0-1 Chapter 21 Lymphatic and immune system Flashcards
immune system
not an organ system, but a population of cells that inhabit all of our organs and defend the body from agents of disease
lymphatic system
- network of organs and vein-like vessels that recover fluid
- inspect it for disease agents
- activate immune responses
- return the fluid to the bloodstream
Lymphatic and Immune Systems
functions
maintain fluid balance
•protect body from infection and disease
Functions of Lymphatic System
fluid recovery
immunity
lipid absorption
fluid recovery
–fluid continually filters from the blood capillaries into the tissue spaces
•blood capillaries reabsorb 85%
•15% (2 –4 L/day) of the water and about half of the plasma proteins enters lymphatic system and then returned to the blood
immunity
excess filtered fluid picks up foreign cells and chemicals from the tissues
•passes through lymph nodes where immune cells stand guard against foreign matter
•activate a protective immune response
lipid absorption
lacteals in small intestine absorb dietary lipids that are not absorbed by the blood capillaries
Components of the Lymphatic System
lymph
lymphatic vessels
lymphatic tissues
lymphatic organs
lymph
–the recovered fluid
lymphatic vessels
–transport the lymph
lymphatic tissues
composed of aggregates of lymphocytes and macrophages that populate many organs in the body
lymphatic organs
–defense cells are especially concentrated in these organs
–separated from surrounding organs by connective tissue capsules
lymph
–clear, colorless fluid, similar to plasma, but much less protein
–extracellular fluid drawn into lymphatic capillaries
lymphatic capillaries
(terminal lymphatics)
–sacs of thin endothelial cells that loosely overlap each other
–closed at one end
–cells tethered to surrounding tissue by protein filaments
–endothelium creates valve-like flaps that open when interstitial fluid pressure is high, and close when it is low
Lymphatic Vessels
larger ones composed of three layers
–tunica interna:
–tunica media:
–tunica externa:
•converge into larger and larger vessels
tunica interna
endothelium and valves
tunica media
elastic fibers, smooth muscle
tunica externa
thin outer layer
Route of Lymph Flow
- lymphatic capillaries
- collecting vessels
- six lymphatic trunks:
- two collecting ducts:
- subclavian veins
two collecting ducts:
right lymphatic duct
thoracic duct
right lymphatic duct
receives lymph from right arm, right side of head and thorax; empties into right subclavian vein
thoracic duct
larger and longer, begins as a prominent sac in abdomen called the cisterna chyli; receives lymph from below diaphragm, left arm, left side of head, neck, and thorax; empties into left subclavian vein
Mechanisms of Lymph Flow
- lymph flows under forces similar to those that govern venous return, except no pump (heart)
- lymph flows at low pressure and slower speed than venous blood
- moved along by rhythmic contractions of lymphatic vessels
- flow aided by skeletal muscle pump
- arterial pulsation rhythmically squeeze lymphatic vessels
- thoracic pump aids flow from abdominal to thoracic cavity
- valves prevent backward flow
- rapidly flowing blood in subclavian veins, draws lymph into it
- exercise significantly increases lymphatic return
natural killer (NK) cells
–large lymphocytes that attack and destroy bacteria, transplanted tissue, host cells infected with viruses or have turned cancerous
–responsible for immune surveillance
T lymphocytes (T cells)
–mature in thymus
B lymphocytes (B cells)
–activation causes proliferation and differentiation into plasma cells that produce antibodies
macrophages
–very large, avidly phagocytic cells of the connective tissue
–develop from monocytes
–phagocytize tissue debris, dead neutrophils, bacteria, and other foreign matter
–process foreign matter and display antigenic fragments to certain T cells alerting the immune system to the presence of the enemy
–antigen presenting cells (APCs)
dendritic cells
–branched, mobile APCs found in epidermis, mucous membranes, and lymphatic organs
–alert immune system to pathogens that have breached their surface
reticular cells
–branched stationary cells that contribute to the stroma of a lymphatic organ
–act as APCs in the thymus
lymphatic (lymphoid) tissue
aggregations of lymphocytes in the connective tissues of mucous membranes and various organs
diffuse lymphatic tissue
simplest form
–lymphocytes are scattered, rather than densely clustered
–prevalent in body passages open to the exterior
•respiratory, digestive, urinary, and reproductive tracts
MALT
mucosa-associated lymphatic tissue (MALT)
lymphatic nodules (follicles)
dense masses of lymphocytes and macrophages that congregate in response to pathogens
–constant feature of the lymph nodes, tonsils, and appendix
Peyer patches
dense clusters in the ileum, the distal portion of the small intestine
Lymphatic Organs
•lymphatic organs have well-defined anatomical sites
–have connective tissue capsule that separates the lymphatic tissue from neighboring tissues
