Immune System
Chemokines are a type of cytokines that are released by infected cells. Infected host cells release chemokines in order to initiate an immune response, and to warn neighboring cells of the threat.
Innate Immune System
The innate immune system is made of defenses against infection that can be activated immediately once a pathogen attacks. The innate immune system is essentially made up of barriers that aim to keep viruses, bacteria, parasites, and other foreign particles out of your body or limit their ability to spread and move throughout the body. The innate immune system includes:
Physical Barriers
such as skin, the gastrointestinal tract, the respiratory tract, the nasopharynx, cilia, eyelashes and other body hair.
Defense Mechanisms
such as secretions, mucous, bile, gastric acid, saliva, tears, and sweat.
General Immune Responses
such as inflammation, complement, and non-specific cellular responses. The inflammatory response actively brings immune cells to the site of an infection by increasing blood flow to the area. Complement is an immune response that marks pathogens for destruction and makes holes in the cell membrane of the pathogen. Check out our video that explains inflammation and complement, which we will touch on later.
The innate immune system is always general, or nonspecific, meaning anything that is identified as foreign or non-self is a target for the innate immune response. The innate immune system is activated by the presence of antigens and their chemical properties.
Cells of the Innate Immune System
There are many types of white blood cells, or leukocytes, that work to defend and protect the human body. In order to patrol the entire body, leukocytes travel by way of the circulatory system.
The following cells are leukocytes of the innate immune system:
Phagocytes, or Phagocytic cells: Phagocyte means “eating cell”, which describes what role phagocytes play in the immune response. Phagocytes circulate throughout the body, looking for potential threats, like bacteria and viruses, to engulf and destroy. You can think of phagocytes as security guards on patrol.
This article explains how phagocytes know what to engulf, and how phagocytosis works.
Macrophages: Macrophages, commonly abbreviated as “Mφ”, are efficient phagocytic cells that can leave the circulatory system by moving across the walls of capillary vessels. The ability to roam outside of the circulatory system is important, because it allows macrophages to hunt pathogens with less limits. Macrophages can also release cytokines in order to signal and recruit other cells to an area with pathogens.
Mast cells: Mast cells are found in mucous membranes and connective tissues, and are important for wound healing and defense against pathogens via the inflammatory response. When mast cells are activated, they release cytokines and granules that contain chemical molecules to create an inflammatory cascade. Mediators, such as histamine, cause blood vessels to dilate, increasing blood flow and cell trafficking to the area of infection. The cytokines released during this process act as a messenger service, alerting other immune cells, like neutrophils and macrophages, to make their way to the area of infection, or to be on alert for circulating threats.
Neutrophils: Neutrophils are phagocytic cells that are also classified as granulocytes because they contain granules in their cytoplasm. These granules are very toxic to bacteria and fungi, and cause them to stop proliferating or die on contact.
The bone marrow of an average healthy adult makes approximately 100 billion new neutrophils per day. Neutrophils are typically the first cells to arrive at the site of an infection because there are so many of them in circulation at any given time.
Eosinophils: Eosinophils are granulocytes target multicellular parasites. Eosinophils secrete a range of highly toxic proteins and free radicals that kill bacteria and parasites. The use of toxic proteins and free radicals also causes tissue damage during allergic reactions, so activation and toxin release by eosinophils is highly regulated to prevent any unnecessary tissue damage.
While eosinophils only make up 1-6% of the white blood cells, they are found in many locations, including the thymus, lower gastrointestinal tract, ovaries, uterus, spleen, and lymph nodes.
Basophils: Basophils are also granulocytes that attack multicellular parasites. Basophils release histamine, much like mast cells. The use of histamine makes basophils and mast cells key players in mounting an allergic response.
Natural Killer cells: Natural Killer cells (NK cells), do not attack pathogens directly. Instead, natural killer cells destroy infected host cells in order to stop the spread of an infection. Infected or compromised host cells can signal natural kill cells for destruction through the expression of specific receptors and antigen presentation.
Dendritic cells: Dendritic cells are antigen-presenting cells that are located in tissues, and can contact external environments through the skin, the inner mucosal lining of the nose, lungs, stomach, and intestines. Since dendritic cells are located in tissues that are common points for initial infection, they can identify threats and act as messengers for the rest of the immune system by antigen presentation. Dendritic cells also act as bridge between the innate immune system and the adaptive immune system.
