To understand immune system function it is necessary to first ask and get an answer to the question – what is the immune system? Knowledge of the basic medical terminology heightens that understanding. The immune system is a complex and integrated array of organs, tissues, cells and molecules that defends and protects the body from the untoward effects of foreign and dangerous particles and substances that might enter or have entered. It cannot just be a brigade of defense and protection though. It must also be able to distinguish between what is self and what is not. Otherwise it would cause autoimmune disease in which the body attacks self. What makes this state of balance possible is the major histocompatibility complex (MHC).
The current thinking among experts in the field of immunology is that foreignness alone is not the primary factor that triggers an immune response. Rather, it is foreignness that transmits “danger signals.” After all, the ingredients in coffee are not a part of self, but don’t trigger an immune response in most people.
In humans and other mammals immunity consists of 3 lines of defense. They are mechanical barriers, innate immunity and adaptive immunity. Barriers are the skin, lining of the gut, lungs and mucous membranes of various canals and cavities of the body. The surfaces of barriers contain chemicals such as those in tears, saliva, mucus, bacteria and some of the constituents of the innate immune system designed to kill germs.
Adaptive immune system – It is a more advanced and third line of defense against microbes and other disease causing agents. An adaptive immune response is delayed and takes anywhere from 4 days to weeks to commence. It confers active acquired immunity which is that resulting from prior exposure to a pathogen or its antigens. It has a cell-mediated arm and a humoral arm.
Cell-mediated immunity is any aspect of the adaptive immune response in which T cells that recognize specific antigens have the major role.
Humoral immunity is that aspect of the adaptive immune response in which antibodies play the major role. Passive immunity is the humoral immunity transferred to someone who receives serum containing antibodies.
B cell activation – It is a process in which naïve B cells develop into effector cells capable of producing antibodies. It occurs primarily in the lymphoid tissue of lymph nodes and spleen. After leaving the bone marrow partially developed cells with a B-cell receptor (BCR) on their surfaces circulate between the blood stream and lymphoid organs where they either die or encounter an activating antigen. Activation of a B cell begins with it encountering an antigen and receiving a signal from it. Upon recognition of that antigen with its BCR the B cell then internalizes the antigen through that receptor. After the antigen enters the cytoplasm of the cell, the cell processes it through a series of chemical reactions. It then presents a fragment of the processed antigen to its MHC II molecule and displays it for presentation to a helper CD4 T cell. Recognition and binding of the antigen-MHC II complex by a helper T cell activates the helper T cell. The activated T cell in turn completes the activation of the B cell by sending a second stimulatory signal to it. Following that second signal which completes the activation of the B cell three main of cytokine directed events follow. First of all, the B cell begins to proliferate and forms a clone of cells with immunoglobulin surface receptors capable of recognizing and binding to the antigen that activated the parent B cell. Sites of intense B cell proliferation are germinal centers by name. Secondly, the cloned daughter cells differentiate into effector B cells capable of secreting large amounts of antibodies identical to the BCR on their surfaces. Plasma cell is the term for this terminally developed B cell. Thirdly, some of the activated B cells develop into B memory cells.
Clonal expansion – It is the formation and proliferation of antigen-specific daughter lymphocytes from stimulation of the parent lymphocyte by an antigen. It precedes their differentiation into effector cells.
Delayed hypersensitivity – It is a form of cell-mediated immunity which becomes manifest upon skin exposure to antigen. TH1 cells mediate the response which involves collaboration between phagocytic dendritic cells, CD8 cells, CD4 cells and macrophages. Examples include a positive TB skin test, contact dermatitis (such as poison ivy) and drug rash.
Immunological memory – It is the tendency for the adaptive immune response to a subsequent encounter with an antigen to be faster and more effective. It is long-lived and involves specialized B and T lymphocyte memory cells.
Innate immune system – It is the second line of defense following penetration of the body’s natural barriers of protection by sources of infection. It is the part of the immune system which is always present and does not require priming. Its main components are granulocytes, macrophages, natural killer cells, cytokines and complement. Those components are present and the blood stream, other body fluids and tissues. Its response is immediate within minutes to a few days of an infection. It also primes the adaptive immune system if it alone is not successful in warding off an infection. It does not involve memory.