primary lymphatic organs
–red bone marrow and thymus
–site where T and B cells become immunocompetent–able to recognize and respond to antigens
secondary lymphatic organs
–lymph nodes, tonsils, and spleen
–immunocompetent cells populate these tissues
Red Bone Marrow
red bone marrow is involved in hemopoiesis(blood formation) and immunity
–soft, loosely organized, highly vascular material
–separated from osseous tissue by endosteum of bone
–as blood cells mature, they push their way through the reticular and endothelial cells to enter the sinus and flow away in the blood stream
thymus
member of the endocrine, lymphatic, and immune systems
–houses developing lymphocytes
–secretes hormones regulating their activity
–bilobed organ located in superior mediastinum between the sternum and aortic arch
reticular epithelial cells
seal off cortex from medulla forming blood-thymus barrier
produce signaling molecules
thymosin, thymopoietin, thymulin, interleukins, and interferon
lymph nodes
the most numerous lymphatic organs –about 450 in typical young adult –serve two functions: •cleanse the lymph •act as a site of T and B cell activation
parenchyma divided into
cortex and medulla
–germinal centers where B cells multiply and differentiate into plasma cells
Lymph Node Locations
cervical lymph nodes axillary lymph nodes thoracic lymph nodes abdominal lymph nodes intestinal and mesenteric lymph nodes inguinal lymph nodes popliteal lymph nodes
cervical lymph nodes
–deep and superficial group in the neck
–monitor lymph coming from head and neck
axillary lymph nodes
–concentrated in armpit
–receive lymph from upper limb and female breast
thoracic lymph nodes
–in thoracic cavity especially embedded in mediastinum
–receive lymph from mediastinum, lungs, and airway
abdominal lymph nodes
–occur in posterior abdominopelvic wall
–monitor lymph from the urinary and reproductive systems
intestinal and mesenteric lymph nodes
–found in the mesenteries, adjacent to the appendix and intestines
–monitor lymph from the digestive tract
inguinal lymph nodes
–in the groin and receive lymph from the entire lower limb
popliteal lymph nodes
–occur on the back of the knee
–receive lymph from the leg proper
lymphadenopathy
collective term for all lymph node diseases
lymphadenitis
swollen, painful node responding to foreign antigen
lymph nodes are common sites for
metastatic cancer
–swollen, firm and usually painless
metastasis
phenomenon in which cancerous cells break free from the original, primary tumor, travel to other sites in the body, and establish new tumors.
tonsils
patches of lymphatic tissue located at the entrance to the pharynx
–guard against ingested or inhaled pathogens
–each covered with epithelium
tonsillar crypts
have deep pits –tonsillar crypts lined with lymphatic nodules –tonsillitis and tonsillectomy
three main sets of tonsils
palatine tonsils
lingual tonsils
pharyngeal tonsil (adenoid)
palatine tonsils
- pair at posterior margin of oral cavity
* most often infected
lingual tonsils
•pair at root of tongue
pharyngeal tonsil (adenoid)
- single tonsil on wall of nasopharynx
- covered by epithelium
- pathogens get into tonsillar crypts and encounter lymphocytes
spleen
the body‟s largest lymphatic organ
spleen highly vascular and vulnerable to trauma and infection
parenchyma exhibits two types of tissue:
red pulp
white pulp
red pulp
sinuses filled with erythrocytes
white pulp
lymphocytes, macrophages surrounding small branches of splenic artery
functions
–blood production in fetus
–blood reservoir
–„erythrocyte graveyard‟ -RBC disposal
–white pulp monitors blood for foreign antigens
splenectomy
ruptured spleen
pathogens
environmental agents capable of producing disease
–infectious organisms, toxic chemicals, and radiation
three lines of defenses against pathogens
first line of defense
external barriers, skin and mucous membranes
second line of defense
several nonspecific defense mechanisms
•leukocytes and macrophages, antimicrobial proteins, immune surveillance, inflammation, and fever
•effective against a broad range of pathogens
third line of defense
the immune system
•defeats a pathogen, and leaves the body of a „memory‟ of it so it can defeat it faster in the future
nonspecific resistance
guards equally against a broad range of pathogens
–their effectiveness does not depend on prior exposure
–skin and mucous membranes
–leukocytes and macrophages, antimicrobial proteins, immune surveillance, inflammation, and fever
immunity
specific defense because it results from prior exposure to a pathogen
–usually provides future protection only against that particular one
External Barriers
skin
mucous membranes
skin
–makes it mechanically difficult for microorganisms to enter the body
–toughness of keratin
–too dry and nutrient-poor to support microbial growth
defensins
peptides that kill microbes by creating holes in their membranes
acid mantle
thin film of lactic acid from sweat which inhibits bacterial growth