The Complement System
The complement system (also called the complement cascade) is a mechanism that complements other aspects of the immune response. Typically, the complement system acts as a part of the innate immune system, but it can work with the adaptive immune system if necessary.
The complement system is made of a variety of proteins that, when inactive, circulate in the blood. When activated, these proteins come together to initiate the complement cascade, which starts the following steps:
Opsonization: Opsonization is a process in which foreign particles are marked for phagocytosis. All of the pathways require an antigen to signal that there is a threat present. Opsonization tags infected cells and identifies circulating pathogens expressing the same antigens.
Chemotaxis: Chemotaxis is the attraction and movement of macrophages to a chemical signal. Chemotaxis uses cytokines and chemokines to attract macrophages and neutrophils to the site of infection, ensuring that pathogens in the area will be destroyed. By bringing immune cells to an area with identified pathogens, it improves the likelihood that the threats will be destroyed and the infection will be treated.
Cell Lysis: Lysis is the breaking down or destruction of the membrane of a cell. The proteins of the complement system puncture the membranes of foreign cells, destroying the integrity of the pathogen. Destroying the membrane of foreign cells or pathogens weakens their ability to proliferate, and helps to stop the spread of infection.
Agglutination: Agglutination uses antibodies to cluster and bind pathogens together, much like a cowboy rounds up his cattle. By bringing as many pathogens together in the same area, the cells of the immune system can mount an attack and weaken the infection. Other innate immune system cells continue to circulate throughout the body in order to track down any other pathogens that have not been clustered and bound for destruction.
The steps of the complement cascade facilitate the search for and removal of antigens by placing them in large clumps, making it easier for other aspects of the immune system to do their jobs. Remember that the complement system is a supplemental cascade of proteins that assists, or “complements” the other aspects of the innate immune system.
The innate immune system works to fight off pathogens before they can start an active infection. For some cases, the innate immune response is not enough, or the pathogen is able to exploit the innate immune response for a way into the host cells. In such situations, the innate immune system works with the adaptive immune system to reduce the severity of infection, and to fight off any additional invaders while the adaptive immune system is busy destroying the initial infection.
B cells
After formation and maturation in the bone marrow (hence the name “B cell”), the naive B cells move into the lymphatic system to circulate throughout the body. In the lymphatic system, naive B cells encounter an antigen, which starts the maturation process for the B cell. B cells each have one of millions of distinctive surface antigen-specific receptors that are inherent to the organism’s DNA. For example, naive B cells express antibodies on their cell surface, which can also be called membrane-bound antibodies.
When a naive B cell encounters an antigen that fits or matches its membrane-bound antibody, it quickly divides in order to become either a memory B cell or an effector B cell, which is also called a plasma cell. Antibodies can bind to antigens directly.
The antigen must effectively bind with a naive B cell’s membrane-bound antibody in order to set off differentiation, or the process of becoming one of the new forms of a B cell.
Memory B cells express the same membrane-bound antibody as the original naive B cell, or the “parent B cell”. Plasma B cells produce the same antibody as the parent B cell, but they aren’t membrane bound. Instead, plasma B cells can secrete antibodies. Secreted antibodies work to identify free pathogens that are circulating throughout the body. When the naive B cell divides and differentiates, both plasma cells and memory B cells are made.
B cells also express a specialized receptor, called the B cell receptor (BCR). B cell receptors assist with antigen binding, as well as internalization and processing of the antigen. B cell receptors also play an important role in signaling pathways. After the antigen is internalized and processed, the B cell can initiate signaling pathways, such as cytokine release, 7 to communicate with other cells of the immune system. For more information on cell signalling, check out this article on cell-to-cell communication.
T cells
Once formed in the bone marrow, T progenitor cells migrate to the thymus (hence the name “T cell”) to mature and become T cells. While in the thymus, the developing T cells start to express T cell receptors (TCRs) and other receptors called CD4 and CD8 receptors. All T cells express T cell receptors, and either CD4 or CD8, not both. So, some T cells will express CD4, and others will express CD8.
Unlike antibodies, which can bind to antigens directly, T cell receptors can only recognize antigens that are bound to certain receptor molecules, called Major Histocompatibility Complex class 1 (MHCI) and class 2 (MHCII). These MHC molecules are membrane-bound surface receptors on antigen-presenting cells, like dendritic cells and macrophages. CD4 and CD8 play a role in T cell recognition and activation by binding to either MHCI or MHCII.
