The Immune System

The immune system, also called the lymphatics system, is a disease-fighting system in the blood and lymph (1).

The immune system protects against foreign matter, both living and nonliving (1).

The immune system protects the body against pathogens, removes pathogens, cancerous cells, and provides immunity to these foreign substances (1).

Immune surveillance – is a function that arises in the body that surveys the body for cancer cells (1).

There are two types of immune responses.

Innate– Innate response defends against cells and does not need identification of the foreign cells’ origin (1).

Adaptive-Adaptive responses need a specific location of the foreign substance for lymphocytes to attach and remove the cell (1).

Bacteria are unicellular organisms that have an outer cell wall as well as a plasma membrane. Bacteria can damage tissues and release toxins that enter the blood (1).

Viruses are nucleic acids surrounded by a protein coat. These are not living organisms and lack the enzyme machinery for metabolism. They also do not have ribosomes for protein synthesis. The lack of these ribosomes means that they must exist inside other cells for the virus to survive. Some viruses might multiply, kill the cell, or lie dormant before causing cell damage (1).

The immune system can regulate and protect the body from these foreign substances by cell-to-cell signaling (1).

Cell-Mediating Immune Defenses

Leukocytes are white blood cells. Leukocytes can divide within myeloid cells and lymphoid cells (1).

Myeloid cells are neutrophils, basophils, eosinophils, monocytes, and macrophages (1).

Neutrophils are found in the bone marrow and work by phagocytosis (1).

Basophils are in the bone marrow and carry out functions similar to mast cells (1).

Eosinophils are in the bone marrow and destroy parasites and work in hypertensive situations (1).

Monocytes are an area in the bone marrow and work similarly to macrophages (1).

Macrophages are known for phagocytosis, which is when a cell engulfs another cell and destroys it. These cells find themselves in different epithelia types, such as skin, respiratory, and digestive environments (1).

Dendritic cells are similar to macrophages but scatter in almost all tissues, especially the digestive tracts. Dendritic cells can function as phagocytes and travel to lymphatic vessels and lymphoid organs like the spleen (1).

Mast cells stem in the connective tissues. Mature mast cells are not found in the blood but will activate locally, sometimes acting as histamine. Histamine helps stimulate the innate immune response (1).

Macrophages, dendritic cells, and mast cells are all in the category of myeloid cells (1).

Macrophages are in the bone marrow and work by phagocytosis. They present antigens to help T cells and secrete cytokines for inflammation and activation of an immune response (1).

Dendritic cells are found in many tissues and work by phagocytosis and antigen presentation (1).

Mast cells are in the bone marrow and release histamine and other chemicals involved in inflammation (1).

Next, the second group of leukocytes includes lymphoid cells (1).

These cells include B cells, T cells, natural killer cells, and plasma cells (1).

B cells initiate an antibody-mediated immune response by binding specific antigens to the plasm membrane receptor (1).

T cell-(CD8), also known as cytotoxic T cells, bind to antigens on the plasma membrane of target cells and directly destroy the cells (1).

Helper T cells (CD4) secrete cytokines that help activate B cells, T cells, NK cells, and macrophages (1).

Natural killer cells bind directly to virus-infected cells and kill the cancer cells (1).

Plasma cells are in the lymphoid organs. These cells secrete antibodies (1).

Immune Cell Secretions: Cytokines

The way that these immune cells communicate is through protein messengers called cytokines. Cytokines regulate host cell division (1).

Cytokines can also circulate in the blood and possibly initiate hormonal effects on organs to help protect the organs and increase host defenses. One cytokine can work in a network of other cytokines where they communicate to protect the body and work among a wide range of cells (1).

Interleukin 1 is a cytokine and works as an antigen-presenting cell that targets helper T cells. The primary function is to induce fever (1).

Interleukin 2 targets T cells, NK cells, B cells and promotes conversion to plasma cells (1).

Interferons (type I) stimulates cells to produce antiviral proteins (1).

