Category: 3. Innate Immunity

The idea of using the immune system to help the body fight disease has been in existence for some time; vaccines, which allow the body to remember disease-causing pathogens, provide an excellent example. There are many diseases, though, in which the desired outcome is not to enhance the immune system, but to suppress its unwanted effects. Lupus, rheumatoid arthritis and multiple sclerosis, for instance, are autoimmune diseases in which the immune system erroneously attacks the body. Chronic inflammation, connected with wound trauma, diabetes, cardiovascular disease and neurodegenerative disease, is another example of immune-system overreaction. The idea of using innate immunity to either enhance or suppress overall immunity is a new avenue by which we can have profound impact on improving human health.

In striving to understand the innate immune system, the CIIID’s ultimate goal is to regulate overall immune response to distinct disease processes, thus using the power of immunity to improve human health. In doing so, we will improve the body’s ability to fight pathogens and to control the immune response when it goes off track — and we will change medicine forever.

Manipulating immune function — enhancing it or suppressing it — will rest on our ability to control the two aspects of the immune system: innate immunity, mentioned above, and adaptive immunity.

The innate immune system: the first line of defense

The innate immune system is the first part of the body to detect invaders such as viruses, bacteria, parasites and toxins, or to sense wounds or trauma. Upon detection of these agents or events, the innate immune system activates cells to attack and destroy the outsider, or to initiate repair, while also informing and modulating the adaptive immune response that follows this first line of defense.

The adaptive immune system: the second, specific response

Adaptive immune cells are the second and specific line of defense, and they are called to action by the innate immune system. After recognizing the invader, the cells can multiply and combat it, leading to recovery from disease and protection against its return. 

The immune system protects the body from disease. Over the past decade, however, researchers have come to understand that the innate immune system — the part of the immune system that serves as the body’s first line of defense — is implicated in an enormous number of disease processes that affect many millions of people around the world.

Sometimes the immune system runs too hot, erroneously attacking the body. Sometimes, it runs too cold — its defenses insufficient to defend against invaders. We now know that the tipping point between running too hot or too cold often depends on the innate immune response, but we don’t know how to prevent it from going off course. The CIIID’s goal is to determine how to fine-tune the innate immune system (so that it knows exactly when to turn on and how to protect the body), and then how to turn it off before it causes any collateral damage.

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:

1. 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.
2. 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.
3. 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.
4. 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.

Complement cascade diagramThe 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.

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.

Phagocytosis diagram 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.

Macrophage and cytokines diagram

• 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.

Mast cell and histamine diagram

• 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.

Neutrophil and granules diagramThe 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.

Eosinophil and granules diagram

• 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 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.

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.

Every day we are alive, humans encounter potentially harmful disease causing organisms, or “pathogens”, like bacteria or viruses. Yet most of us are still able to function properly and live life without constantly being sick. That’s because the human body requires a multilayered immune system to keep it running smoothly. The two main classes of the immune system are the innate immune system and the adaptive immune system, or “acquired immunity”. In this article, we’ll discuss the first line of defense: the innate immune system.

Self vs. Non-self: How does the body know?

In order to be effective, the immune system needs to be able to identify which particles are foreign, and which are a part of your body. Let’s define some terms before we jump in to how this works:

• Self refers to particles, such as proteins and other molecules, that are a part of, or made by, your body. They can be found circulating in your blood or attached to different tissues. Something that is self should not be targeted and destroyed by the immune system. The non-reactivity of the immune system to self particles is called tolerance.
• Non-self refers to particles that are not made by your body, and are recognized as potentially harmful. These are sometimes called foreign bodies. Non-self particles or bodies can be bacteria, viruses, parasites, pollen, dust, and toxic chemicals. The non-self particles and foreign bodies that are infectious or pathogenic, like bacteria, viruses, and parasites, make proteins called antigens that allow the human body to know that they intend to cause damage.
• Antigens are anything that causes an immune response. Antigens can be entire pathogens, like bacteria, viruses, fungi, and parasites, or smaller proteins that pathogens express. Antigens are like a name tag for each pathogen that announce the pathogens’ presence to your immune system. Some pathogens are general, whereas others are very specific. A general antigen would announce “I’m dangerous”, whereas a specific antigen would announce “I’m a bacteria that will cause an infection in your gastrointestinal tract” or “I’m the influenza virus”.
• Cytokines are molecules that are used for cell signaling, or cell-to-cell communication. Cytokines are similar to chemokines, wherein they can be used to communicate with neighboring or distant cells about initiating an immune response. Cytokines are also used to trigger cell trafficking, or movement, to a specific area of the body.
• 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.