Chapter 22 Lymphatic / Immunity

Dendritic cells

- function as antigen-presenting cells; presented to T cells (and, to a lesser extent, B cells), which are then activated

cisterna chyli

Intestinal trunk and lumbar trunks all drain into a large, swollen vessel

Basophils

Located primarily in blood, although a related type of cell (mast cells) are located in mucous membranes Like regular basophils, mast cells contain granules with chemicals that trigger Eosinophils; particularly involved in allergic responses

lymph node function

Lymph flows into node through multiple small lymphatic vessels (afferent lymphatic vessels) then percolates through reticular network, where pathogens in lymph become trapped in reticular "net" Trapped pathogens then encounter leukocytes and dendritic cells, which eliminate these threats Lymph that has been "cleaned" of pathogens drains out through efferent lymphatic vessels on other side of node at hilum Lymph nodes trap approximately 90% of pathogens in lymph; prevents these pathogens from being delivered to blood, where they could easily spread to other tissues and organs

Lymphatic vessels and circulation

Lymph is collected in vessels called lymph-collecting vessels which merge to form larger vessels, lymph trunks Nine lymph trunks drain lymph from specific body regions: jugular trunks (left and right) subclavian trunks (left and right) Lumbar trunks (Left and right) Intestinal trunk Bronchomediastinal trunks (left and right)

lymphatic capillaries

Lymphatic vessels begin in tissues with tiny lymphatic capillaries; which form network around blood capillary beds. Lymphatic capillaries differ both structurally and functionally from blood capillaries: Specialized lymphatic capillaries known as lacteals collect fat in the small intestine Lymphatic capillaries are blind-ended, which makes lymphatic vasculature a one-way system that only moves lymph away from tissues. Cells of lymphatic capillary walls are not tightly joined, and instead are able to flap open and closed Fluid that leaks from blood capillaries increases interstitial fluid pressure; forces lymphatic endothelial cells apart; fluid enters lymphatic capillaries When pressure in interstitial fluid decreases, endothelial cells flap shut. These vessels are also leaky enough to allow cells such as macrophages and other immune cells to enter lymph

lymph circulation

Lymphatic vessels make up a low-pressure circuit because there is no main pump to drive lymph through vessels, and most of them are transporting lymph against gravity. Lymph vessels have valves to stop backflow Lymph vessels has 2 pumps to assist with fluid movement respiratory pump and skeletal muscular pump Lymph flow through vessels is driven in part by contractions of smooth muscle found in walls of lymph-collecting vessels

Basic Structures of lymphatic system

Lymphatic vessels, tonsils lymph nodes, spleen, and thymus (lymphoid follicles)

Lymphoid organs house leukocytes

Macrophages - mature monocytes that are very active phagocytes B and T lymphocytes Dendritic cells -derived from bone marrow while others originate from connective tissue Reticular cells - particularly abundant in organs such as spleen and lymph nodes; produce reticular fibers composed of a specialized, thin type of collagen protein

Innate immunity Macrophages

Macrophages are activated by a variety of stimuli, including certain molecules present on pathogens, chemicals secreted by damaged cells, and signals from cells of adaptive immunity Activated local macrophages are generally first cells to respond to a cellular injury, where they ingest other cells and cellular debris Macrophages kill pathogens they have ingested with chemicals, including hydrogen peroxide and hypochlorous acid (active component in bleach) Macrophages also have cytotoxic effects, secreting chemicals onto pathogens that are too large to ingest Macrophages function as antigen-presenting cells T cells become activated by these antigens and in turn secrete substances that increase activity of macrophages, in an example of a positive feedback loop

B CELL ACTIVATION: PHASE III

Memory B cells are responsible for antibody-mediated immunological memory, which allows B cells to respond more efficiently when antigen is encountered a second time Upon first exposure to an antigen, a B cell clone specific for that antigen recognizes it, proliferates, and differentiates into plasma and memory B cells, and plasma cells begin to secrete antibodies; response is called primary immune response: Effective, but slow—there is an initial 4- to 5-day lag phase as the B cells proliferate, differentiate into plasma cells and memory cells, and begin to secrete antibodies Antibody levels peak about 7-14 days after antigen is encountered; it is during lag phase that you generally feel "sick" Future exposure to same antigen results in activation of memory B cell formed during primary immune response When these memory B cells encounter antigen for which they are specific, secondary immune response begins; lasts longer than primary response Has a shorter lag phase (about 1-3 days), and its antibody levels peak more rapidly (3-5 days) and reach a peak 100-1000 times larger Major antibody involved in secondary response is IgG, whereas it's IgM in primary response Antibodies secreted in secondary immune response are more effective — they bind more tightly (have a higher affinity for their antigens)

Nonphagocytic cells (include NK cells, dendritic cells and basophils):

NK cells have the remarkable ability to recognize cancerous cells and cells infected with certain viruses in spite of fact they cannot recognize specific antigens; are cytotoxic Secrete an antimicrobial cytokine that activates macrophages and enhances phagocytosis

Overview of Immune cells

Natural killer (NK) cells, located in blood and spleen, function primarily in innate immunity Dendritic cells, located in many lymphoid organs; part of innate immune response, but their main role is to activate T cells of adaptive immunity Proteins: Antibodies - proteins produced by plasma cells that function in adaptive immunity Complement system - functions in innate immunity Cytokines - diverse group of proteins secreted by cells of both innate and adaptive immunity; have a variety of effects, including regulating development and activity of immune cells

reticular tissue

Predominant tissue type of lymphatic system is reticular tissue; contains specialized cells and thin reticular fibers; interweave to form "nets" that trap disease-causing pathogens Lymphatic reticular tissue is typically called lymphoid tissue