mucous membranes
–digestive, respiratory, urinary, and reproductive tracts are open to the exterior and protected by mucous membranes
–mucus physically traps microbes
lysozyme
enzyme destroys bacterial cell walls
phagocytes
phagocytic cells with a voracious appetite for foreign matter
five types of leukocytes
–neutrophils –eosinophils –basophils –monocytes –lymphocytes
Neutrophils
wander in connective tissue killing bacteria
–phagocytosis and digestion
–produces a cloud of bactericidal chemicals
killing zone
–degranulation
•lysosomes discharge into tissue fluid
–respiratory burst –neutrophils rapidly absorb oxygen
•toxic chemicals are created (O2.-, H2O2, HClO)
–kill more bacteria with toxic chemicals than phagocytosis
Eosinophils
- found especially in the mucous membranes
- stand guard against parasites, allergens(allergy causing agents), and other pathogens
- kill tapeworms and roundworms by producing superoxide, hydrogen peroxide, and toxic proteins
Basophils
secrete chemicals that aid mobility and action of WBC other leukocytes
histamine
a vasodilator which increases blood flow
•speeds delivery of leukocytes to the area
heparin
inhibits the formation of clots
•would impede leukocyte mobility
mast cells
also secrete these substances
–type of connective tissue cell very similar to basophils
Lymphocytes
•three basic categories •circulating blood contains –80% T cells –15% B cells –5% NK cells •many diverse functions
monocytes
emigrate from the blood into the connective tissue and transform into macrophages
macrophage system
all the body‟s avidly phagocytic cells, except leukocytes
wandering macrophages
actively seeking pathogens
•widely distributed in loose connective tissue
fixed macrophages
phagocytize only pathogens that come to them
microglia
in central nervous system
alveolar macrophages
in lungs
hepatic macrophages
in liver
Antimicrobial Proteins
proteins that inhibit microbial reproduction and provide short-term, nonspecific resistance to pathogenic bacteria and viruses
two families of antimicrobial proteins:
–interferons
–complement system
interferons
secreted by certain cells infected by viruses
–of no benefit to the cell that secretes them
–alert neighboring cells and protect them from becoming infected
–bind to surface receptors on neighboring cells
–alerted cell synthesizes various proteins that defend it from infection
–also activates NK cells and macrophages
–activated NK cells destroy malignant cells
complement system
a group of 30 or more globular proteins that make powerful contributions to both nonspecific resistance and specific immunity
–synthesized mainly by the liver
–circulate in the blood in inactive form
–activated by presence of the pathogen
activated complement brings about four methods of pathogen destruction
- inflammation
- immune clearance
- phagocytosis
- cytolysis
three routes of complement activation
- classical pathway
- alternative pathway
- lectin pathway
classical pathway
–requires antibody molecule to get started
–thus part of specific immunity
–antibody binds to antigen on surface of the pathogenic organism
•forms antigen-antibody (Ag-Ab) complex
–changes the antibody‟s shape
•exposing a pair of complement-binding sites
•binding of the first complement (C1) sets off a reaction cascade called complement fixation
–results in a chain of complement proteins attaching to the antibody
alternative pathway
–nonspecific, does not require antibody
–C3 breaks down in the blood to C3a and C3b
•C3b binds directly to targets such as human tumor cells, viruses, bacteria, and yeasts
•triggers cascade reaction with autocatalytic effect where more C3 is formed
lectin pathway
Exists
mechanisms of action of complement proteins
- inflammation
- immune clearance
- phagocytosis
- cytolysis
inflammation
- C3a stimulates mast cells and basophils to secrete histamine and other inflammatory chemicals
- activates and attracts neutrophils and macrophages
- speed pathogen destruction in inflammation
immune clearance
- C3b binds with antigen-antibody complexes to red blood cells
- these RBCs circulate through the liver and spleen
- macrophages of those organs strip off and destroy the Ag-Ab complexes leaving RBCs unharmed
- principal means of clearing foreign antigens from the bloodstream
phagocytosis
•neutrophils and macrophages cannot phagocytize “naked” bacteria, viruses, or other pathogens
•C3b assist them by opsonization
–coats microbial cells and serves as binding sites for phagocyte attachment
–makes the foreign cell more appetizing
cytolysis
•C3b splits other complement proteins
•bind to enemy cell
•attract more complement proteins –membrane attack complex forms
–forms a hole in the target cell
–electrolytes leak out, water flows in rapidly, and cell ruptures
Membrane Attack Complex
complement proteins form ring in plasma membrane of target cell causing cytolysis
immune surveillance
a phenomenon in which natural (NK) killer cells continually patrol the body on the lookout for pathogens and diseased host cells.