Interferons (type II) are NK cells and activate helper T cells to stimulate proliferating cytotoxic compounds (1).

Chemokines are from endothelial cells and target neutrophils and leukocytes at sites of injury and inflammation (1).

Innate Immune Responses

The innate immune response uses molecules like carbohydrates and lipids that tag on microbial cell walls. This sensor detects the presence of foreign cells (1).

Defenses at Body Surfaces

The first line of defense against pathogens is the actual barrier of the cell. Even organs can have their natural barriers like the skin. Body structures like hairs on the body or in the nose can filter and protect against substances. Tear glands have a cleansing ability to keep the eyes moist but also prevent bacteria from growing. Mucus secretes by the respiratory system and has antimicrobial chemicals that prevent substances from entering the blood (1).

Even the acid from the stomach in its specific pH can kill pathogens (1).

Inflammation

Inflammation is a response to infection. Inflammation displays by swelling or occurs from tissue repair by an invader. For example, a cut can have an inflammatory response. Chemical mediators flood to the defense of this cut on the skin to protect the barrier and prevent infection, thus calling a slight inflammatory reaction (1).

Vasodilation and Increased Permeability to Protein

1. Bacteria introduces into a wound.
2. Chemical mediators cause vasodilation and capillary permeability.
3. Diapedesis results in neutrophils entering the tissue, where they engulf bacteria and mediate the damage.
4. Capillaries return to normal.

Important Local Inflammatory Mediators

Kinins dilate vessels.

Complement directly kills pathogens.

Histamine is responsible for increased vascular permeability.

Eicosanoids trigger vasodilation and induce fever.

Platelet-activating factor amplifies many aspects of inflammation and helps in platelet aggregation.

Cytokines secreted by activated immune cells produce chemoattraction for leukocytes.

Lysosomal enzymes destroy pathogen macromolecules.

Chemotaxis

Chemotaxis is the onset of inflammation where neutrophils move to the damaged area. The process regulates by messenger molecules like chemoattractants involving protein and carbohydrates on the endothelial cell and the neutrophil (1).

Steps of Chemotaxis

1. Margination is when neutrophils enter the damaged area.
2. Diapedesis projects neutrophils into endothelial walls. 
3. Once the neutrophils are in the walls, they use the process of phagocytosis to kill the cells. The phagocyte can bind tightly to the pathogen and initiate phagocytosis. This process is known as an opsonin. A phagosome is when the phagocyte engulfs the bacterium. Once there is a lysosomal fusion, the vessels are now called phagolysosomes. The process can present nitric oxide and hydrogen peroxide, destroying the foreign substance (1).
4. Complement is a process where plasma proteins provide another means for extracellular killing. An implement is simply a cascade of proteins that activate more proteins to the affected area (1).
   1. C3 initiates C3b, which acts as an opsonin and leads to membrane attack complex (MAC). The MAC embeds itself in the bacterial plasma membrane. This system activates a first complement protein, C1, known as the classical complement pathway (1).
   2. The alternating complement pathway is not antibody-dependent and bypasses C1. The alternative path initiates interactions between carbohydrates on the microbes’ surface and inactivates complement molecules beyond C1. These lead to C3b, the opsonin (1).

Opsonin

Opsonin works in innate responses and also uses C-reactive proteins. These proteins are produced by the liver and work to increase inflammation significantly (1).

Tissue Repair

The final stage of inflammation is tissue repair. Collagen is a substance that proliferates the angiogenesis process, which brings together chemical mediators and produces growth factors that promote the healing process (1).

Interferons

Type 1 Interferons include several proteins that nonspecifically inhibit viral replication inside host cells. Type 1 interferons bind to plasma membrane receptors and secrete them on other cells (1).

Type 2 interferons called interferon-gamma produces by immune cells. This interferon also makes type 1 interferons even more powerful and enhances cell killing by macrophages (1).

