Chapter 23: The Immune System

• Chapter 23 is about the Immune System.

Overview of the Immune System: Functions

• Excess interstitial fluid is drained from interstitial space into lymphatic vessels, then returned to bloodstream.
• Dietary fats and fat-soluble vitamins are transported from the small intestine to the bloodstream.
• Infectious organisms including bacteria, viruses, fungi, and parasites, are recognized and killed.
• Own cells are both recognized and tolerated, as are non-harmful foreign molecules like food and environmental substances.
• Immunological memory cells are produced in order to prevent infection from the same organism in the future.

Anatomy of the Lymphatic System

• Fluid accumulates in the interstitial fluid which can cause edema (swelling).
• Fluid buildup main causes:
  • Increased capillary hydrostatic pressure
  • Kidneys not functioning properly
  • Valve failure leads to high pressure in veins
  • Lack of skeletal muscle contraction that bedridden patients suffer
  • Medications
  • Decreased plasma proteins
  • Blocked lymphatic vessels
• Bone marrow contains hematopoietic stem cells that differentiate into red and white blood cells and platelets, alongside B cells that undergo a maturation process.
• Thymus contains thymocytes (immature T cells) that undergo a maturation process to eliminate any cells that recognize “self” antigens.
• Mature B and T cells that are "tolerant" of self-antigens migrate to the lymph nodes to react only to specific infections that match their specific receptors.
• Lymph nodes contain immune cells that recognize and fight infections, some toxins, and dead cells carried in the lymph.
• Lymph nodes are located in larger numbers in areas where microorganisms can enter the body, such as the ears, mouth, lungs, urogenital region, and digestive tract, as well as near mammary glands.
• Spleen red pulp contains macrophages, red blood cells, and platelets, and is the location of the breakdown of old red blood cells.
• Spleen white pulp contains lymphocytes, macrophages, and dendritic cells involved in the adaptive immune response.
• Lymphatic nodules are similar to lymph nodes except they are not surrounded by a capsule.
• Examples of lymphatic nodules are tonsils, adenoids, Peyer's patches located around small intestines, gut-associated lymphoid tissue (GALT)

Innate Immune Response

• First line of defense is the skin that provides protection from foreign invaders.

• Skin and mucus provide a physical barrier.

• Mucous membranes are found in the digestive system and respiratory system.

• Specialized immune cells are found throughout the layers of the skin to detect invasion and destroy invaders.

• When a foreign pathogen (bacteria, virus, fungus, or parasite) enters the body, the immune system detects foreign proteins on the surface of the pathogen termed antigens.

• Antigens can also be peptides, lipoproteins, glycoproteins, or carbohydrates.

• Oil glands (sebaceous) make the skin surface very acidic and sweat contains the enzyme lysozyme, which attacks and digests the cell walls of many bacteria (not normal flora).

• Lysozyme is also present in tears.

• The linings of the digestive and respiratory tracts provide potential routes of entry for microbes.

  • Lysozyme is present in saliva.
  • Hydrochloric acid and digestive enzymes provide protection in the digestive tract.
  • Sticky mucus traps most microorganisms in the respiratory tract and cilia continually move mucus up toward the throat.
  • Resident bacteria-normal flora in the digestive tract helps prevent infections.

• Second line of defense is engaged when a pathogen crosses the boundaries of the skin or mucous membranes, indicating an ongoing infection where cellular and chemical defenses come into play.

  • Cells and proteins kill invading microbes.
  • The inflammatory response occurs, along with the temperature response.

• Neutrophils are the most numerous of all white blood cells and are the predominant cell type in pus; they are also first-responders that produce chemicals involved in the inflammatory response, like histamine, vasodilators, reactive oxygen species, and cytokines.

• Neutrophils are phagocytic cells that engulf many types of microbes, mostly bacteria and opsonized pathogens, and migrate from blood vessels to the infection area within tissues, being attracted to damaged cells by chemotaxis/migration.

• Basophils are the least common type of white blood cell, and release histamine and several cytokines involved in the inflammatory response, playing a role in allergic reactions and parasitic infections, specifically ectoparasites like ticks or lice.

• Eosinophils are involved in parasitic infections like helminths and worms, manufacturing many chemicals including histamine involved in allergies, asthma, and inflammation.

• Mast cells are primarily involved in allergic reactions and anaphylaxis, and prevalent in tissues near openings to the body, like mouth, nose, skin, lungs, and the GI tract.

  • They release histamine if interaction with IgE antibodies occurs.
  • Plays an important protective role in wound healing

• Monocytes circulate in the blood, responding to inflammatory signals by migrating into tissues and differentiating into macrophages or dendritic cells.

• Dendritic cells are important antigen-presenting cells (APCs) that stimulate lymphocytes (B cells and T cells) in the spleen, lymph nodes, or lymphoid nodules and initiate the adaptive immune response.

  • Dendritic cells are phagocytic cells that can engulf pathogens or opsonized pathogens, being present in tissues that are in contact with the environment, like the skin (Langerhans cells), lungs, and the GI tract.

• Macrophages are important APCs that stimulate lymphocytes in the lymphatic tissues and initiate the adaptive immune response.

  • Macrophages are phagocytic cells that can engulf pathogens or opsonized pathogens, secreting toxic chemicals that directly kill invading organisms, along with cytokines and chemicals involved in the inflammatory response.

• Natural killer cells specifically kill virus-infected cells and cancer cells by lysis with perforin or induction of apoptosis.

  • They can kill cells opsonized with antibodies, and produce antigen-specific memory cells important for detecting the same infection a second time.