Antimicrobial Proteins

Proteins that inhibit microbial reproduction and provide short-term, nonspecific resistance to pathogenic bacteria and viruses Include complement proteins and several types of cytokines

fever

Pyrogens act on hypothalamus. Hypothalamus normally functions as body's thermostat; maintains body temperature within normal range through a series of negative feedback loops Pyrogens cause hypothalamic thermostat to reset to a higher range Hypothalamus interprets normal body temperature as being too low, which triggers negative feedback loop; elicits sensation of cold, or having "chills," when a fever occurs Hypothalamus triggers responses that elevate body temperature to new, higher range; includes familiar sign of shivering; increased muscle activity that generates heat to bring body temperature to new set point Fevers may be alleviated, or "break"; results from hypothalamus being reset to normal temperature range; causes hypothalamus to sense febrile temperature as being too high; triggers negative feedback mechanisms to lower body's temperature Mechanisms include sweating and dilation of blood vessels serving skin

Innate immunity: internal defenses

Rapid response of innate immunity consists of two main components: a group of antimicrobial molecules, and other cells such as neutrophils, macrophage and NK cells. Cells of innate immunity - Pathogens that are able to bypass body's surface barriers next meet second line of defense: phagocytic cells and nonphagocytic cells Phagocytes - include macrophages, neutrophils, and eosinophils Agranulocytes known as monocytes exit bloodstream and take up residence in various tissues where they develop into macrophages

Anti-inflammatory meds

Reduce inflammation and accompanying pain by blocking production of prostaglandins Prostaglandins and related leukotrienes are derived from a fatty acid called arachidonic acid that is present in nearly all cell membranes; when cell is damaged or triggered in some other way, enzyme phospholipase A2 catalyzes a reaction that cleaves arachidonic acid Products of this reaction may be acted on by two broad classes of enzymes: cyclooxygenases, which produce prostaglandins, and lipooxygenases which produce leukotrienes First, and largest, group of medications consists of nonsteroidal anti-inflammatories (NSAIDs); work by inhibiting cyclooxygenase enzyme and preventing formation of prostaglandins; example of a common medication available over counter is ibuprofen Corticosteroids make up a second group of medications Mimic actions of hormone cortisol; inhibits formation of both prostaglandins and leukotrienes; leads to a wider-ranging and more potent anti-inflammatory effect Generally used for conditions with more severe inflammation or inflammation due primarily to leukotrienes (such as allergy-related inflammation) Examples of common corticosteroids include cortisone and prednisone

lymphedema

Role of lymphatic system in regulating volume of interstitial fluid becomes readily apparent in lymphedema Edema - The excess accumulation of fluid in the interstitial tissue spaces; many conditions can cause mild to moderate edema, including trauma, vascular disease, and heart failure However, edema seen with lymphedema is typically severe and can be disfiguring Lymphedema is generally due to removal of lymphatic vessels during surgery or blockage of vessels from pathogens such as parasites Both conditions prevent lymphatic vessels from transporting excess interstitial fluid back to cardiovascular system; fluid therefore accumulates in tissues of affected body part, causing it to enlarge

B CELL Activation: phase II

Second phase of antibody-mediated immune response involves antibodies and their effects Study of antibodies is called serology, which examines structure and functions of antibodies as well as their applications to medicine and research Basic subunit of an antibody is a Y-shaped molecule formed from four peptide chains, two heavy (H) and two light (L) chains Each of these chains has two types of regions: Constant (C) region - relatively similar among antibody classes; responsible for many of antibodies' effects Variable (V) region - unique sequence of amino acids responsible for antigen recognition and binding An antibody has V regions at tips of two arms of molecule, so basic subunit of an antibody has two antigen-binding sites, one on each arm A single antibody subunit is a monomer that can be combined with other subunits to form larger structures such as a dimer or a pentamer There are five basic classes of antibody; grouped according to structure of their C regions. Two-letter abbreviation "Ig," which stands for "immunoglobulin," followed by a letter that designates its class IgG, IgA, IgM, IgE, and IgD; remember with mnemonic GAMED: IgG - most prevalent antibody in body; only antibody able to cross from blood of a pregnant woman to her developing fetus via placenta IgA - usually a dimer; gives this antibody four antigen-binding sites; present in secretions from skin, mucous membranes, and exocrine glands IgM - largest antibody; pentamer, for a total of 10 antigen-binding sites; generally first antibody secreted by plasma cells when body is invaded by a pathogen; also exists as a single subunit embedded in B cell plasma membrane, where it functions as a B cell receptor IgE - single-subunit antibody; generally present in very low amounts in body's fluids Binds to two types of antigen: antigens associated with parasitic pathogens such as tapeworms, and environmental antigens known as allergens, which are linked with inflammatory reactions (allergies) Bind to mast cells in mucous membranes, and when they come into contact with their specific antigens, trigger mast cells to release contents of their granules (degranulation) Responsible for common allergy symptoms such as a runny nose and watery eyes IgD - unique because it is only antibody not secreted by B cells in significant amounts; its single subunit is located on surface of B cells, where it acts as an antigen receptor that helps activate B cells in a similar manner to IgM Antibodies in a particular class feature similar C regions, but each antibody has a unique V region that determines its ability to recognize and bind a certain antigen

right lymphatic duct

which drains into junction of right internal jugular and right subclavian veins; drains upper right side of body