natural killer (NK) cells attack and destroy:
natural killer (NK) cells attack and destroy:
–bacteria, cells of transplanted organs, cells infected with viruses, and cancer cells
•recognizes enemy cell
•NK cells bind to it
•release proteins called perforins
•secrete a group of protein degrading enzymes –granzymes
–enter through pore and degrade cellular enzymes and induce apoptosis
perforins
–polymerize a ring and create a hole in its plasma membrane
Action of NK cell
- NK cell releases perforins, which polymerize and form a hole in the enemy cell membrane
- Granzymes from NK cell enter perforin hole and degrade enemy cell enzymes.
- Enemy cell dies by apoptosis
- Macrophage engulfs and digests dying cell.
fever
an abnormal elevation of body temperature
–pyrexia, febrile
–results from trauma, infections, drug reactions, brain tumors, and other causes
fever is an
adaptive defense mechanism, in moderation, does more good than harm
–promotes interferon activity
–elevates metabolic rate and accelerates tissue repair
–inhibits reproduction of bacteria and viruses
antipyretic
fever-reducing medications by inhibiting PGE2
initiation of fever by exogenous pyrogens
fever producing agents
–glycolipids on bacterial and viral surfaces
–attacking neutrophils and macrophages secrete chemicals, interleukins, interferons, and others that act as endogenous pyrogens
–stimulate neurons in the anterior hypothalamus to secrete prostaglandin E2
–PGE2raises hypothalamic set point for body temperature
stages of fever
onset, stadium, defervescence
Course of a Fever
- Infection and pyrogen secretion
- Hypothalamic thermostat is reset to highe rset point
- Onset (body temperature rises
- Stadium(body temperature oscillates around new set point)
- Infection ends, set point returns to normal
- Defervescence (body temperature returns to normal)
Reye Syndrome
serious disorder in children younger than 15 following an acute viral infection such as chicken pox or influenza
–swelling of brain neurons
–fatty infiltration of liver and other viscera
–pressure of swelling brain
•nausea, vomiting, disorientation, seizures and coma
•30% die, survivors sometimes suffer mental retardation
•can be triggered by the use of aspirin to control fever
NEVER give aspirin to
children with chickenpox or flulike symptoms
inflammation
local defensive response to tissue injury of any kind, including trauma and infection
general purposes of inflammation
–limit spread of pathogens, then destroys them
–remove debris from damaged tissue
–initiate tissue repair
four cardinal signs of inflammation
- redness
- swelling
- heat
- pain
suffix -itis denotes
inflammation of specific organs: arthritis, pancreatitis, dermatitis
cytokines
class of chemicals that regulate inflammation and immunity
–secreted mainly by leukocytes
–alter the physiology or behavior of receiving cell
–act at short range, neighboring cells (paracrines) or the same cell that secretes them (autocrines)
–include interferon, interleukins, tumor necrosis factor, chemotactic factors, and others
paracrines
act at short range, neighboring cells
autocrines
act on the same cell that secretes them
three major processes of inflammation
–mobilization of body defenses
–containment and destruction of pathogens
–tissue cleanup and repair
Mobilization of Defenses
most immediate requirement for dealing with tissue injury is to get the defensive leukocytes to the site quickly
•local hyperemia–increasing blood flow beyond normal rate is a way to do this
vasoactive chemicals
dilate local blood vessels
–endothelial cells separate increasing capillary permeability
–fluid, leukocytes, and plasma proteins leave the bloodstream
•complement, antibodies, and clotting proteins
selectins
cell-adhesion molecules made by endothelial cells that aid in the recruitment of leukocytes
•make membranes sticky and snag leukocytes
margination
adhesion of the leukocytes to the vessel wall
•selectins cause leukocytes to adhere to blood vessel walls
diapedesisor emigration
leukocytes crawl through gaps in the endothelial cells and enter tissue fluid
extravasated
cells and chemicals that have left the bloodstream
basis for the four cardinal signs of inflammation
- redness
- swelling
- heat
- pain
heat–
results from hyperemia
redness
due to hyperemia, and extravasated RBCs in the tissue
swelling
(edema) –due to increased fluid filtration from the capillaries
pain
from direct injury to the nerves, pressure on the nerves from edema, stimulation of pain receptors by prostaglandins, bacterial toxins, and a kinin called bradykinin
