Chapter 22 - Lymphatic System and Immunity

 

Lymphatic System

•      Lymph

•      Lymphatic vessels

•      Lymphatic tissue

•      Lymphatic nodules

•      Lymph nodes

•      Tonsils

•      Spleen

•      Thymus

 

Lymphatic System: Overview

•      Consists of two semi-independent parts

•    A meandering network of lymphatic vessels

•    Lymphoid tissues and organs scattered throughout the body

•      Returns interstitial fluid and leaked plasma proteins back to the blood

•      Lymph – interstitial fluid once it has entered lymphatic vessels

 

Lymphatic Vessels

•      A one-way system in which lymph flows toward the heart

•      Lymph vessels include:

•    Microscopic, permeable, blind-ended capillaries

•    Lymphatic collecting vessels

•    Trunks and ducts

 

Lymphatic Capillaries

•      Similar to blood capillaries, with modifications

•    Remarkably permeable

•    Loosely joined endothelial minivalves

•    Withstand interstitial pressure and remain open

•      The minivalves function as one-way gates that:

•    Allow interstitial fluid to enter lymph capillaries

•    Do not allow lymph to escape from the capillaries

•      During inflammation, lymphatic capillaries can absorb:

•    Cell debris

•    Pathogens

•    Cancer cells

•      Cells in the lymph nodes:

•    Cleanse and “examine” lymph

•      Lacteals – specialized lymph capillaries present in intestinal mucosa

•    Absorb digested fat and deliver chyle to the blood

 

Lymphatic Collecting Vessels

•      Have the same three tunics as veins

•      Have thinner walls, with more internal valves

•      Anastomose more frequently

•      Collecting vessels in the skin travel with superficial veins

•      Deep vessels travel with arteries

•      Nutrients are supplied from branching vasa vasorum

 

Lymphatic Trunks

•      Lymphatic trunks are formed by the union of the largest collecting ducts

•      Major trunks include:

•    Paired lumbar, bronchomediastinal, subclavian, and jugular trunks

•    A single intestinal trunk

•      Lymph is delivered into one of two large ducts

•    Right lymphatic duct – drains the right upper arm and the right side of the head and thorax

•    Thoracic duct – arises from the cisterna chyli and drains the rest of the body

 

Lymphatic Transport

•      The lymphatic system lacks an organ that acts as a pump

•      Vessels are low pressure conduits

•      Uses the same methods as veins to propel lymph

•    Pulsations of nearby arteries

•    Contractions of smooth muscle in the walls of the lymphatics

 

Functions of the Lymphatic System

•      Fluid balance

•    Excess interstitial fluid enters lymphatic capillaries and becomes lymph

•      Fat absorption

•    Absorption of fat and other substances from digestive tract

•      Defense

•    Microorganisms and other foreign substances are filtered from lymph by lymph nodes and from blood by spleen

 

Lymphatic Vessels

•      Carry lymph away from tissues

•      Lymphatic capillaries

•     More permeable than blood capillaries

•     Epithelium functions as series of one-way valves

•      Lymphatic capillaries join to form

•      Lymphatic vessels

•    Have valves that ensure one-way flow

•      Lymph nodes: Distributed along vessels and filter lymph

•      Lymphatic trunks: Jugular, subclavian, bronchomediastinal, intestinal, lumbar

•      Lymphatic ducts: Right and thoracic which connect to large veins

 

Lymphoid Cells

•      Lymphocytes are the main cells involved in the immune response

•      The two main varieties are T cells and B cells

 

Lymphocytes

•      T cells and B cells protect the body against antigens

•      Antigen – anything the body perceives as foreign

•    Bacteria and their toxins, and viruses

•    Mismatched RBCs or cancer cells

•      T cells

•    Manage the immune response

•    Attack and destroy foreign cells

•      B cells

•    Produce plasma cells, which secrete antibodies

•    Antibodies immobilize antigens

 

Other Lymphoid Cells

•      Macrophages – phagocytize foreign substances and help activate T cells

•      Dendritic cells – spiny-looking cells with functions similar to macrophages

•      Reticular cells – fibroblastlike cells that produce a stroma, or network, that supports other cell types in lymphoid organs

 

Lymphatic Tissue and Nodules

•      Lymphatic tissue

•     Consists mainly of lymphocytes

•     Encapsulated or not

•      Lymphatic nodules

•     Numerous in loose connective tissue of digestive (Peyer’s patches), respiratory, urinary, reproductive systems

 

Lymphoid Tissue

•      Diffuse lymphatic tissue – scattered reticular tissue elements in every body organ

•    Larger collections appear in the lamina propria of mucous membranes and lymphoid organs

•      Lymphatic follicles (nodules) – solid, spherical bodies consisting of tightly packed reticular elements and cells

•    Have a germinal center composed of dendritic cells and B cells

•    Found in isolation and as part of larger lymphoid organs

 

Lymphoid Organs

•      Lymphoid organs – discrete, encapsulated collections of diffuse lymphoid tissue and follicles

•      Examples include the lymph nodes, spleen, and thymus

 

Lymph Nodes

•      Nodes are imbedded in connective tissue and clustered along lymphatic vessels

•      Aggregations of these nodes occur near the body surface in inguinal, axillary, and cervical regions of the body

•      Their two basic functions are:

•    Filtration – macrophages destroy microorganisms and debris

•    Immune system activation – monitor for antigens and mount an attack against them

•       Organized in cortex and medulla

•       Substances removed by phagocytosis or stimulate lymphocytes or both

•       Only structures to filter lymph

•      Afferent and efferent vessels

 

Structure of a Lymph Node

•      The cortex contains follicles with germinal centers, heavy with dividing B cells

•      Dendritic cells nearly encapsulate the follicles

•      The deep cortex houses T cells in transit

•      T cells circulate continuously among the blood, lymph nodes, and lymphatic stream