T-cells

T cells are formed in bone marrow, but they leave bone marrow and migrate to thymus to mature: T cells undergo gene rearrangements that lead to a huge variety of genetically distinct T cells Each population of T cells that can respond to a specific antigen is known as a clone There are millions of different clones in immune system, but only a few cells of each clone exist in body at any given time Some T cell clones are capable of recognizing and responding to pathogens, whereas others are not; thymus "screens" these cells and mediates destruction of those clones that cannot recognize antigens The thymus ensures that an individual is immunocompetent, or able to mount a normal response to foreign antigens Other T cell clones, known as self-reactive T cells, recognize your own cells as foreign and would attack your cells if released into circulation T cells that survive thymus screening are released into circulation when they mature; known as naïve T cells because they have not yet encountered their specific antigens Only certain antigens, called immunogens, are capable of generating a response from immune system Antigens present on your own cells, called self antigens, are not immunogens in your body Haptens are very small antigens that are immunogenic only if they are attached to a protein carrier T cell receptors are found on surface of every T cell; receptor must bind a specific antigen before cell can become activated Unique portion of antigen to which receptor binds is known as its antigenic determinant

major histocompatibility complex (MHC) molecules:

T cells can only interact with pieces of antigen bound to glycoproteins called major histocompatibility complex (MHC) molecules: Name comes from fact that MHC molecules are major determinants of compatibility among tissue and organ donors and recipients MHC molecules are found on nearly all nucleated cells except erythrocytes; make blood products considerably easier to donate than other organs and tissues MHC molecules serve as "docking sites" for specific components of antigens that are then displayed to T cells Class I MHC molecules - found on surface of plasma membrane on nearly all nucleated cells Present endogenous antigens, or those synthesized inside cell Cytotoxic T (TC) cells generally interact only with class I MHC molecules Class II MHC molecules are found only on surfaces of antigen-presenting cells Helper T (TH) cells generally interact with class II MHC molecules Class II MHC molecules present exogenous antigens, or those cell takes in by phagocytosis An endogenous antigen is either a foreign antigen present on a pathogen that lives inside your cell, such as an intracellular bacterium, or a foreign or self antigen encoded by your DNA; includes normal self antigens, foreign cancer antigens made by mutated DNA, and foreign viral antigens (when a virus infects cell, it inserts its genetic material into DNA and triggers synthesis of its proteins, including antigens) Endogenous antigens can be foreign or self, but exogenous antigens are nearly always foreign

Tonsils

Three main tonsils: Pharyngeal tonsil (adenoid) - located in posterior nasal cavity (nasopharynx) Palatine tonsils - in posterolateral oral cavity Lingual tonsil - at base of tongue Epithelium lining tonsils indents deeply in several locations, forming tonsillar crypts that trap bacteria and debris Tonsil location puts them into contact with a large number of potential pathogens; as a result, commonly become inflamed, a condition known as tonsillitis

Part 1: Release of inflammatory mediators and cardinal signs of inflammation:

Tissue damage initiates inflammatory response as damaged cells and local mast cells release inflammatory mediators Inflammatory mediators can include histamine, serotonin, cytokines, bradykinin, prostaglandins, and leukotrienes Activated complement proteins trigger release of inflammatory mediators from cells such as basophils and mast cells Injured area becomes red and swollen, feels warm to touch, and hurts Vasodilation - occurs due to inflammatory mediators such as histamine and bradykinin What will this do? What signs will occur? Increased capillary permeability - occurs as inflammatory mediators increase "leakiness" of local capillary beds Proteins in fluid include clotting proteins such as fibrinogen, complement proteins, and proteins needed for tissue repair Occurrence of pain - several inflammatory mediators, particularly bradykinin and prostaglandins, trigger action potentials in peripheral processes of sensory neurons, Recruitment of other cells - inflammatory mediators cause chemotaxis; macrophages and neutrophils while complement proteins are simultaneously being activated

Specialized MALT is found in three locations in gastrointestinal tract

Tonsils - located around oral and nasal cavities Peyer's patches (aggregated lymphoid nodules) -located in last portion of small intestine (called ileum) Appendix - protrudes from large intestine

Type I: Immediate hypersensitivity

Type I: Immediate hypersensitivity - most common type; known commonly as allergies and accompanying disorders as allergic disorders: First exposure to an allergen - allergen binds a B cell which triggers B cell differentiation into plasma cells that secrete antibodies Plasma cells secrete IgE instead of IgG or IgM Subsequent exposures to identical allergens in a sensitized individual result in a rapid response (occurs within a few minutes); occurs when allergens bind to IgE molecules on sensitized mast cells or basophils forming cross-links Allergen exposure may also result in a skin rash; small areas of skin appear red and elevated, known as hives, or urticarial; more potent reactions occur in patients with asthma Anaphylactic shock - most dramatic immediate hypersensitivity reaction; involves a systemic release of histamine and other inflammatory mediators; mediators are responsible for life-threatening events: Severe spasm of smooth muscle of respiratory tract Systemic vasodilation, which causes blood pressure to drop and decreases blood flow to all organs, including brain Increased capillary permeability in all of body's capillaries; further lowers blood pressure and causes body-wide swelling as there is a massive loss of fluid to tissue spaces and lungs

Eosinophils

a white blood cell containing granules that are readily stained by eosin.