• Interferons are produced in cells infected by viruses or bacterial toxins, being secreted to the surrounding area.

  • Neighboring (uninfected) cells, warned by the interferons, produce proteins that inhibit viral replication upon infection, thereby activating natural killer cells.
  • Interferons can activate p53, and they are partly responsible for unwellness during sickness.

• Complement system consists of about 20 different proteins circulating freely in the plasma (made in liver) in an inactive state, activating to form a membrane attack complex.

  • The membrane attack complex forms a pore opening in the foreign cell's membrane, causing water to rush in and burst the cell.
  • Triggered by antibodies, the complement system facilitates phagocytosis.

• Mast cells and basophils release histamine and prostaglandins in damaged tissues, causing vasodilation that makes capillaries more permeable, allowing white blood cells to enter the tissue to cause redness and swelling.

  • Prostaglandins activate pain sensors, and cause aching when sick.

• Neutrophils and macrophages kill microbes and engulf dead cells.

  • Pus is a mixture of dead cells and white blood cells.

• Symptoms of inflammation include redness, pain, swelling, and heat.

• Macrophages trigger fever via a signal to the hypothalamus for the purpose of curbing microbial growth, a process potentially dangerous due to inactivation of the body's cellular enzymes when the body temperature is too high.

  • A fever up to 39°C is beneficial, while one of 40°C should be treated with an antipyretic.
  • A fever over 42°C can be fatal.

Adaptive Immune Response

• The cells involved:
  • B cells contain a specific receptor for a specific antigen that is a membrane-bound immunoglobulin /antibody, and circulate between blood and lymphatic tissues. - B cells become phagocytic when antigen matches receptor, and act as antigen-presenting cells that produce cytokines.
• When activated by a helper T cell, B cells differentiate into plasma cells and secrete antibodies, also able to produce memory cells.
  • Helper T cells don't directly kill any invading microorganisms, only responding to antigen presented by APC (macrophage, dendritic cell, or B cell).
    • Helper T cells produces cytokines that activate B cells, cytotoxic T cells, macrophages, dendritic cells, and NK cells and can produce memory cells.
  • Cytotoxic T cells can directly kill virus-infected cells, cancer cells, and transplant tissue by binding to antigen presentation on MHC class I molecules and producing memory cells.
  • Regulatory T cells inhibit other immune cells at the end of an infection and prevents auto-reactive immune cells-the cells that escaped the negative selection process in the bone marrow or thymus-from damaging tissues.
• Monocytes are in constant circulation in the bloodstream and when they encounter a pathogen, they differentiate into macrophages.
  • Macrophages have a very long lifespan (months to years), while neutrophils only live for a few hours.
  • Macrophages recognize pathogens by pathogen-associated molecular patterns (PAMPs), and phagocytose and digest the microbes.
• Macrophages then display the digested microbe proteins on their cell surfaces to alert other immune cells in a process termed antigen presentation.
• MHC I protein is found on all cells in the body, allowing the immune system to recognize one's own cells.
• Antigen-presenting immune cells (macrophages and dendritic cells) have MHCI and MHC II surface proteins, important for "presenting” antigens to lymphocytes, activating the lymphocytes (B cells and T cells).
• Lymphocytes are white blood cells critical to the specific immune response, originating in the bone marrow.
  • T cells migrate to the thymus gland for maturation during embryonic development, identifying microorganisms/viruses by specific surface antigens .
  • B cells complete maturation in the bone marrow, differentiating into plasma cells that secrete antibodies when an antigen is encountered.
  • B cells coat the antigen, marking the cell bearing that antigen for destruction
• The T cell response is also called the cell-mediated response, where CD4+ helper T cells secrete cytokines to activate B cells, cytotoxic T cells, NK cells, and macrophages.
  • CD8+ cytotoxic T cells destroy virus-infected cells, cancer cells, and transplant tissue cells with perforin.
  • Regulatory T cells inhibit B cells and T cells.
  • Cytotoxic T cells generally fight intracellular infections by killing the infected cells.
• Helper T cells differentiate into subtypes
  • TH1 cells increase activation of cytotoxic T cells in the case of viral infection.
  • TH2 cells increase activation of B cells in the case of a bacterial infection.
• Some helper T cells turn into memory cells and other regulatory T cells/TH17 to slow down the immune response and prevent reactions against any self-antigens.
• Some become tolerant (TH0), and do not react to food antigens, normal flora bacteria, and harmless environmental molecules.
• B cells differentiate into plasma cells when activated by an infectious organism, then secrete antibodies (specific for that infection).
• The B cell response is also called the humoral immune response, fighting any extracellular infection (bacteria, viruses outside of cells, parasites, fungi, and toxins produced by bacteria).
• Activated B cells can bind to free, unprocessed antigens, as antigen particles enter B cells by endocytosis, where antigens are processed and placed on the surface complexed with MHC II proteins. Helper T cells able to recognize the specific antigen bind to the antigen-MHC II protein complex, stimulating the release of interleukin-2 (IL-2) to further the immune response.
• Due to a first infection, a large clone of lymphocytes that recognize a pathogen remains/ B&T memory cells, helping the secondary immune response that will be more effective upon further encounter with that same pathogen.
• Types of Adaptive Immunity:*
• Naturally acquired active immunity: after an infection where memory cells are produced
• Naturally acquired passive immunity: through transfer of antibodies from mother to baby during breast feeding, that temporarily prevents infection in the baby.
• Artificially acquired active immunity: through vaccination - transfer of an antigen that stimulates the immune system to produce memory cells without infection
• Artificially acquired passive immunity: transfer of antibodies provides the organism with temporary immunity