Containment and Destruction of Pathogens
•a priority of inflammation is to prevent the pathogens from spreading throughout the body
fibrinogen
that filters into tissue fluid clots
•forms a sticky mesh that walls off microbes
heparin
prevents clotting at site of injury
•pathogens are in a fluid pocket surrounded by clot
•attacked by antibodies, phagocytes, and other defenses
neutrophils
the chief enemy of bacteria, accumulate at the injury site within an hour
–after leaving the bloodstream, they exhibit chemotaxis
chemotaxis
attraction to chemicals such as bradykinin and leukotrienes that guide them to the injury site
neutrophils are quickest to respond and kill bacteria by
–phagocytosis
–respiratory burst
–secrete cytokines for recruitment of macrophages and additional neutrophils
eosinophilia
elevated eosinophil count in allergy or parasitic infection
Tissue Cleanup
monocytes the primary agents of tissue cleanup and repair
–arrive in 8 to 12 hours and become macrophages
–engulf and destroy bacteria, damaged host cells, and dead and dying neutrophils
edema contributes to tissue cleanup
–swelling compresses veins and reduces venous drainage
–forces open valves of lymphatic capillaries promoting lymphatic drainage
–lymphatics collect and remove bacteria, dead cells, proteins, and tissue debris better than blood capillaries
pus
accumulation of dead neutrophils, bacteria, other cellular debris, and tissue fluid form a pool of yellowish fluid
abscess
accumulation of pus in a tissue cavity
Tissue Repair
platelet-derived growth factor secreted by blood platelets and endothelial cells in injured area
–stimulates fibroblasts to multiply
–synthesize collagen
•hyperemia delivers oxygen, amino acids, and other necessities for protein synthesis
•increased heat increases metabolic rate, speeds mitosis, and tissue repair
•fibrin clot forms a scaffold for tissue reconstruction
•pain makes us limit the use of a body part so it has a chance to rest and heal.
immune system
composed of a large population of widely distributed cells that recognize foreign substances and act to neutralize or destroy them
two characteristics distinguish immunity from nonspecific resistance
specificity
memory
specificity
immunity directed against a particular pathogen
memory
when re-exposed to the same pathogen, the body reacts so quickly that there is no noticeable illness
two types of immunity
cellular (cell-mediated) immunity:
humoral (antibody-mediated) immunity
cellular (cell-mediated) immunity:
(T cells)
•lymphocytes directly attack and destroy foreign cells or diseased host cells
•means of ridding the body of pathogens that reside inside human cells, where they are inaccessible to antibodies
•kills cells that harbor them
humoral (antibody-mediated) immunity
(B cells)
•mediated by antibodies that do not directly destroy a pathogen
•indirect attack where antibodies assault the pathogen
•can only work against the extracellular stage of infectious microorganisms
natural active immunity
–production of one‟s own antibodies or T cells as a result of infection or natural exposure to antigen
artificial active immunity
–production of one‟s own antibodies or T cells as a result of vaccination against disease
vaccine
consists of dead or attenuated (weakened) pathogens that stimulate the immune response without causing the disease
booster shots
periodic immunizations to stimulate immune memory to maintain a high level of protection
natural passive immunity
–temporary immunity that results from antibodies produced by another person
•fetus acquires antibodies from mother through placenta, milk
artificial passive immunity
–temporary immunity that results from the injection of immune serum (antibodies) from another person or animal
•treatment for snakebite, botulism, rabies, tetanus, and other diseases
antigen
any molecule that triggers an immune response
–large molecular weights of over 10,000 amu
•complex molecules with structures unique to the individual
•proteins, polysaccharides, glycoproteins, glycolipids
•can distinguish „self‟ molecules from foreign
epitopes
(antigenic determinants) –certain regions of an antigen molecule that stimulate immune responses
haptens
too small to be antigenic in themselves
–must combine with a host macromolecule
–create a unique complex that the body recognizes as foreign
–cosmetics, detergents, industrial chemicals, poison ivy, and animal dander