Type II: Antibody-mediated hypersensitivity

antibodies produced by immune response to foreign antigens also bind to self antigens These reactions occur when foreign antigens bind to normal self antigens, when donor erythrocytes infused into another individual are mismatched using the ABO/Rh antigen groups, or when self-reactive B cells are not destroyed in bone marrow, which leads to autoimmunity First possibility occurs in a reaction caused by penicillin, which can bind to erythrocytes in certain individuals; alters erythrocyte antigens and causes them to be recognized as foreign; activated B cells secrete antibodies that lead to complement activation and complement-mediated lysis of erythrocytes

peyer's patch

are also exposed to a large number of potential pathogens because of their location; allows them to defend against any bacteria that have escaped from large intestine

Immunodeficiency disorders

are caused by a decrease in function of one or more components of immune system; there are two basic types of immunodeficiency disorders: Primary immunodeficiencies - genetic or developmental in nature Secondary immunodeficiencies - acquired through infection, trauma, cancer, or certain medications

Part 2: Phagocyte response

arrival and activation of phagocytes is divided into stages that are based on which phagocytes enter area and processes occurring there: Local macrophages ("first responders") are activated within minutes of cellular injury; enlarge and begin to phagocytize pathogens and damaged cells; only phagocytes present within first hour or so of inflammatory response; perform critical function of containing invading pathogens Neutrophils migrate (chemotaxis) to damaged tissue and phagocytize bacteria and cellular debris Inflammatory mediators and activated complement proteins attract neutrophils and enable them to leave blood and enter tissue; make capillary endothelium in damaged area "sticky", and neutrophils adhere to capillary wall (process called margination) Inflammatory mediators increase capillary permeability; allows for diapedesis; destroy bacteria and other cellular debris Bone marrow releases stored neutrophils into blood; leads to a rapid rise in level of circulating neutrophils Monocytes migrate to tissue (chemotaxis) and become macrophages Bone marrow increases production of leukocytes, leading to leukocytosis; cytokines produced by activated phagocytes act on cells in bone marrow to increase production of neutrophils and monocytes over next 3-4 days Leads to an elevated number of circulating leukocytes, commonly referred to as a "high white cell count" Cells such as fibroblasts can begin process of healing once everything is cleared Accumulation of dead leukocytes, dead tissue cells, and fluid leads to a whitish mixture known as pus (a wound filled with pus is called purulent)

Appendix

blind-ended, worm-shaped tube that juts from large intestine; defends body from bacteria in large intestine, specifically those that could be pathogenic

Absorption of dietary fats

breakdown products of fats in diet are too large to pass between endothelial cells of blood capillaries: Dietary fats instead enter small lymphatic vessels in small intestine. Travel through lymphatic vessels and are delivered to blood with lymph

Surface barriers

first line of defense against any potential threat to body is coverings of body surfaces; skin and mucous membranes, and certain products they secrete: Both skin and mucosae provide a continuous physical barrier to block entry of potential pathogens into body The skin produces sebum and dehydrating environment where most pathogens have an issue thriving

Functions of the lymphatic system

fluid recovery, immunity, lipid absorption

Complete blood count with differential

group of blood tests that are performed automatically by machine to determine the number, type, and characteristics of various cells in the blood One of first laboratory tests ordered when a patient is admitted to hospital is a complete blood count (CBC); Unfortunately, inflammation is nonspecific. For this reason, a differential, which measures relative prevalence of different types of leukocytes in blood, is ordered along with CBC If infection is caused by bacteria, who will be more prevalent? neutrophils Viral pathogens tend to induce primarily a lymphocyte-dominant response, so numbers of lymphocytes in blood would likely be elevated with a viral infection Inflammation due to parasites or allergies, who will you look for? eosinophils

Complement

group of molecules collectively known as complement system consists of 20 or more plasma proteins that are produced primarily by liver: Complement proteins are designated with a "C" and a number; involved in both innate and adaptive immunity Circulate primarily in their inactive forms; must be activated by a complex cascade of events mediated by enzymes Two main series of enzymatic reactions, or pathways, activate complement proteins: classical and alternative pathways Classical pathway - begins when inactive complement proteins bind to antibodies bound to antigen Alternative pathway - begins when inactive complement proteins encounter foreign cells such as bacteria Two pathways converge at cleavage of an inactive complement protein called C3 into its active form C3b, which in turn cleaves inactive protein C5 into its active component C5b Activated complement proteins lead to following main effects: Cell lysis - mediated by C5b C5b binds to surface of a pathogen and provides a docking site for several other activated complement proteins; together these complement proteins form a structure collectively known as membrane attack complex, or MAC MAC inserts itself into plasma membrane of target cell and creates a pore Enhanced inflammation - inflammatory response is a nonspecific response to cellular injury; several complement proteins enhance this response by triggering basophils and mast cells Neutralize viruses - C3b and components of membrane attack complex bind to certain viruses and neutralize them, or block them from infecting host cells Enhancing phagocytosis - C3b acts as an opsonin by binding to pathogens; opsonization makes phagocytes bind more strongly to a pathogen and enhances phagocytosis Clearance of immune complexes: C3b binds to immune complexes (clusters of antigens bound to antibodies) and triggers their phagocytosis; clears complexes from circulation, which is critical to preventing these complexes from lodging in different tissues around body