•      Medullary cords extend from the cortex and contain B cells, T cells, and plasma cells

•      Throughout the node are lymph sinuses crisscrossed by reticular fibers

•      Macrophages reside on these fibers and phagocytize foreign matter

•      Nodes are bean shaped and surrounded by a fibrous capsule

•      Trabeculae extended inward from the capsule and divide the node into compartments

•      Nodes have two histologically distinct regions: a cortex and a medulla

 

Circulation in the Lymph Nodes

•      Lymph enters via a number of afferent lymphatic vessels

•      It then enters a large subcapsular sinus and travels into a number of smaller sinuses

•      It meanders through these sinuses and exits the node at the hilus via efferent vessels

•      Because there are fewer efferent vessels, lymph stagnates somewhat in the node

•    This allows lymphocytes and macrophages time to carry out their protective functions

 

Homeostatic Imbalances of the Lymph Nodes

•      If lymph nodes are overwhelmed by large numbers of antigen:

•    They become inflamed and tender to the touch

•   Such nodes are called buboes (or erroneously, swollen glands)

•      Nodes can also become secondary cancer sites

•    Such nodes are swollen, but are not painful

•   This distinguishes cancerous nodes from infected ones

 

Other Lymphoid Organs

•      The tonsils, spleen, and thymus gland

•      Peyer’s patches and bits of lymphatic tissue scattered in connective tissue

•      All are composed of reticular connective tissue and all help protect the body

•      Only lymph nodes filter lymph

 

Tonsils

•       Large groups of lymphatic nodules in nasopharynx and oral cavity

•       Provide protection against bacteria and other harmful material

•       Groups

•     Palatine

•     Pharyngeal

•     Lingual

•      Simplest lymphoid organs; form a ring of lymphatic tissue around the pharynx

•      Location of the tonsils

•    Palatine tonsils – either side of the posterior end of the oral cavity

•    Lingual tonsil – lies at the base of the tongue

•    Pharyngeal tonsil – posterior wall of the nasopharynx

•    Tubal tonsils – surround the openings of the auditory tubes into the pharynx

•      Lymphoid tissue of tonsils contains follicles with germinal centers

•      Tonsil masses are not fully encapsulated

•      Epithelial tissue overlying tonsil masses invaginates, forming blind-ended crypts

•      Crypts trap and destroy bacteria and particulate matter

 

Spleen

•      Located in left superior side of abdomen

•    Can be ruptured in traumatic abdominal injuries resulting in bleeding, shock, death

•      Blood flows through at 3 different rates

•    Fast (most), slow, intermediate

•      Functions

•    Destroys defective RBCs

•    Detects and responds to foreign substances

•     Limited reservoir for blood

•      Largest lymphoid organ, located on the left side of the abdominal cavity beneath the diaphragm

•      It extends to curl around the anterior aspect of the stomach

•      It is served by the splenic artery and vein, which enter and exit at the hilus

•      Functions

•    Site of lymphocyte proliferation

•    Immune surveillance and response

•    Cleanses the blood

 

Additional Spleen Functions

•      Stores breakdown products of RBCs 

•    Spleen macrophages salvage and store iron for later use by bone marrow

•      Site of fetal erythrocyte production (normally ceases after birth)

•      Stores blood platelets

 

Structure of the Spleen

•      Surrounded by a fibrous capsule, it has trabeculae that extend inward and contains lymphocytes, macrophages, and huge numbers of erythrocytes

•      Two distinct areas of the spleen are:

•    White pulp – area containing mostly lymphocytes suspended on reticular fibers and involved in immune functions

•    Red pulp – remaining splenic tissue concerned with disposing of worn-out RBCs and bloodborne pathogens

 

Thymus

•      A bilobed organ that secrets hormones (thymosin and thymopoietin) that cause T lymphocytes to become immunocompetent

•      The size of the thymus varies with age

•    In infants, it is found in the inferior neck and extends into the mediastinum, where it partially overlies the heart

•    It increases in size and is most active during childhood

•    It stops growing during adolescence and then gradually atrophies

•       Located in superior mediastinum

•       Divisions: Cortex and medulla

•       Site of maturation of T cells

 

Internal Anatomy of the Thymus

•      Thymic lobes contain an outer cortex and inner medulla

•      The cortex contains densely packed lymphocytes and scattered macrophages

•      The medulla contains fewer lymphocytes and thymic (Hassall’s) corpuscles

 

Thymus

•      The thymus differs from other lymphoid organs in important ways

•    It functions strictly in T lymphocyte maturation

•    It does not directly fight antigens

•      The stroma of the thymus consists of star-shaped epithelial cells (not reticular fibers)

•      These star-shaped thymocytes secret thymosins and thymopoietins that stimulate lymphocytes to become immunocompetent

 

MALT

•      MALT – mucosa-associated lymphatic tissue, composed of:

•    Peyer’s patches, tonsils, and the appendix (digestive tract)

•    Lymphoid nodules in the wall of the bronchi (respiratory tract)

•      MALT protects the digestive and respiratory systems from foreign matter

 

Aggregates of Lymphoid Follicles

•      Peyer’s patches – isolated clusters of lymphoid tissue, similar to tonsils

•    Found in the wall of the distal portion of the small intestine

•    Similar structures are found in the appendix

•      Peyer’s patches and the appendix:

•    Destroy bacteria, preventing them from breaching the intestinal wall

•    Generate “memory” lymphocytes for long-term immunity

 

Immunity

•      Ability to resist damage from foreign substances as microorganisms and harmful chemicals

•      Categories

•     Innate or nonspecific resistance

•   Mechanical mechanisms: Prevent entry or remove microbes

•   Chemical mediators: Promote phagocytosis and inflammation

•   Cells: Involved in phagocytosis and production of chemicals

•     Adaptive or specific immunity

•   Specificity: Ability to recognize a particular substance

•   Memory: Ability to remember previous encounters with a particular substance and respond rapidly