Immunological tolerance – It is the ability of the immune system to not mount an immune response to self and to harmless substances that are not a part of self. The lack of an immune response to beneficial bacteria in the gut and respiratory tract and to food is an example of the latter.
T cell tolerance or the education of T cells to tolerate and not attack self occurs primarily in the thymus. It takes place in two areas of the gland – the cortex and the medulla. In the cortex immature T cells bearing CD8 and CD4 markers commit to developing into CD8 or CD4 cells after recognizing and binding self-antigen of MHC I or MHC II of cortical epithelial cells or dendritic cells. Cells that recognize self-antigens survive, but those that don’t die. The name for this process of tolerance development is restriction. As surviving naïve CD8 and CD4 cells enter the medulla of the thymus negative selection occurs in which cells that recognize self-antigen of medullary thymic cells but bind too tightly undergo deletion or death.
Additionally, there is a pathway of deletion resulting from an immune regulator protein expressed by the autoimmune regulator (AIRE) gene. To grasp the concept it is necessary to first understand that every cell in the body with a nucleus has the body’s entire DNA or genetic code. Different parts of the genetic code are turned-on in different cells. The AIRE gene is turned-on in medullary thymic cells and gives them the ability to make and display on their MHC II molecules self-protein of tissues of various parts of the body. The regulator protein also causes the deletion or elimination of T cells that bind the resulting MHC/self-antigen complexes.
Some T cells escape the central tolerance pathways and can still mount an immune response to self. Therefore, peripheral pathways of tolerance also exist. Some of those pathways are also involved in the development of tolerance to substances that are not self, such as beneficial bacteria on surface barriers and food. One of the better understood and researched alternate pathways of tolerance involves the regulatory T cell.
B cell tolerance is less well-understood but experts believe it involves some of the same pathways as T cell central tolerance but in the setting of the bone marrow. Since B cell activation requires helper T cell involvement, T cell tolerance begets peripheral B cell tolerance.
Inflammation – The local buildup of fluid, white blood cells and plasma proteins triggered by physical injury, infection or a local response of the immune system.
Opsonization – It is the process of changing the surface of a pathogen or other foreign particle so that a neutrophil or macrophage can more easily engulf it. Antibodies and complement perform that function. – Opsonize v. Opsonizing adj.
T cell activation – It is the stimulation of naïve T cells to become effector cells. It involves the migration of naïve T cells from their place of education in the thymus to a lymphoid organ. It occurs primarily in lymph nodes.
CD4 T cell activation begins with dendritic cells moving from sites of infection or other foreign particles and presenting antigen to naïve CD4 T cells surveilling lymph nodes in search of a foreign particle to engage. The antigen receptor of the CD4 cell along with the CD4 marker serving as a co-receptor interacts with the antigen on the MHC II molecule of the dendritic cell. That interaction causes the sending of a signal to the T cell. That signal enables the T cell to be able to recognize the antigen but full activation of the T cell requires another signal. That co-stimulatory signal occurs between molecules on the surface of the dendritic cell and T cell that are different from those involved in signal 1. Following activation there is mutual stimulation involving cytokine release between the dendritic cell and activated CD4 cell which results in further differentiation of the CD4 cell into a more specialized effector lymphocyte.
CD8 T cell activation occurs in a similar way to CD4 T cell activation with some differences. The first step is the digestion of an infecting microorganism into protein fragments via a series of chemical reactions within the cytoplasm of the infected cell. The portion of the MHC I marker which is in the cytoplasm of the cell then transports the antigen (protein fragment) to the surface of the molecule where it showcases it for recognition by the T cell receptor (TCR) of a CD8 T lymphocyte. Upon recognition and binding, a signal is sent involving molecules on the surfaces of the CD8 cell and the infected cell. Since CD8 cells target intracellular pathogens, whether they are in antigen presenting cells, epithelial cells or other tissue cells they interact with an MHC I surface molecule instead of an MHC II molecule. A CD8 instead of a CD4 marker is the co-receptor for signal 1. Most importantly, full activation requires a second stage in which a helper CD4 cell activated by the same antigen sends a signal to the CD8 cell through the release of specific cytokines.