Toll-like Receptors

Pathogen-associated molecular patterns include:

1. There are 
2. lipopolysaccharide and other lipids and carbohydrates.
3. Viral and bacterial nucleic acids.
4. Lastly, a protein found in the flagellum typical for many bacteria.

The products work to recognize a pattern of bacteria features (1).

Toll proteins bind to extracellular fluid, induce second-messenger formation, induce attachment of a microbe to a macrophage, and use phagocytosis and subsequent destruction (1).

Pattern-recognition Receptors recognize and bind to a wide variety of ligands found in many pathogens (1).

Adaptive Immune Responses

The antigen is a molecule that triggers an adaptive immune response or any molecule that the host does not recognize as self (1).

1. Lymphocytes recognize an antigen.
2. Lymphocyte activation is when the binding of an antigen to a receptor occurs. Clonal expansion occurs when daughter lymphocytes develop from a single gene and recognize a specific antigen. These cells can also turn into memory cells to recognize the antigen if it returns in the future. These antibodies opsonize pathogens and target them for attack by innate immune cells—the great majority of the B cells, plasma cells, and T cells die by apoptosis (1).

Lymphoid Organs and Lymphocyte Origins

Lymphoid Organs

Lymphoid organs subdivide into primary lymphoid organs and secondary lymphoid organs (1).

Primary lymphoid organs are the bone marrow and thymus (1).

Secondary lymphoid organs include the lymph nodes, spleen, tonsils, and lymphocyte accumulations in the lining of the intestinal, respiratory, genital, and urinary tracts (1).

Thymus

The thymus lies in the upper part of the chest. The thymus contains mostly immature lymphocytes that will develop into mature T cells. The lymph flows through lymph nodes scattered along the vessels. The spleen is the alignment of the secondary lymphoid organs in the left part of the abdominal cavity. The spleen is to the circulating blood what the lymph nodes are to the lymph (1).

The tonsil adenoids are a group of small rounded lymphoid organs in the pharynx. They fill with lymphocytes, macrophages, and dendritic cells (1).

Humoral and Cell-Mediated Responses:

B cells secrete antibodies that reach antibodies and help the body to find outside cells. These responses are antibody-mediated and are an effective defense against pathogens, viruses, and bacteria (1).

Humoral responses, on the other hand, are cell-mediated with T cells. Cytotoxic T cells and helper T cells directly attack cells, bind to them, and instantly kill them (1).

Regulatory T cells inhibit the function of B and T cells. These cells work as a way of homeostasis for the body to regulate these B and T cells and provide some negative feedback (1).

Summary

In the bone marrow, there are hematopoietic stem cells that divide into myeloid and lymphoid stem cells. From lymphoid stem cells come immature T cells and mature B cells in the bone marrow (1).

Then from the bone marrow, the immature T cells go into the thymus, turning into a mature helper T cell (1).

In comparison, the mature B cell goes into secondary lymphoid organs, activates by antigens, forms with plasma cells, and creates antibodies to protect the body (1).

Attacking Foreign Substances Summary

Antigens present to B cells, helper T cells, and cytotoxic T cells (1).

The B cells activate plasma cells, which turn into antibodies. The antibodies guide phagocytes, complement cells, and NK class to attack antigen-bearing cells (1).

When the antigen presents to cytotoxic T cells, they can combine with cytokines and directly attack antigen-bearing cells (1).

It is important to note that helper T cells can either form into plasma cells or combine with cytokines to attack cells directly. Essentially they can do both of what the B cells and cytotoxic T cells can do (1).

B Cell Receptors

B-cell-forming antibodies constitute proteins called immunoglobulins. There are five primary immunoglobulins-A, D, E, G, and M (1).

These immunoglobulins have a stem called the FC portion. The Fc represents the heavy chain while the light chain holds the specific antigen-binding sites (1).

T Cell receptors

T-cell reports are two changed proteins. T-cells cannot combine with antigens unless they first go through the plasma membrane proteins. Major histocompatibility complex proteins help the T cell to recognize an antigen. There are Class I MHC proteins on the surface of most cells. Class II MHC proteins are on the surface of macrophages, B cells, and dendritic cells (1).