 

Immunity: Two Intrinsic Defense Systems

•      Innate (nonspecific) system responds quickly and consists of:

•    First line of defense – intact skin and mucosae prevent entry of microorganisms

•    Second line of defense – antimicrobial proteins, phagocytes, and other cells

•   Inhibit invaders spread throughout the body

•   Inflammation is its hallmark and most important mechanism

•      Adaptive (specific) defense system

•    Third line of defense – mounts attack against particular foreign substances

•   Takes longer to react than the innate system

•   Works in conjunction with the innate system

 

Mechanical Mechanisms and Chemical Mediators

•      Mechanical Mechanisms

•     Skin, tears, saliva, mucous membranes, mucus

•      Chemical Mediators

•     Complement

•   Group of 20 proteins

•   Circulate in blood in inactive form

•   Become activated in cascade form: Classical or alternative pathway

•     Interferons

•   Prevent viral replication

 

Innate Immunity:  Surface Barriers

•      Skin, mucous membranes, and their secretions make up the first line of defense

•      Keratin in the skin:

•    Presents a formidable physical barrier to most microorganisms

•    Is resistant to weak acids and bases, bacterial enzymes, and toxins

•      Mucosae provide similar mechanical barriers

 

Innate Immunity:Epithelial Chemical Barriers

•      Epithelial membranes produce protective chemicals that destroy microorganisms

•    Skin acidity (pH of 3 to 5) inhibits bacterial growth

•    Sebum contains chemicals toxic to bacteria

•    Stomach mucosae secrete concentrated HCl and protein-digesting enzymes

•    Saliva and lacrimal fluid contain lysozyme

•    Mucus traps microorganisms that enter the digestive and respiratory systems

 

Innate Immunity:  Respiratory Tract Mucosae

•      Mucus-coated hairs in the nose trap inhaled particles

•      Mucosa of the upper respiratory tract is ciliated

•    Cilia sweep dust- and bacteria-laden mucus away from lower respiratory passages

 

Internal Defenses: Cells and Chemicals

•      The body uses nonspecific cellular and chemical devices to protect itself

•    Phagocytes and natural killer (NK) cells

•    Antimicrobial proteins in blood and tissue fluid

•    Inflammatory response enlists macrophages, mast cells, WBCs, and chemicals

•      Harmful substances are identified by surface carbohydrates unique to infectious organisms

 

Complement

•      20 or so proteins that circulate in the blood in an inactive form

•      Proteins include C1 through C9, factors B, D, and P, and regulatory proteins

•      Provides a major mechanism for destroying foreign substances in the body

•      Amplifies all aspects of the inflammatory response

•      Kills bacteria and certain other cell types (our cells are immune to complement)

•      Enhances the effectiveness of both nonspecific and specific defenses

 

Complement Pathways

•      Complement can be activated by two pathways: classical and alternative

•      Classical pathway is linked to the immune system

•    Depends upon the binding of antibodies to invading organisms

•    Subsequent binding of C1 to the antigen-antibody complexes (complement fixation)

•      Alternative pathway is triggered by interaction among factors B, D, and P, and polysaccharide molecules present on microorganisms

•      Each pathway involves a cascade in which complement proteins are activated in an orderly sequence and where each step catalyzes the next

•      Both pathways converge on C3, which cleaves into C3a and C3b

•      C3b initiates formation of a membrane attack complex (MAC)

•      MAC causes cell lysis by interfering with a cell’s ability to eject Ca2+

•      C3b also causes opsonization, and C3a causes inflammation

 

Interferon Family

•      Interferons are a family of related proteins each with slightly different physiological effects

•      Lymphocytes secrete gamma (g) interferon, but most other WBCs secrete alpha (a) interferon

•      Fibroblasts secrete beta (b) interferon

•      Interferons also activate macrophages and mobilize NK cells

•      FDA-approved alpha IFN is used:

•    As an antiviral drug against hepatitis C virus

•    To treat genital warts caused by a herpes virus

•    Cancer?

 

Innate Immunity: Cells

•      White blood cells

•     Most important cellular components of immune system

•     Methods

•   Chemotaxis

•   Phagocytosis

•      Neutrophils

•     Phagocytic and first cells to enter infected tissue

•      Macrophages

•     Monocytes that leave blood, enter tissues

•     Large phagocytic cells

•      Basophils and mast cells

•     Promote inflammation

•      Eosinophils

•     Reduce inflammation

•      Natural killer cells

•     Lyse tumor and virus-infected cells

 

Phagocytes

•      Macrophages are the chief phagocytic cells

•      Free macrophages wander throughout a region in search of cellular debris

•      Kupffer cells (liver) and microglia (brain) are fixed macrophages

•      Neutrophils become phagocytic when encountering infectious material

•      Eosinophils are weakly phagocytic against parasitic worms

•      Mast cells bind and ingest a wide range of bacteria

 

Mechanism of Phagocytosis

•      Microbes adhere to the phagocyte

•      Pseudopods engulf the particle (antigen) into a phagosome

•      Phagosomes fuse with a lysosome to form a phagolysosome

•      Microbes in the phagolysosome are enzymatically digested

•      Indigestible and residual material is removed by exocytosis

 

Natural Killer (NK) Cells

•      Cells that can lyse and kill cancer cells and virus-infected cells

•      Natural killer cells:

•    Are a small, distinct group of large granular lymphocytes

•    React nonspecifically and eliminate cancerous and virus-infected cells

•    Kill their target cells by releasing cytolytic chemicals

•    Secrete potent chemicals that enhance the inflammatory response

 

Inflammatory Response

•      Tissue injury regardless of type can cause inflammation

•      Response initiated by chemical mediators that produce vasodilation, chemotactic attraction, increased vascular permeability