T cell receptors have to undergo a process called rearrangement, causing the nearly limitless recombination of a gene that expresses T cell receptors. The process of rearrangement allows for a lot of binding diversity. This diversity could potentially lead to accidental attacks against self cells and molecules because some rearrangement configurations can accidentally mimic a person’s self molecules and proteins. Mature T cells should recognize only foreign antigens combined with self-MHC molecules in order to mount an appropriate immune response.
In order to make sure T cells will perform properly once they have matured and have been released from the thymus, they undergo two selection processes:
Positive selection ensures MHC restriction by testing the ability of MHCI and MHCII to distinguish between self and nonself proteins. In order to pass the positive selection process, cells must be capable of binding only self-MHC molecules. If these cells bind nonself molecules instead of self-MHC molecules, they fail the positive selection process and are eliminated by apoptosis.
Negative selection tests for self tolerance. Negative selection tests the binding capabilities of CD4 and CD8 specifically. The ideal example of self tolerance is when a T cell will only bind to self-MHC molecules presenting a foreign antigen. If a T cell binds, via CD4 or CD8, a self-MHC molecule that isn’t presenting an antigen, or a self-MHC molecule that presenting a self-antigen, it will fail negative selection and be eliminated by apoptosis.
These two selection processes are put into place to protect your own cells and tissues against your own immune response. Without these selection processes, autoimmune diseases would be much more common.
After positive and negative selection, we are left with three types of mature T cells: Helper T cells (T\[\text{}_{H}\] cells), Cytotoxic T cells (T\[\text{}_{C}\] cells), and T regulatory cells (T\[\text{}_{reg}\] cells).
Helper T cells express CD4, and help with the activation of T\[\text{}_{C}\] cells, B cells, and other immune cells.
Cytotoxic T cells express CD8, and are responsible for removing pathogens and infected host cells.
T regulatory cells express CD4 and another receptor, called CD25. T regulatory cells help distinguish between self and nonself molecules, and by doing so, reduce the risk of autoimmune diseases.
Humoral vs. Cell Mediated Immunity
Immunity refers to the ability of your immune system to defend against infection and disease. There are two types of immunity that the adaptive immune system provides, and they are dependent on the functions of B and T cells, as described above.
Humoral immunity is immunity from serum antibodies produced by plasma cells. More specifically, someone who has never been exposed to a specific disease can gain humoral immunity through administration of antibodies from someone who has been exposed, and survived the same disease. “Humoral” refers to the bodily fluids where these free-floating serum antibodies bind to antigens and assist with elimination.
Cell-mediated immunity can be acquired through T cells from someone who is immune to the target disease or infection. “Cell-mediated” refers to the fact that the response is carried out by cytotoxic cells. Much like humoral immunity, someone who has not been exposed to a specific disease can gain cell-mediated immunity through the administration of T\[\text{}_{H}\] and T\[\text{}_{C}\] cells from someone that has been exposed, and survived the same disease. The T\[\text{}_{H}\] cells act to activate other immune cells, while the T\[\text{}_{C}\] cells assist with the elimination of pathogens and infected host cells.
Immunological memory
Because the adaptive immune system can learn and remember specific pathogens, it can provide long-lasting defense and protection against recurrent infections. When the adaptive immune system is exposed to a new threat, the specifics of the antigen are memorized so we are prevented from getting the disease again. The concept of immune memory is due to the body’s ability to make antibodies against different pathogens.
A good example of immunological memory is shown in vaccinations. A vaccination against a virus can be made using either active, but weakened or attenuated virus, or using specific parts of the virus that are not active. Both attenuated whole virus and virus particles cannot actually cause an active infection. Instead, they mimic the presence of an active virus in order to cause an immune response, even though there are no real threats present. By getting a vaccination, you are exposing your body to the antigen required to produce antibodies specific to that virus, and acquire a memory of the virus, without experiencing illness.
Some breakdowns in the immunological memory system can lead to autoimmune diseases. Molecular mimicry of a self‐antigen by an infectious pathogen, such as bacteria and viruses, may trigger autoimmune disease due to a cross-reactive immune response against the infection. One example of an organism that uses molecular mimicry to hide from immunological defenses is Streptococcus infection.