Secondary immunodeficiency disorders

have multiple forms, many of which are induced artificially to combat cancers originating in bone marrow or to prevent transplant rejection: Cancers of immune cells and lymphoid organs that depress immune response in some way also cause secondary immunodeficiency Most common cause of secondary immunodeficiency by far is virally induced disease acquired immunodeficiency syndrome, or AIDS Progression of HIV-1 infection can be divided into three phases: Acute phase lasts about three months; characterized by a sharp decline in TH cells and a sharp rise in HIV-1 virions; patients may exhibit flu-like symptoms during this phase, although condition often goes unnoticed Chronic phase begins with production of antibodies to HIV-1 virions, an initial slight recovery in number of TH cells, and a decline in number of HIV-1 virions; may last eight or more years in untreated individuals Final phase when an individual is said to have AIDS; characterized by progressively declining numbers of TH cells and progressively increasing numbers of HIV-1 virions; without treatment, duration of final phase is generally no more than three years Signs and symptoms of AIDS are due largely to destruction of TH cells: Loss of TH cells causes entire adaptive immune response to fail (some innate responses remain), Other consequences of AIDS include cancers such as Kaposi's sarcoma, which affects blood vessels and leads to purple-red skin lesions Currently, there are a number of drug therapies for HIV-1; three main mechanisms by which most drugs work: Some drugs inhibit enzyme reverse transcriptase, or inhibit viral enzymes needed to synthesize mature virions, while other drugs block entry of HIV-1 into its target cells Drugs are typically administered in combination as a "cocktail" to inhibit as many aspects of viral replication cycle as possible

Role of TH cells

helper T cells have no phagocytic or cytotoxic abilities; TH cells exert their effects through secretion of cytokines that activate and enhance various components of immune response In this way, they "help" immune response, hence their common name TH cells are required for normal function of all components of immune system, some of main functions of TH cells include: Innate immunity: stimulation of macrophages TH cells secrete cytokine interleukin-3, which stimulates macrophages to become more efficient phagocytes Also causes macrophages to produce interleukin-12, which stimulates TH cells to generate more interleukin-3 in a positive feedback loop Adaptive cell-mediated immunity: activation of TC cells TH cells secrete cytokine interleukin-2 (IL-2); required to activate TC cells In absence of TH cells and IL-2, most TC cells fail to activate and become unresponsive to antigen Adaptive antibody-mediated immunity: stimulation of B cells TH cells directly bind to B cells and stimulate them to proliferate and differentiate Also secrete various interleukins that stimulate B cell proliferation and increase antibody production

Type III: Immune complex-mediated

hypersensitivity reactions are mediated by immune complexes or clusters of soluble antigens (those not attached to cell surface) bound to antibodies Immune complexes are generally cleared by phagocytes, but some are difficult for macrophages to ingest and become deposited in various places in body Once deposited in these organs and tissues, unphagocytized immune complexes initiate an inflammatory reaction, which attracts neutrophils and causes damage to affected tissues

Innate, or nonspecific, immunity

immunity responds to all pathogens or classes of pathogen in same way Innate immune system consists of antimicrobial proteins and certain cells that respond quickly; dominant response to pathogens for first 12 hours after exposure Cells and proteins exist in bloodstream, even in absence of a stimulus

Inflammatory response

innate response that occurs when a cell is damaged by anything, including trauma, bacterial or viral invasion, toxins, heat, or chemicals; two basic stages to inflammatory response: 1. Damaged cells release inflammatory mediators that cause local changes in damaged tissue 2. Phagocytes arrive at area and clean up damaged tissue

Isografts

involve organs and tissues transplanted between two genetically identical individuals; like autografts these result in no response from TC cells because antigens bound to class I MHC molecules are not recognized as foreign

Type IV: Delayed-type hypersensitivity (DTH)

is unique in that it is mediated by T cells rather than antibodies TH cells recognize antigens bound to MHC molecules as foreign and mediate their destruction by activating and recruiting macrophages and in some cases TC cells Reaction generally takes 2-3 days to manifest, hence its name; TH cells must be sensitized by an initial exposure, and reaction occurs with subsequent exposures Contact dermatitis is a common DTH reaction in which skin comes into contact with an allergen such as oils in poison ivy or poison oak, certain metals, or other chemicals that form complexes with skin proteins; result in a rash that is itchy and occasionally painful Other forms of DTH are caused by intracellular pathogens that are not easily cleared by immune response; one such pathogen is bacterium Mycobacterium tuberculosis; causes respiratory infection tuberculosis Mantoux test, also known as PPD test (for purified protein derivative), involves injection of a small amount of a protein derived from cell wall of Mycobacterium tuberculosis bacterium just underneath skin Positive: leads to an area of induration—a hard, swollen area caused by infiltration of macrophages and subsequent cellular destruction Interferon Gamma Release Assay (IGRA) is TB blood test. The lest looks for TB within the blood. Is starting to become more commonplace secondary to false- positive or false negative PPD tests.

Spleen

largest lymphoid organ in body; located on lateral side of left upper quadrant of abdominopelvic cavity: Purplish-brown organ about size of a large bar of soap; internal structure consists of a network of reticular fibers made by reticular cells Two distinct histological regions are found in reticular network: red pulp, which contains macrophages that destroy old erythrocytes, and white pulp, which filters pathogens from blood and contains leukocytes and dendritic cells

Mucosa-associated lymphatic tissue (MALT)

loosely organized clusters of lymphoid tissue that protects mucous membranes, MALT protect oral and nasal cavities; found scattered throughout gastrointestinal tract, respiratory passages, and, to a limited extent, genitourinary tract Much of MALT in body consists of loosely organized clusters of B and T cells that lack a connective tissue capsule

Immune functions

lymphatic system plays an important role in immune system; lymphoid organs filter pathogens from lymph and blood; also house several types of leukocytes, and play a role in their maturation

Primary immunodeficiency disorders

may impair either innate or adaptive immunity; most common dysfunctions of innate immunity involve deficient complement proteins or abnormalities in phagocytes Common dysfunctions of adaptive immunity include hypogammaglobulinemias; Another common form of primary immunodeficiency involving adaptive immunity is a cluster of disorders referred to as severe combined immunodeficiency, or SCID Different forms of SCID are caused by failures of lymphoid cell lines in bone marrow