Cytotoxic T cells associate with class I MHC proteins, and helper T cells associate with class II MHC proteins (1).

CD4 proteins are on the helper T class and CD8 proteins on the cytotoxic T cells. CD4 binds to class II MHC whereas CD8 binds to class I MHC proteins (1).

Antigen Presentation to T cells

T cells can bind antigens when they appear on a host cell (1).

When a macrophage has phagocytosed a microbe or antigen from helper T cells, it breaks down into polypeptide fragments. These then bind with class II MHC proteins. This complex transports to the cell surface. The components are called epitopes and are complexed to MHC proteins and presented to the T cell (1).

B cells process antigens and present them to helper T cells in the same way as dendritic cells (1).

B cells present antigens to helper T cells and also differentiate antibody-secreting plasma cells (1).

The binding of helper T cell receptors and antigens to class II MHC proteins initiates a stimulus for helper T cell activation. Interleukin 1 and tumor necrosis factor-alpha are secreted in large amounts on the helper T cell and provide another activation incentive (1).

Summary

APC participates in activating the helper T cell in three ways (1).

1. Antigen presentation.
2. Provision of a stimulus.
3. Lastly, there is a secretion of interleukin one and tumor necrosis factor-alpha.

Presentation to Cytotoxic T cells

Antigens arise when viruses take up a host cell and use the viral nucleic acid to cause the cell to manufacture the viral proteins and not the host cell’s proteins. However, our body has proteins called oncogenes that encode proteins that are generally not found in the body. Therefore, they can complex with the host cells. MHC I proteins and a cytotoxic T cell complex can bind to it (1).

NK Cells

NK Cells are a distinct class of lymphocytes (1).

NK Cells are not antigen-specific. They can attack cells without recognizing the antigen (1).

Development of Immune Tolerance

The clonal deletion occurs when T cells are exposed to proteins in the thymus and occur first in fetal and postnatal life. Clonal activation occurs in the thymus and causes potentially self-reacting T cells to become nonresponsive (1).

Summary

1. Secondary lymphoid organs bind to specific receptors on the plasma membranes of B cells.
2. Antigen-presenting cells present to help T cells classify class II MHC proteins, provide a stimulus, and secret cytokines that act on the helper T class.
3. The helper T cells secrete Interleueken 2, which stimulates the helper T class and activates antigen-bound B cells.
4. The plasma cells secrete antibodies for the antigen.
5. These antibodies combine with antigens on the surface of the bacteria.
6. Any antibody bound to antigens facilitates phagocytosis, and NK cells bind to the antibody’s Fc portion.

Antigen Recognition, B-cell activation

When bacteria enter the lymphatic system and get taken in the blood, B cells recognize the bacteria’s antigen and bind (1).

The macrophage phagocyte the bacteria through class II MHC proteins and then initiate interleukins and cytokines on the helper T cell (1).

These helper T cells travel to the lymph node or spleen, and the B cell causes plasma cells to make antibodies for immunization (1).

Antibody Secretion

IgA secretes by plasma cells in the lining of gastro, respiratory, and genitourinary tracts. They are primary antibodies in milk (1).

IgM and IgG provide specific immunity against bacteria and viruses (1).

IgE provides a defense to parasites and allergic responses (1).

IgD is still unclear.

Effect of Antibodies

Antibodies bind to antigens and are similar to other killing mechanisms like phagocytes, neutrophils, and macrophages to ensure the bacteria’s killing (1).

Antibodies can act directly as opsonins phagocyte the bacterium (1).

Activation of the Complement System

In the adaptive immune response, the piece of an antibody of IgG or IgM binds to the antigen and activates the classical complement pathway. The first molecule, C1, binds to the Fc portion. Polypeptides combine to form the MAC or membrane attack complex. C3b functions as an opsonin and enhances phagocytosis (1).