•      Types

•    Local: Symptoms are redness, heat, swelling, pain, loss of function

•    Systemic: Symptoms are increase in neutrophil numbers, fever and shock

 

Inflammation: Tissue Response to Injury

•      The inflammatory response is triggered whenever body tissues are injured

•    Prevents the spread of damaging agents to nearby tissues

•    Disposes of cell debris and pathogens

•    Sets the stage for repair processes

•      The four cardinal signs of acute inflammation are redness, heat, swelling, and pain

 

Inflammatory Response

•      Begins with a flood of inflammatory chemicals released into the extracellular fluid

•      Inflammatory mediators:

•    Include complement and cytokines

•    Are released by injured tissue, phagocytes, lymphocytes, and mast cells

•    Cause local small blood vessels to dilate, resulting in hyperemia

 

Inflammatory Response: Vascular Permeability

•      Chemicals liberated by the inflammatory response increase the permeability of local capillaries

•      Exudate (fluid containing proteins, clotting factors, and antibodies):

•    Seeps into tissue spaces causing local edema (swelling)

•    The edema contributes to the sensation of pain

 

Inflammatory Response: Edema

•      The surge of protein-rich fluids into tissue spaces (edema):

•    Helps to dilute harmful substances

•    Brings in large quantities of oxygen and nutrients needed for repair

•    Allows entry of clotting proteins, which prevent the spread of bacteria

 

Inflammatory Response: Phagocytic Mobilization

•      Occurs in four main phases:

•    Leukocytosis – neutrophils are released from the bone marrow in response to leukocytosis-inducing factors released by injured cells

•    Margination – neutrophils cling to the walls of capillaries in the injured area

•    Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis

•    Chemotaxis – inflammatory chemicals attract neutrophils to the injury site

 

Fever

•      Abnormally high body temperature in response to invading microorganisms

•      The body’s thermostat is reset upwards in response to pyrogens, chemicals secreted by leukocytes and macrophages exposed to bacteria and other foreign substances

•      High fevers are dangerous because they can denature enzymes

•      Moderate fever can be beneficial, as it causes:

•    The liver and spleen to sequester iron and zinc (needed by microorganisms)

•    An increase in the metabolic rate, which speeds up tissue repair

 

Adaptive Immunity

•      Involves the ability to recognize, respond to, and remember a particular substance

•      Stimulants

•     Antigens: Large molecules

•   Foreign: Not produced by body, introduced from outside

•   Self-antigens: Produced by body

•     Haptens: Small molecules and capable of combining

•      Types

•     Humoral or Antibody-mediated: B cells

•     Cell-mediated: T cells

 

Adaptive (Specific) Defenses

•      The adaptive immune system is a functional system that:

•    Recognizes specific foreign substances

•    Acts to immobilize, neutralize, or destroy them

•    Amplifies inflammatory response and activates complement

 

Adaptive Immune Defenses

•      The adaptive immune system is antigen-specific, systemic, and has memory

•      It has two separate but overlapping arms

•    Cellular, or cell-mediated immunity

•    Humoral, or antibody-mediated immunity

 

Antigens (Ags)

•      Substances that can mobilize the immune system and provoke an immune response

•      The ultimate targets of all immune responses are mostly large, complex molecules not normally found in the body (nonself)

 

Complete Antigens

•      Important functional properties

•    Immunogenicity – the ability to stimulate proliferation of specific lymphocytes and antibody production

•    Reactivity – the ability to react with the products of the activated lymphocytes and the antibodies released in response to them

•      Complete antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides

 

Haptens (Incomplete Antigens)

•      Small molecules, such as peptides, nucleotides, and many hormones, that are not immunogenic but are reactive when attached to protein carriers

•      If they link up with the body’s proteins, the adaptive immune system may recognize them as foreign and mount a harmful attack (allergy)

•      Haptens are found in poison ivy, dander, some detergents, and cosmetics (also antibiotics like Penicillin)

 

Antigenic Determinants

•      Antigenic determinants

•     Specific regions of a given antigen recognized by a lymphocyte

•      Antigenic receptors

•     Surface of lymphocyte that combines with antigenic determinant

•      Only certain parts of an entire antigen are immunogenic

•      Antibodies and activated lymphocytes bind to these antigenic determinants

•      Most naturally occurring antigens have numerous antigenic determinants that:

•    Mobilize several different lymphocyte populations

•    Form different kinds of antibodies against it

•      Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity

 

Cells of the Adaptive Immune System

•      Two types of lymphocytes

•    T lymphocytes – non-antibody-producing cells that constitute the cell-mediated arm of immunity

•    B lymphocytes – oversee humoral immunity

•      Antigen-presenting cells (APCs):

•    Do not respond to specific antigens

•    Play essential auxiliary roles in immunity

 

Lymphocytes

•      Immature lymphocytes released from bone marrow are essentially identical

•      Whether a lymphocyte matures into a B cell or a T cell depends on where in the body it becomes immunocompetent

•    T cells mature in the thymus

•    B cells mature in the bone marrow

 

Origin and Development of Lymphocytes

•      B and T cells

•     Originate in red bone marrow

•     Move to lymphatic tissue from processing sites and continually circulate

•     Clones are small groups of identical lymphocytes

•      Positive selection

•     Ensures survival of lymphocytes that react against antigens

•      Negative selection

•     Eliminates lymphocytes that react against self-antigens

•      Primary lymphatic organs (red bone marrow, thymus)

•     Where lymphocytes mature into functional cells

•      Secondary lymphatic organs

•     Where lymphocytes produce an immune response

 

T Cells and B Cells

•      T cells mature in the thymus under negative and positive selection pressures while B cells become immunocompetent and self-tolerant in bone marrow

•    Negative selection – eliminates cells that are strongly anti-self and anti-nothing