Allografts

most common type of grafts; involve organs and tissues transplanted between two nonidentical individuals of same species

Regulation of interstitial fluid volume

net filtration pressure in blood capillaries favors filtration, meaning that water is lost from plasma to interstitial fluid Fluid lost must be returned to circulation, or both blood volume and blood pressure will drop too low to maintain homeostasis Lymphatic vessels pick up excess fluid in extracellular space, transport it through body, and deliver it back to circulatory system When the fluid exits extracellular space and enters lymphatic vessels, it is known as lymph

Both processes end up with same result:

portions of antigens displayed on plasma membrane attached to MHC molecules; these MHC-antigen complexes then interact with and activate T cells

Role of TC cells

primary function of cytotoxic T cells is to kill other cells, specifically those with foreign antigens bound to class I MHC molecules: Can detect abnormalities in any cell type with a nucleus; critical for detection of cancer cells, foreign cells, and cells infected with intracellular pathogens such as viruses and bacteria Activated in same way as TH cells, with addition that they require IL-2 from TH cells in order to activate fully; protective mechanism prevents abnormal TC cell activation An activated TC cell binds its target cell, after which it releases a protein called perforin Perforin perforates target cell's plasma membrane; TC cell then releases enzymes that can now enter target cell's cytosol. These enzymes catalyze reactions that degrade target cell proteins and eventually lead to fragmentation of target cell's DNA and its death TC cells also bind to proteins on plasma membrane of target cells; induce process of apoptosis; When target cell begins to degrade, TC cell detaches and searches for a new target cell

Interleukins

proteins (cytokines) that stimulate the growth of B and T lymphocytes stimulate production of neutrophils by bone marrow, stimulate NK cells, trigger production of interferons, and activate T cells Many cytokines (like TNF) induce "flu-like" symptoms; including fever, chills, and aches (aches are due to stimulation of inflammation)

Cytokines

proteins produced by several types of immune cells: Tumor necrosis factor (TNF)- cytokine secreted primarily by activated macrophages in response to certain bacteria and other pathogens; attracts phagocytes to area of infection, increases phagocytes activity, and stimulates phagocytes to release additional cytokines Interferons - inhibiting virus replication cytokines produced by macrophages, dendritic cells, NK cells, and cells of adaptive immunity; produced in response to infection with intracellular agents such as viruses or intracellular bacteria; primary action is to inhibit viral replication inside host cells

Lumbar trunks

receive lymph from lower limbs and pelvic area; jugular trunks receive lymph from head and neck

Bronchomediastinal trunks

receive lymph from thoracic cavity

subclavian trunks

receive lymph from upper limbs and thoracic wall

Intestinal trunk

receives fat-containing lymph from small lymphatic vessels in small intestine

Xenografts

relatively rare procedures that involve organs and tissues transplanted between two individuals of different species, such as a pig and a human

adaptive, or specific, immunity

respond individually to unique glycoprotein markers called antigens; present on all cells and most biological molecules, including our own cells; identify a cell or molecule as belonging to a specific group There are two "arms" of adaptive immune system: First arm is cell-mediated immunity; brought about by two types of T cells Second arm is antibody-mediated immunity (humoral immunity); carried out by B cells and proteins they produce, called antibodies Adaptive immunity responds more slowly than innate immunity because one must be exposed to a specific antigen for response to be initiated. Hence name acquired immunity, as it takes 3-5 days to mount a response, but after this point, it is dominant response Adaptive immunity has the capacity for immunological memory, in which exposure to an antigen is "remembered" by specific lymphocytes and antibodies Innate immunity lacks capacity for immunological memory and will respond in same way with repeat exposure to a pathogen Adaptive immunity and innate immunity work together. Response to a pathogen involves a highly integrated series of events within both parts of immune system

pathogens evade surface barriers

1. Enzymes called collagenases, As bacteria destroy tissues, they produce large quantities of gas, leading to the common name of gas gangrene 2. Enzymes that catalyze destruction of neutrophils; what will this do? 3. Some fungi are quite resistant to phagocytosis. Still other fungal species actually survive inside macrophages 4. Certain pathogens tolerate an acidic pH; for example, poliovirus is able to survive highly acidic environment of stomach when it is ingested, allowing it to replicate in digestive tract and potentially invade rest of body

Cooperation: Lymphatic System and Immunity

1. Lymphoid organs and tissues provide a residence for cells of the immune system; B cells, T cells, and macrophages frequently take up residence in lymphoid organs such as lymph nodes, MALT, and spleen 2. Lymphoid organs and tissues trap pathogens for immune system 3. Lymphoid organs activate cells of immune system; lymphoid organs house cells such as dendritic cells, which play a crucial role in activating B and T cells; thymus is required for selection of a functional population of T cells Lymphatic system plays a greater role in adaptive immunity than in innate immunity

Neutrophils

A type of white blood cell that engulfs invading microbes and contributes to the nonspecific defenses of the body against disease. use hydrogen peroxide, hypochlorous acid, and lysozyme Can ingest many types of cells, but are particularly effective at destroying bacterial pathogens Release cytotoxic contents of their granules onto large pathogens to damage their plasma membranes Chemotaxis