Summary

Bacterium initiates binding on the antibody. C1 starts MAC and C3b, which helps phagocytes bind and kill the bacterium (1).

Antibody-Dependent Cellular Cytotoxicity

When antibodies link to NK cells and directly kill the bacterium, this is called antibody-dependent cellular cytotoxicity or ADCC (1).

Toxins secreted by bacteria can also initiate antigens to induce antibody production (1).

Active and Passive Humoral Immunity

Active immunity results when the body faces contact with microorganisms and initiates antigenic components (1).

 A vaccine is nearly tiny quantities of dead pathogens exposed by the body’s immune response (1).

 Passive immunity transfers the antibodies directly from one person to another (1).

 For example, IgG can move across the placenta via IgG antibodies and move across the mother’s epithelial layer to the child through breast milk (1).

 Summary

 Innate defense resists the first initial entry of the bacteria or the virus (1).

 Adaptive immunity attempts to eliminate the bacteria or the virus by phagocytosis or some other complement system (1).

When a cell is infected, the class I MAC protein starts. A T cell receptor can form a cytotoxic T-cell, carried along with many parts of the body through the blood (1).

Macrophages are also activated through the class 2 MHC protein and initiate the helper T cells to initiate other cytokines that release more cytotoxic T-cells. Perforin granzymes allow the entry of cytotoxic enzymes into the cell and induce apoptosis. Once this occurs, viruses are not able to replicate (1).

System Manifestations of Infection

 Infection begins with microbes and bacteria, causing tissue injury. Then, monocytes and macrophages release cytokines into different parts of the body; for example, there will be increased leukocytes in the bone marrow. There will also be increased retention of ions in the liver and iron (1).

1. In the brain, there will be decreased appetite and possibly some fatigue. 
2. In the adipose tissue, there will be an increase in free fatty acids. 
3. In the hypothalamus, there will be increased ACTH which will then increase cortisol (1).

 Many factors alter the resistance to infection. Those who have pre-existing conditions like diabetes can have slower responses to leukocyte function. Stress and mental health can also affect immune defenses in releasing adequate neurotransmission and hormones (1).

Physical exercise based on intensity and duration can have long-lasting effects due to increased immune functions related to NK cells that increase host resistance. Loss of sleep is also a huge determinant of the activity of NK cells. Severe combined immunodeficiency or SCID is when B & T cells are absent. This disorder occurs in infants, and when untreated, these infants will die in the first year because they are not resistant to bacteria and viruses (1). 

 Acquired immune deficiency syndrome or AIDS stems from the human immunodeficiency virus or HIV. HIV is a part of the retrovirus family and has a virus with a nucleic acid core of RNA (1).

The virus will enter the host cell and transcribe the virus’s RNA into DNA. The DNA of the virus is what causes the death of the cell. HIV specifically enters helper T cells. In other words, this virus doesn’t just attack normal random cells. They specifically attack cells that are responsible for creating an immune response. HIV infects helper T cells because of the CD4 protein on the helper T-cell (1).

HIV has a protein called gp120. This protein attaches to the receptor of the T-cell. Once in the helper T-cell, HIV can directly kill the helper T-cell because it’s replicating its DNA into the cell. Simultaneously, it also indirectly kills the cell because the body’s immune system recognizes the foreign host and attacks the helper T-cell. In other words, you have the body attacking itself because of these foreign cells (1).

HIV infection leads to AIDS over time as the body continues to kill more and more helper T cells. Over ten years, HIV infection can turn into AIDS. The major routes of transmission of HIV are through blood transfers from one person to another, through sexual intercourse with an infected partner, contact from an infected mother to her fetus, and transfer via breast milk when nursing (1).

 Treatment of HIV includes a battery of four specific drugs. Two of these drugs work by HIV reverse transcriptase. This drug converts the viral RNA into the host cell’s DNA. 1/3 of the drug will inhibit the HIV enzyme that cleaves a large protein required for HIV. This cleavage forces the drug to block the enzyme of HIV and will prevent the fusion of the virus with the T cell (1).

