to kill the cells that are infected by these pathogens. Cytotoxic T cells are also activated by the IL-2 produced by TH-1 cells. Infected cells present the antigens on their surfaces through the major histocompatibility complex-1 (MHC-1.) Cytotoxic T cells recognize these antigens and in response to these cells.
Note that the antigens are presented on the major histocompatibility complex-1 (MHC-1) present on the surface of all nucleated cells. Major histocompatibility complex-2 (MHC-2) is present only on the APCs.
Cytotoxic T Lymphocytes, Perforins, and Granzymes
Cytotoxic T cells produce perforins. Perforins break the membranes of pathogens. Cytotoxic T cells also produce granzymes. Granzymes enter the infected cells via the holes that perforins made and initiate cell death.
IL-4, T Helper 2 Cells, B Lymphocytes, Plasma Cells, Antibodies/Immunoglobulins
IL-4 production also occurs during the initial immune response. Initial producer of the IL-4 is unknown. This IL-4 converts naïve T cells to T helper-2 (TH-2) cells. Activated TH-2 cells also secrete IL-4. IL5 is produced as well by the activated TH-2 cells. IL4 and IL5 are important activators and regulators of B lymphocytes. Activated B-cells are called plasma cells. Plasma cells produce antibodies. Antibodies are specialized proteins that attack various antigens. (Antibodies are produced by the B lymphocytes, and are the only plasma proteins that are not synthesized by the liver.) These y-shaped antibodies are also called immunoglobulins. We will study the functions of immunoglobulins in the next sections.