Immunological memory

A vaccination, also known as an immunization, involves exposing an individual to an antigen to elicit a primary immune response and generate memory cells Then if individual is exposed to antigen a second time, a secondary immune response will occur and symptoms will be minimal Subunit vaccines - with certain pathogens, only a portion of pathogen that causes disease is required to develop immunity For example, bacteria responsible for tetanus and diphtheria secrete disease-causing toxins Vaccinations called toxoids contain inactivated toxins from these bacteria; induce immune system to produce antibodies to toxins There are two types of antibody-mediated immunity; active and passive Active immunity So named because body's cells actively respond to an antigen, may be received naturally through exposure to an antigen via infection or via a vaccination Results in production of memory cells and large numbers of antibodies and is, therefore, relatively long-lasting, ranging from years to a lifetime Length of time during which active immunity lasts depends on several factors, particularly extent of exposure Passive immunity Occurs when preformed antibodies are passed from one organism to another, or artificially acquired, from an injection with preformed antibodies Lasts only amount of time that antibodies stay in bloodstream, which is about three months on average

Thymus

small, encapsulated organ found superior to the heart; consists of two lobes; doesn't trap pathogens: Secretes hormones that enable it to carry out its primary function: generating a population of functional T cells capable of protecting body from pathogens Large and very active in infants and children, reaching its maximum size in individuals about 12-14 years old After this point, it begins to atrophy and thymic tissue is gradually replaced with fat as its T cell production declines By age 65, rate of T cell production falls to about 2% of rate at which an infant produces T cells

Lobule of the thymus

Adult thymus consists of subunits called thymic lobules (thymic corpuscles); visible externally as "lumps" on surface of thymus Each lobule contains two regions: Cortex contains densely packed T cells Medulla contains fewer of these cells, and is thought instead to be mostly site of destruction of certain populations of T cells that could react to body's own cells There are no lymphoid follicles in thymus because it lacks B cells

lymph nodes

Along pathway of lymphatic vessels are clusters of lymphoid organs called lymph nodes Pathogens such as bacteria and cancer cells in interstitial fluid have an easier time entering lymphatic capillaries than blood capillaries Lymph nodes limit spread of pathogens through body by acting as filters, trapping pathogens and preventing them from traveling elsewhere

Lymph nodes

small, vaguely bean-shaped clusters of lymphatic tissue located along lymphatic vessels throughout body: Specific clusters of lymph nodes include: axillary lymph nodes, cervical lymph nodes, inguinal lymph nodes, and mesenteric lymph nodes Lymph nodes have an external connective tissue capsule that surrounds a network of reticular fibers filled with macrophages, lymphocytes, and dendritic cells Interior of a node is divided into two main regions: outer cortex and inner cortex Cortex consists of lymphoid follicles divided by inward extensions of capsule, called trabeculae Between cortex and medulla is a zone composed primarily of T cells, while medulla contains fewer leukocytes than cortex, it does contain mature B cells

Adaptive immunity: Antibody-mediated

Antibody-mediated immunity involves B cells and proteins secreted by B cells, called plasma cells B cells have B cell receptors that bind to specific antigens A group of B cells that bind to a specific antigen is known as a clone Antibodies secreted by a B cell clone bind to same antigen as B cell receptor

Four basic kinds of tissue and organ transplants (grafts):

Autografts Isografts Allografts Xenografts

AUTOIMMUNE DISORDERS

Autoimmune disorders occur when populations of self-reactive T cells or B cells that secrete antibodies bind to self antigens (called autoantibodies) Release of self antigens not previously encountered by T cells; can lead to autoimmune disorder, multiple sclerosis: Some antigens are sequestered, meaning that they are not exposed to developing T cells Infection or trauma might release a sequestered protein and its antigens into circulation, activating T cells specific for this antigen Foreign antigens mimic self antigens; this mechanism can lead to autoimmune disorder, rheumatic fever: Certain viral and bacterial antigens closely resemble normal self antigens Normally, T cells specific for these antigens do not attack self cells because of lack of co-stimulatory signals If an individual comes into contact with these pathogens, co-stimulatory signals may activate these T cells, which then attack self cells Cells may inappropriately express class II MHC molecules An inappropriately expressed class II MHC molecule activates T cells and triggers an immune response to these normal self antigens This appears to be case with type 1 diabetes mellitus, in which immune system destroys insulin-producing cells of pancreas Certain pathogens nonspecifically activate B cells Many pathogens can induce production of cytokines that nonspecifically activate B cells, resulting in production of autoantibodies Proposed mechanism behind disease systemic lupus erythematosus; infection with a certain virus is followed by production of antibodies to proteins in DNA, erythrocytes, platelets, and leukocytes

B CELL Activation: phase 1

B cells develop and mature within red bone marrow from lympoid cell line; billions of B cells are produced each day: Only about 10% of these cells finish their maturation process because B cell clones that recognize self antigens (self-reactive B cells) are destroyed B cell clones that complete maturation enter circulation and eventually take up residence in lymphoid organs When antigens enter body, they are captured in these lymphoid organs B cells that are not exposed to their specific antigens within a few days to a few weeks die Naïve B cells that do encounter their antigens become activated by following process: B cell clone binds its antigen and is activated; clonal selection is process when an antigen binds to a B cell receptor on surface of a specific B cell clone (said to be sensitized) Sensitized B cell processes antigen and presents it on its class II MHC molecules; B cell then binds to a TH cell to become fully activated; starts a series of events inside cell that triggers transcription of antibody genes and multiple other changes that activate B cell B cell divides repeatedly; resulting cells differentiate into: Plasma cells - secrete antibodies Memory B cells - long-lived cells that do not secrete antibodies but will respond to antigens upon a second exposure Dendritic cells and other APCs continue to expose plasma cells and other B cells to antigen, and in response they keep proliferating, differentiating, and actively secreting antibodies

graft rejection

Both allografts and xenografts contain antigens that organ recipient's immune system recognizes as foreign; leads to a reaction from immune system that, if left untreated, results in rejection of organ or tissue A rejected organ or tissue first fails to function properly, and then its cells die as TC cells destroy them, a condition known as necrosis Rejection can lead to death of transplant recipient from organ failure and from blood clots and other complications of necrotic tissue