 Antibiotics

 Antibiotics are any molecule that kills bacteria. For example, penicillin is an antibiotic that can kill bacteria cell walls and protein synthesis in DNA replication (1).

 Erythromycin also blocks the movement of ribosomes of bacterial messenger RNA. The antibiotic can induce genes that transfer to future resistance (1).

 The use of antibiotics requires caution because sometimes these drugs can contribute to a new infection by destroying good bacteria that are needed in the body to protect themselves. In other words, antibiotics do not always differentiate between good and bad bacteria in the body (1).

Harmful Immune Responses

 Graft rejection is when the immune system does not successfully recognize a transplant and instead attacks the organ. There are drugs and radiation that reduce graft rejection. A drug called cyclosporine does not kill lymphocytes but blocks the production of other cytokines. These drugs inhibit rejection when transplants occur (1).

Blood group O can neither receive a transfusion from A or B but can universally donate to antibodies A to B (1).

AB can receive antigens A and B but can not give antibodies A or B (1).

A can receive from A but cannot deliver to B. 

B can receive from B but cannot give to antibody A. 

Cross-matching takes place when there is a test for the incompatibilities of different blood groups (1).

 There are many different types of erythrocytes and more than 40 antigens. One complex antigen is the Rh factor. Humans are either RH positive or Rh-negative (1).

If a mother is Rh-negative and the fetus is RH positive, the mother makes anti-Rh antibodies. After the first pregnancy, the mother will have complications with future pregnancies. In a second pregnancy, the immune system will attack the fetus because it sees the fetus as a foreign substance (1).

For the fetus, this disease is a hemolytic disease of the newborn. The mother is given gamma globulins against the RH positive erythrocytes after delivering to the RH positive infant. These antibodies enter the mother’s blood and prevent them from inducing antibody synthesis, thus protecting the fetus (1).

This reaction does not occur for types A, B, or O blood groups. The Rh antibodies are much stronger than those blood groups (1).

 Hypersensitivities

 Hypersensitivity is a disease in which immune responses to environmental antigens cause inflammation and damage to the body itself. Cytotoxic hypersensitivity is when antibodies bind to antigens and lead to tissue injury. Another type of complex immune hypersensitivity is when antibodies combine with antigens and get trapped within capillary walls (1).

These immune complexes activate complement and induce an inflammatory response in the organ. In another type of hypersensitivity, the information is independent of antibodies. This reaction prevents helper T cells from forming and causes delayed hypersensitivity. An example would be the tuberculosis skin test (1).

Immediate hypersensitivities are IgE mediated and involve allergies. Immune complex hypersensitivity is related to IgG or IgM blood types (1).

For immediate hypersensitivities, the IgE antibodies circulate in the body, connect to the antigens, and trigger an inflammatory response. Anaphylaxis is an allergic response that can cause death concerning a circulatory or respiratory failure. Late phase reactions can last many hours or many days, and this is when eosinophils migrate to the inflamed area (1).

Autoimmune Disease

 An autoimmune disease is an immune attack triggered by the body’s antigens. An example is a disease called multiple sclerosis, where myelin attacks the body (1).

Myasthenia gravis is also an attack on skeletal muscle cells. Rheumatoid arthritis is an attack on the joints of the skeletal system. Lastly, type 1 diabetes is an attack on insulin-producing cells that interfere with production (1).

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 Excessive inflammatory responses can include septic shock, which is a dangerously high fever. Alzheimer’s disease is also an inflammation disorder (1).

Asthma, rheumatoid arthritis, and inflammatory bowel disease are chronic inflammatory diseases. These diseases are mediators of inflammation where the body reacts almost by default to protect the body, but instead, it creates more problems than relief of symptoms (1).

Sources

Hill, Richard W., et al. Animal Physiology. Oxford University Press, 2018.

Vander, Arthur J., et al. Vander’s Human Physiology: The Mechanisms of Body Function. McGraw-Hill Education, 2019.