•    Positive selection – selects cells with a weak response to self-antigens, which thus become both immunocompetent and self-tolerant

 

Antigen-Presenting Cells (APCs)

•      Major rolls in immunity are:

•    To engulf foreign particles

•    To present fragment of antigens on their own surfaces, to be recognized by T cells

•      Major APCs are dendritic cells (DCs), macrophages, and activated B cells

•      The major initiators of adaptive immunity are DCs, which actively migrate to the lymph nodes and secondary lymphoid organs and present antigens to T and B cells

 

Immunocompetent B or T cells

•      Display a unique type of receptor that responds to a distinct antigen

•      Become immunocompetent before they encounter antigens they may later attack

•      Are exported to secondary lymphoid tissue where encounters with antigens occur

•      Mature into fully functional antigen-activated cells upon binding with their recognized antigen

•      It is genes, not antigen, that determine which foreign substance our immune system will recognize and resist

 

Self-Antigens: MHC Proteins

•      Our cells are dotted with protein molecules (self-antigens) that are not antigenic to us but are strongly antigenic to others

•      One type of these, MHC proteins, mark a cell as self

•      The two classes of MHC proteins are:

•    Class I MHC proteins – found on virtually all body cells

•    Class II MHC proteins – found on certain immune response cells

 

Major Histocompatability Complex (MHC)

•      Are coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual

•      Each MHC molecule has a deep groove that displays a peptide, which is a normal cellular product of protein recycling

•      In infected cells, MHC proteins bind to fragments of foreign antigens, which play a crucial role in mobilizing the immune system

 

MHC Proteins

•      Most lymphocyte activation involves glycoproteins of cell surfaces called MHC molecules

•    Class I molecules display antigens on surface of nucleated cells, resulting in destruction of cells

•    Class II molecules display antigens on surface of antigen-presenting cells, resulting in activation of immune cells

 

Antigen Recognition and MHC Restriction

•      Immunocompetent T cells are activated when the variable regions of their surface receptors bind to a recognized antigen

•      T cells must simultaneously recognize:

•    Nonself (the antigen)

•    Self (a MHC protein of a body cell)

 

MHC Proteins

•      Both types of MHC proteins are important to T cell activation

•      Class I MHC proteins

•    Always recognized by CD8+ T cells

•    Display peptides from endogenous antigens

 

Class I MHC Proteins

•      Endogenous antigens are:

•    Degraded by proteases and enter the endoplasmic reticulum

•    Transported via TAP (transporter associated with antigen processing)

•    Loaded onto class I MHC molecules

•    Displayed on the cell surface in association with a class I MHC molecule

 

Class II MHC Proteins

•      Class II MHC proteins are found only on mature B cells, some T cells, and antigen-presenting cells

•      A phagosome containing pathogens (with exogenous antigens) merges with a lysosome

•      Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum

•      Class II MHC proteins migrate into the phagosomes where the antigen is degraded and the invariant chain is removed for peptide loading

•      Loaded Class II MHC molecules then migrate to the cell membrane and display antigenic peptides for recognition by CD4 cells

 

Antigen Recognition

•      Provides the key for the immune system to recognize the presence of intracellular microorganisms

•      MHC proteins are ignored by T cells if they are complexed with self protein fragments

•      If MHC proteins are complexed with endogenous or exogenous antigenic peptides, they:

•    Indicate the presence of intracellular infectious microorganisms

•    Act as antigen holders

•    Form the self part of the self/anti-self complexes recognized by T cells

 

Cell-Mediated Immune Response

•      Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed

•      Two major populations of T cells mediate cellular immunity

•    CD4+ cells (T4 cells) are primarily helper T cells (TH)

•    CD8+ cells (T8 cells) are cytotoxic T cells (TC) that destroy cells harboring foreign antigens

 

Helper T Cells (TH)

•      Regulatory cells that play a central role in the immune response

•      Once primed by APC presentation of antigen, they:

•    Chemically or directly stimulate proliferation of other T cells

•    Stimulate B cells that have already become bound to antigen

•      Without TH, there is no immune response

 

T Cell Activation: Step One – Antigen Binding

•      T cell antigen receptors (TCRs):

•    Bind to an antigen–MHC protein complex

•    Have variable and constant regions consisting of two chains (alpha and beta)

•      MHC restriction – TH and TC bind to different classes of MHC proteins

•      TH cells bind to antigens linked to class II MHC proteins

•      Mobile APCs (Langerhans’ cells) quickly alert the body to the presence of antigen by migrating to the lymph nodes and presenting antigen

 

T Cell Activation: Step Two – Costimulation

•      Before a T cell can undergo clonal expansion, it must recognize one or more costimulatory signals

•      This recognition may require binding to other surface receptors on an APC

•    Macrophages produce surface B7 proteins when nonspecific defenses are mobilized

•    B7 binding with the CD28 receptor on the surface of T cells is a crucial costimulatory signal

•      Other costimulatory signals include cytokines and interleukin 1 and 2

 

Cytokines

•      Mediators involved in cellular immunity, including hormonelike glycoproteins released by activated T cells and macrophages

•      Some are costimulators of T cells and T cell proliferation

•      Interleukin 1 (IL-1) released by macrophages costimulates bound T cells to:

•    Release interleukin 2 (IL-2)

•    Synthesize more IL-2 receptors

•      IL-2 is a key growth factor, which sets up a positive feedback cycle that encourages activated T cells to divide

•      It is used therapeutically to enhance the body’s defenses against cancer

•      Other cytokines amplify and regulate immune and nonspecific responses

•      Examples include:

•    Perforin and lymphotoxin – cell toxins

•    Gamma interferon – enhances the killing power of macrophages

•    Inflammatory factors

 

T Cell Activation: Costimulation

•      Depending upon receptor type, costimulators can cause T cells to complete their activation or abort activation