Basic steps of how exogenous antigens are displayed by class II MHC molecules are:

Cell phagocytoses a pathogen Phagocytic vesicle fuses with a lysosome; pathogen is degraded and its antigens are fragmented Lysosome fuses with a vesicle from RER that contains class II MHC molecules, and an antigen fragment binds to MHC molecule MHC-antigen complex is inserted into cell's plasma membrane

Basic steps by which a class I MHC molecule processes and displays an endogenous antigen are:

Cell synthesizes either a self antigen or a foreign antigen Antigen is broken down by enzymes in cytosol An antigen fragment containing antigenic determinant is transported into rough endoplasmic reticulum (RER); coupled with a class I MHC molecule in RER membrane MHC-antigen complex leaves RER by a vesicle and is inserted into cell's plasma membrane

Intro to adaptive immunity

Cell-mediated immunity is first arm of adaptive immune system Cell-mediated immunity involves different classes of T cells, including: helper T (TH) cells, or CD4 cells, and cytotoxic T (TC) cells, or CD8 cells **Note that "CD" stands for cluster of differentiation These cells respond primarily to cells infected with intracellular pathogens (viruses and intracellular bacteria), cancer cells, and foreign cells such as those from a transplanted organ

T cell activation consists of following steps:

Cells display antigen fragments on their MHC molecules, and MHC-antigen complex binds to receptor of a specific TH or TC cell clone specific for its individual MHC-antigen complex When T cell receptor recognizes and binds this complex, multiple changes are triggered inside T cell and process of activation begins; known as clonal selection TH or TC cell binds a co-stimulator and becomes activated Full T cell activation requires interaction of T cell with other molecules on antigen-presenting cells called co-stimulators T cell receptors normally have low affinity for their MHC-antigen complexes; protective mechanism that prevents unnecessary T cell activation Activated TH or TC cell clone proliferates and differentiates into effector cells (those that cause immediate effects) and memory T cells (responsible for cell-mediated immunological memory) Memory cells respond more quickly and efficiently to subsequent exposures to an antigen; do not need a co-stimulator

Lymph ducts

Cisterna chyli and other lymph trunks drain into one of two lymph ducts Thoracic duct right lymphatic duct

Thoracic duct

Cisterna chyli and trunks from left side of body drain. Drains all of lower body and left side of upper body Thoracic duct, largest lymphatic duct, runs along anterior vertebral column and drains into junction of left internal jugular and left subclavian veins

3 lines of defense of the immune system

Combined components of immune system offer three lines of defense against pathogens: First line of defense - includes cutaneous and mucous membranes that act as surface barriers to block entry of pathogens into body Second line of defense - includes responses of cells and proteins that make up innate immunity Third line of defense - includes responses of cells and proteins of adaptive immunity

Graft rejection is something that must be prevented; done in two ways:

Ensuring that allograft antigens are as similar as possible to recipient's antigens; determined through a process that screens antigens most likely to cause rejection— those associated with MHC molecules, which are encoded on genes called human leukocyte antigen (HLA) genes Suppressing immune response with medications; known as immunosuppressive therapy One of most commonly performed transplant procedures is a bone marrow transplant, also referred to as a hematopoietic stem cell transplant (HSCT)

Autografts

Examples of autografts include skin grafts, in which skin is removed from one part of body and placed on another part to repair skin damaged by trauma such as burns Autografts result in no response from TC cells because antigens bound to class I MHC molecules are not recognized as foreign

Antibody-mediated immune responses have three basic phases:

First phase - B cell clone recognizes its specific antigen; triggers it to change and secrete antibodies Second phase - begins when antibody level in blood rises dramatically; antibodies (immunoglobulins or gamma globulins) are directly responsible for actions that lead to destruction of antigens to which they bind Third phase - persistence of a population of B cells called memory B cells

Functions of antibodies

Functions of secreted antibodies - Agglutination and precipitation Antibodies can bind to antigens on more than one cell; creates a clump of cells that are cross-linked by their attachment to antibodies; known as agglutination Precipitation - similar to agglutination; involves soluble antigens (proteins and other biological molecules) instead of whole cells Both make it easier for phagocytes to ingest complex IgM is most potent agglutinating and precipitating antibody due to its 10 antigen-binding sites Opsonization - involves molecules such as complement and IgG antibodies; Neutralization - what happens?; most neutralizing antibodies are either IgG or IgA Complement activation - IgM and IgG bind to and activate complement proteins of innate immunity; particularly important in defense against cellular pathogens such as bacteria; partly responsible for our reaction to foreign cells like donated erythrocytes Stimulation of inflammation - mast cells directly triggers inflammation by initiating release of inflammatory mediators from basophils; antibodies also trigger inflammation indirectly through their activation of complement Most antibodies don't directly "kill" pathogens; either render pathogens less harmful or facilitate their destruction by phagocytes or complement

Disorders of immune system take three forms:

Hypersensitivity disorders cause immune system to overreact, which can damage tissues Immunodeficiency disorders occur when one or more components of immune system fail Immune system may treat self antigens as foreign and attack body's own tissues in an autoimmune disorder