•      Without costimulation, T cells:

•    Become tolerant to that antigen

•    Are unable to divide

•    Do not secrete cytokines

•      Primary T cell response peaks within a week after signal exposure

•      T cells then undergo apoptosis between days 7 and 30

•      Effector activity wanes as the amount of antigen declines

•      The disposal of activated effector cells is a protective mechanism for the body

•      Memory T cells remain and mediate secondary responses to the same antigen

 

Lymphocyte Inhibition

•      Tolerance: To prevent the immune system from responding to self-antigens

•    Provoked by

•   Deletion of self-reactive lymphocytes

•   Preventing activation of lymphocytes

•   Activation of suppressor T cells

 

Humoral Immunity Response

•      Antigen challenge – first encounter between and antigen and a naive immunocompetent cell

•      Takes place in the spleen or other lymphoid organ

•      If the lymphocyte is a B cell:

•    The challenging antigen provokes a humoral immune response

•   Antibodies are produced against the challenger

 

Helper T Cells

•      TH cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors

•      TH cells stimulate B cells to divide more rapidly and begin antibody formation

•      B cells may be activated without TH cells by binding to T cell–independent antigens

•      Most antigens, however, require TH costimulation to activate B cells

•      Cytokines released by TH cells amplify nonspecific defenses

 

Clonal Selection

•      Stimulated B cell growth forms clones bearing the same antigen-specific receptors

•      A naive, immunocompetent B cell is activated when antigens bind to its surface receptors and cross-link adjacent receptors

•      Antigen binding is followed by receptor-mediated endocytosis of the cross-linked antigen-receptor complexes

•      These activating events, plus T cell interactions, trigger clonal selection

 

Fate of the Clones

•      Most clone cells become antibody-secreting plasma cells

•      Plasma cells secrete specific antibodies at the rate of 2000 molecules per second

•      Secreted antibodies:

•    Bind to free antigens

•    Mark the antigens for destruction by specific or nonspecific mechanisms

•      Clones that do not become plasma cells become memory cells that can mount an immediate response to subsequent exposures to an antigen

 

Antibody-Mediated Immunity

•      Antibodies or Immunoglobulins (Ig)

•     Classes: IgG, IgM, IgA, IgE, IgD

•     Structure

•   Variable region: Part that combines with anitgenic determinant of antigen

•   Constant region: Responsible for activities

 

Antibodies (Ab)

•      Also called immunoglobulins (Igs)

•    Constitute the gamma globulin portion of blood proteins

•    Are soluble proteins secreted by activated B cells and plasma cells in response to an antigen

•    Are capable of binding specifically with that antigen

•      There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE

 

Classes of Antibodies

•      IgD – monomer attached to the surface of B cells, important in B cell activation

•      IgM – pentamer released by plasma cells during the primary immune response

•      IgG – monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity

•      IgA – dimer that helps prevent attachment of pathogens to epithelial cell surfaces

•      IgE – monomer that binds to mast cells and basophils, causing histamine release when activated

 

Basic Antibody Structure

•      Consist of four looping polypeptide chains linked together with disulfide bonds

•    Two identical heavy (H) chains and two identical light (L) chains

•      The four chains bound together form an antibody monomer

•      Each chain has a variable (V) region at one end and a constant (C) region at the other

•      Variable regions of the heavy and light chains combine to form the antigen-binding site

 

Antibody Structure

•      Antibodies responding to different antigens have different V regions but the C region is the same for all antibodies in a given class

•      C regions form the stem of the Y-shaped antibody and:

•    Determine the class of the antibody

•    Serve common functions in all antibodies

•    Dictate the cells and chemicals that the antibody can bind to

•    Determine how the antibody class will function in elimination of antigens

 

Mechanisms of Antibody Diversity

•      Plasma cells make over a billion different types of antibodies

•      Each cell, however, only contains 100,000 genes that code for these polypeptides

•      To code for this many antibodies, somatic recombination takes place

•    Gene segments are shuffled and combined in different ways by each B cell as it becomes immunocompetent

•    Information of the newly assembled genes is expressed as B cell receptors and as antibodies

 

Antibody Diversity

•      Random mixing of gene segments makes unique antibody genes that:

•    Code for H and L chains

•    Account for part of the variability in antibodies

•      V gene segments, called hypervariable regions, mutate and increase antibody variation

•      Plasma cells can switch H chains, making two or more classes with the same V region

 

Antibody Targets

•      Antibodies themselves do not destroy antigen; they inactivate and tag it for destruction

•      All antibodies form an antigen-antibody (immune) complex

•      Defensive mechanisms used by antibodies are neutralization, agglutination, precipitation, and complement fixation

 

Other Mechanisms of Antibody Action

•      Neutralization – antibodies bind to and block specific sites on viruses or exotoxins, thus preventing these antigens from binding to receptors on tissue cells

•      Agglutination – antibodies bind the same determinant on more than one antigen

•    Makes antigen-antibody complexes that are cross-linked into large lattices

•    Cell-bound antigens are cross-linked, causing clumping (agglutination)

•      Precipitation – soluble molecules are cross-linked into large insoluble complexes

 

Monoclonal Antibodies

•      Commercially prepared antibodies are used:

•    To provide passive immunity

•    In research, clinical testing, and treatment of certain cancers

•      Monoclonal antibodies are pure antibody preparations

•    Specific for a single antigenic determinant

•    Produced from descendents of a single cell

 

Immunological Memory

•      Primary immune response – cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen

•    Lag period: 3 to 6 days after antigen challenge

•    Peak levels of plasma antibody are achieved in 10 days

•    Antibody levels then decline

•      Secondary immune response – re-exposure to the same antigen

•    Sensitized memory cells respond within hours

•    Antibody levels peak in 2 to 3 days at much higher levels than in the primary response

•    Antibodies bind with greater affinity, and their levels in the blood can remain high for weeks to months

 

Active Humoral Immunity

•      B cells encounter antigens and produce antibodies against them

•    Naturally acquired – response to a bacterial or viral infection

•    Artificially acquired – response to a vaccine of dead or attenuated pathogens

•      Vaccines – spare us the symptoms of disease, and their weakened antigens provide antigenic determinants that are immunogenic and reactive

 

Passive Humoral Immunity

•      Differs from active immunity in the antibody source and the degree of protection

•    B cells are not challenged by antigen

•    Immunological memory does not occur

•    Protection ends when antigens naturally degrade in the body

•      Naturally acquired – from the mother to her fetus via the placenta

•      Artificially acquired – from the injection of serum, such as gamma globulin

 

Cell-Mediated Immunity

•       Antigen activates effector T cells and produces memory T cells

•       Cytotoxic T cells lyse virus-infected cells, tumor cells, and tissue transplants

•       Cytotoxic T cells produce cytokines, which promote phagocytosis and inflammation

 

Cytotoxic T Cells (TC)

•      TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells

•      They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized

•      Their targets include:

•    Virus-infected cells

•    Cells with intracellular bacteria or parasites

•    Cancer cells

•    Foreign cells from blood transfusions or transplants

•      Bind to self/anti-self complexes on all body cells

•      Infected or abnormal cells can be destroyed as long as appropriate antigen and costimulatory stimuli (e.g., IL-2) are present

•      Natural killer cells activate their killing machinery when they bind to a MICA receptor

•      MICA receptor – MHC-related cell surface protein in cancer cells, virus-infected cells, and cells of transplanted organs

 

Mechanisms of TC Action

•      In some cases, TC cells:

•    Bind to the target cell and release perforin into its membrane

•   Perforin causes cell lysis by creating transmembrane pores

 

Importance of Humoral and Cellular Responses

•      Humoral response

•    Soluble antibodies

•   The simplest ammunition of the immune response

•   Interact in extracellular environments such as body secretions, tissue fluid, blood, and lymph

•      Cellular response

•    T cells recognize and respond only to processed fragments of antigen displayed the surface of body cells

•    T cells are best suited for cell-to-cell interactions, and target:

•   Cells infected with viruses, bacteria, or intracellular parasites

•   Abnormal or cancerous cells

•   Cells of infused or transplanted foreign tissue

 

Acquired Immunity

•      Active natural immunity

•     Results from natural exposure to an antigen

•      Active artificial immunity

•     Results from deliberate exposure to an antigen

•      Passive natural immunity

•     Results from transfer of antibodies from a mother to her fetus or baby

•      Passive artificial immunity

•     Results from transfer of antibodies (or cells) from an immune animal to a nonimmune one

 

Effects of Aging

•      Little effect on lymphatic system

•      Decreased ability of helper T cells to proliferate in response to antigens

•      Decreased primary and secondary antibody responses

•      Decreased ability of cell-mediated immunity to resist intracellular pathogens

 

Immune System Problems

•      Hypersensitivity reactions

•      Autoimmune disease

•      Severe combined immunodeficiency disease (SCID) and Acquired immunodeficiency syndrome (AIDS)

•      Transplantation

•    Acute rejection

•    Chronic rejection

 

Mechanisms of Autoimmune Disease

•      Ineffective lymphocyte programming – self-reactive T and B cells that should have been eliminated in the thymus and bone marrow escape into the circulation

•      New self-antigens appear, generated by:

•    Gene mutations that cause new proteins to appear

•    Changes in self-antigens by hapten attachment or as a result of infectious damage

•      Foreign antigens resemble self-antigens:

•    Antibodies made against foreign antigens cross-react with self-antigens

 

Hypersensitivity

•      Immune responses that cause tissue damage

•      Different types of hypersensitivity reactions are distinguished by:

•    Their time course

•    Whether antibodies or T cells are the principle immune elements involved

•      Antibody-mediated allergies are immediate hypersensitivities

•      The most important cell-mediated allergic condition is delayed hypersensitivity

 

Immediate Hypersensitivity

•      Acute (type I) hypersensitivities begin in seconds after contact with allergen

•      Anaphylaxis – initial allergen contact is asymptomatic but sensitizes the person

•    Subsequent exposures to allergen cause:

•   Release of histamine and inflammatory chemicals

•   Systemic or local responses

•    The mechanism involves IL-4 secreted by T cells

•    IL-4 stimulates B cells to produce IgE

•    IgE binds to mast cells and basophils causing them to degranulate, resulting in a flood of histamine release and inducing the inflammatory response

 

Local Type I Responses

•      Reactions include runny nose, itching reddened skin, and watery eyes

•      If allergen is inhaled, asthmatic symptoms appear – constriction of bronchioles and restricted airflow

•      If allergen is ingested, cramping, vomiting, and diarrhea occur

•      Antihistamines counteract these effects

 

Systemic Response: Anaphylactic Shock

•      Response to allergen that directly enters the blood (e.g., insect bite, injection)

•      Basophils and mast cells are enlisted throughout the body

•      Systemic histamine releases may result in:

•    Constriction of bronchioles

•    Sudden vasodilation and fluid loss from the bloodstream

•    Hypotensive shock and death

•      Treatment – epinephrine is the drug of choice

 

Delayed Hypersensitivities (Type IV)

•      Onset is slow (1–3 days)

•      Mediated by mechanisms involving delayed hypersensitivity T cells (TDH cells) and cytotoxic T cells (TC cells)

•      Cytokines from activated TC are the mediators of the inflammatory response

•      Antihistamines are ineffective and corticosteroid drugs are used to provide relief

•      Example: allergic contact dermatitis (e.g., poison ivy)

•      Involved in protective reactions against viruses, bacteria, fungi, protozoa, cancer, and rejection of foreign grafts or transplants

 

Autoimmune Diseases

•      Loss of the immune system’s ability to distinguish self from nonself

•      The body produces autoantibodies and sensitized TC cells that destroy its own tissues

•      Examples include multiple sclerosis, myasthenia gravis, Graves’ disease, Type I (juvenile) diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis

 

Immunodeficiencies

•      Congenital and acquired conditions in which the function or production of immune cells, phagocytes, or complement is abnormal

•    SCID – severe combined immunodeficiency (SCID) syndromes; genetic defects that produce:

•   A marked deficit in B and T cells

•   Abnormalities in interleukin receptors

•   Defective adenosine deaminase (ADA) enzymes

•   Metabolites lethal to T cells accumulate

•    SCID is fatal if untreated; treatment is with bone marrow transplants

 

Acquired Immunodeficiencies

•      Hodgkin’s disease – cancer of the lymph nodes leads to immunodeficiency by depressing lymph node cells

•      Acquired immune deficiency syndrome (AIDS) – cripples the immune system by interfering with the activity of helper T (CD4) cells

•    Characterized by severe weight loss, night sweats, and swollen lymph nodes

•    Opportunistic infections occur, including pneumocystis pneumonia and Kaposi’s   sarcoma

 

AIDS

•      Caused by human immunodeficiency virus (HIV) transmitted via body fluids – blood, semen, and vaginal secretions

•      HIV enters the body via:

•    Blood transfusions

•    Contaminated needles

•    Intimate sexual contact, including oral sex

•      HIV:

•    Destroys TH cells

•    Depresses cell-mediated immunity

•      HIV multiplies in lymph nodes throughout the asymptomatic period

•      Symptoms appear in a few months to 10 years

•      Attachment

•    HIV’s coat protein (gp120) attaches to the CD4 receptor

•    A nearby protein (gp41) fuses the virus to the target cell

•      HIV enters the cell and uses reverse transcriptase to produce DNA from viral RNA

•      This DNA (provirus) directs the host cell to make viral RNA (and proteins), enabling the virus to reproduce and infect other cells

•      HIV reverse transcriptase is not accurate and produces frequent transcription errors

•    This high mutation rate causes resistance to drugs

•      Treatments include:

•    Reverse transcriptase inhibitors (AZT)

•    Protease inhibitors (saquinavir and ritonavir)

•    New drugs that are currently being developed, which block HIV’s entry to helper T cells


Review Outline - The Lymphatic System

 

       I.   Lymphatic Vessels

A. Distribution and Structure of Lymphatic Vessels

1. Lymph Capillaries

2. Lymphatic Collecting Vessels

B. Lymph Transport

      II.   Lymphoid Cells, Tissues, and Organs: An Overview

A. Lymphoid Cells

B. Lymphoid Tissue

C.      Lymphoid Organs

    III.   Lymph Nodes

A. Structure

B. Circulation

    IV.   Other Lymphoid Organs

A. Spleen

1. Functions

2. Structure

B. Thymus

1. Function

2. Structure

C.      Tonsils

 

Review Outline - Nonspecific Body Defenses and Immunity

 

       I.   Innate (Nonspecific) Defenses

A. Surface Barriers: Skin and Mucosae

1. Skin

2. Mucous Membranes

B. Internal Defenses: Cells and Chemicals

1. Phagocytes

2. Natural Killer Cells

3. Inflammation: Tissue Response to Injury

a.   Interferon

b.    Complement

4. Fever

      II.   Adaptive (Specific) Defenses

A. Aspects of the Immune Response

1. Antigen-Specific

2. Systemic

3. Memory

4. Humoral Immunity

5. Cell-Mediated Immunity

B. Antigens

1. Complete Antigens and Haptens

2. Antigenic Determinants

a. Self-Antigens: MHC Proteins

C.      Cells of the Immune System: An Overview

1.      Lymphocytes

2.      Antigen-Presenting Cells

    III.   Humoral Immune Response

A. Clonal Selection and Differentiation of B Cells

1. Clonal Selection

2. Plasma Cells

B. Immunological Memory

1. Primary Immune Response

2. Secondary Immune Response

3. Immunological Memory

C.      Active and Passive Humoral Immunity

1.  Active Humoral Immunity

a.  Vaccines

2. Passive Humoral Immunity

D. Antibodies

1. Basic Antibody Structure

a. Heavy and Light Chains

b. Variable and Constant Regions

2. Antibody Classes

3.  Mechanisms of Antibody Diversity

4. Antibody Targets and Functions

a. Complement Fixation and Activation

b. Neutralization

5. Monoclonal Antibodies

    IV.   Cell-Mediated Immune Response

A. Introduction

1. Effector Cells

a. Cytotoxic T Cells

2. Regulatory Cells

a. Helper T Cells—CD4 Cells

B. Clonal Selection and Differentiation of T Cells

1. Antigen Recognition and MHC Restriction

a. Class I MHC

b. Class II MHC

c. MHC Restriction

2. T Cell Activation

a. Step 1: Antigen Binding

b. Step 2: Costimulation

3. Cytokines

C.      Specific T Cell Roles

1. Helper T Cells

2. Cytotoxic T Cells

3. Other T Cells

4. Summary of T Cell Roles

D. Organ Transplants and Prevention of Rejection

     V.   Homeostatic Balance of Immunity

A. Immunodeficiencies

B. Autoimmune Diseases

1. Inefficient/Ineffective Lymphocyte Programming

2. Appearance of Self Proteins in the Circulation

3. Cross-Reaction of Antibodies

C. Hypersensitivities

1.  Immediate Hypersensitivities

a.  Anaphylaxis

b.  Atopy

2.  Delayed Hypersensitivities

a.    Allergic Contact Dermatitis

                                      b.  Antibiotic reactions