–penicillin binds to host proteins in allergic individuals
major cells of the immune system
–lymphocytes
–macrophages
–dendritic cells
•especially concentrated in strategic places such as lymphatic organs, skin, and mucous membranes
three categories of lymphocytes
–natural killer (NK) cells –immune surveillance
–T lymphocytes (T cells)
–B lymphocytes (B cells)
Life Cycle of T cells
involves three stages and three anatomical stations in the body
„born‟
•„born‟ in the red bone marrow
–descendant of the pluripotent stem cells (PPSCs)
–released into the blood as still-undifferentiated stem cells that colonize the thymus
mature
maturein thymus
–thymosins stimulate maturing T cells to develop surface antigen receptors
–with receptors in place, the T cells are now immunocompetent –capable of recognizing antigens presented to them by APCs
–reticuloendothelial cells in the thymus test T cells by presenting „self‟ antigens to them
–two ways to fail the test:
•inability to recognize the RE cells, especially their MHC antigens
–would be incapable of recognizing a foreign attack on the body
•reacting to the self antigen
–T cells would attack one‟s own tissues
negative selection
T cells that fail either test must be eliminated
two forms of negative selection
clonal deletion
anergy
clonal deletion
self-reactive T cells die and macrophages phagocytize them
anergy
self-reactive T cells remain alive but unresponsive
self-tolerance
–negative selection leaves the body in a state of self-tolerance in which the surviving T cells respond only to foreign antigens, and tolerating our own
2% of the T cells that reach the thymus leave as
immunocompetent T cells
•move to thymus medulla and undergo positive selection –they multiply and form clones of identical T cells programmed to respond to a specific antigen
naïve lymphocyte pool
immunocompetent T cells but have not yet encountered the foreign antigens
deployment
naïve T cells leave thymus and colonize lymphatic tissues and organs everywhere in the body
B Lymphocytes (B cells) •site of development
–group fetal stem cells remain in bone marrow
–develop into B cells
B cell selection
–B cells that react to self antigens undergo either anergy or clonal deletion same as T cell selection
self-tolerant B cells
synthesize antigen surface receptors, divide rapidly, produce immunocompetent clones
•leave bone marrow and colonize same lymphatic tissues and organs as T cells
Antigen-Presenting Cells (APCs)
are required to help
–dendritic cells, macrophages, reticular cells, and B cells function as APCs
•T cells can not recognize their antigens on their own
function of APCs depends on
major histocompatibility complex (MHC) proteins
–act as cell „identification tags‟ that label every cell of your body as belonging to you
–structurally unique for each individual, except for identical twins
antigen processing
–APC encounters antigen
–internalizes it by endocytosis
–digests it into molecular fragments
–displays relevant fragments (epitopes) in the grooves of the MHC protein
antigen presenting
antigen presenting
–wandering T cells inspect APCs for displayed antigens
–if APC only displays a self-antigen, the T cell disregards it
–if APC displays a nonself-antigen, the T cell initiates an immune attack
–APCs alert the immune system to the presence of foreign antigen
–key to successful defense is to quickly mobilize immune cells against the antigen
–with so many cell types involved in immunity, they require chemical messengers to coordinate their activities –interleukins
interleukins
•chemical signals from one leukocyte to another
cellular (cell-mediated) immunity
a form of specific defense in which the T lymphocytes directly attack and destroy diseased or foreign cells, and the immune system remembers the antigens and prevents them from causing disease in the future
cellular immunity involves four classes of T cells
cytotoxic T (TC) cells helper T (TH) cells regulatory T (TR) cells –T-regs memory (TM) cells
cytotoxic T (TC) cells
killer T cells
•the „effectors‟ of cellular immunity
•carry out attack on enemy cells
helper T (TH) cells
GENERAL MANAGER OF IMMUNITY SYSTEM
•help promote TC cell and B cell action and nonspecific resistance
regulatory T (TR) cells –T-regs
- inhibit multiplication and cytokine secretion by other T cells
- limit immune response
memory (TM) cells
- descend from the cytotoxic T cells
* responsible for memory in cellular immunity
both cellular and humoral immunity occur in three stages:
–recognition
–attack
–memory
thought of as the „three Rs of immunity
–recognize
–react
–remember
T Cell Recognition
recognition phase has two aspects: antigen presentation and T cell activation
antigen presentation
–APC encounters and processes an antigen
–migrates to nearest lymph node
–displays it to the T cells
–when T cell encounters its displayed antigen on the MHC protein, they initiate the immune response
T cells respond to two classes of MHC proteins
MHC–I proteins
MHC–II proteins (human leukocyte antigens –HLAs)
MHC–I proteins
–occur on every nucleated cell in the body
–constantly produced by our cells, transported to, and inserted on plasma membrane
–normal self antigens that do not elicit a T cell response
–viral proteins or abnormal cancer antigens do elicit a T cell response
–infected or malignant cells are then destroyed before they can do further harm to the body
MHC–II proteins (human leukocyte antigens –HLAs)
–occur only on APCs and display only foreign antigens
TC cells respond only to
MHC–I proteins
TH cells respond only to
MHC–II proteins
T cell activation
–begins when TC or TH cell binds to a MHC protein displaying an epitope that the T cell is programmed to recognize
–T cell must then bind to another APC protein related to the interleukins
–T cell must check twice to see if it is really bound to a foreign antigen –costimulation
T cell activation
Sequence
- antigen recognition
- costimulation
- clonal selection
- lethal hit
successful costimulation will trigger
- activated T cell undergoes repeated mitosis
- gives rise to a clone of identical T cells programmed against the same epitope
- some cells of the clone become effector cells and carry out the attack
- other cells become memory cells
Attack : Role of Helper T (TH) Cells
- helper and cytotoxic T cells play different roles in the attack phase
- helper T cell necessary for most immune responses
- play central role in coordinating both cellular and humoral immunity
when helper T cell recognizes the Ag-MHC protein complex
secrete interleukins that exert three effects:
secrete interleukins that exert three effects:
- attract neutrophils and NK cells
- attract macrophages, stimulate their phagocytic activity, and inhibit them from leaving the area
- stimulate T and B cell mitosis and maturation
Attack : Cytotoxic T (TC) Cells
- cytotoxic T (TC) cell are the only T cells directly attack other cells
- when TCcell recognizes a complex of antigen and MHC–I protein on a diseased or foreign cell it „docks‟ on that cell
delivers a lethal hit of toxic chemicals
•perforin and granzymes–kill cells in the same manner as NK cells
•interferons–inhibit viral replication
–recruit and activate macrophages
•tumor necrosis factor (TNF) –aids in macrophage activation and kills cancer cells
–goes off in search of another enemy cell while the chemicals do their work
Memory
•immune memory follows primary response
•following clonal selection, some TC and TH cells become memory cells
–long-lived
–more numerous than naïve T cells
–fewer steps to be activated, so they respond more rapidly
T cell recall response
upon re-exposure to same pathogen later in life, memory cells launch a quick attack so that no noticeable illness occurs
–the person is immune to the disease
Humoral Immunity
•humoral immunity is a more indirect method of defense than cellular immunity
•B lymphocytes of humoral immunity produce antibodies that bind to antigens and tag them for destruction by other means
–cellular immunity attacks the enemy cells directly
works in three stages like cellular immunity
–recognition
–attack
–memory
Humoral Immunity
•recognition
–immunocompetent B cell has thousands of surface receptorsfor one antigen
–activation begins when an antigen binds to several of these receptors
•links them together
•taken into the cell by receptor-mediated endocytosis
•small molecules are not antigenic because they cannot link multiple receptors together
•B cell processes (digests) the antigen
•links some of the epitopesto its MHC–II proteins
•displays these on the cell surface
usually B cell response goes no further unless
a helper T cellbinds to this Ag-MHCP complex
•bound THcell secretes interleukins that activate B cell
triggers clonal selection
•B cell mitosis gives rise to an entire battalion of identical B cells programmed against the same antigen
•most differentiate into plasma cells
•larger than B cells and contain an abundance of rough ER
•secrete antibodies at a rate of 2,000 molecules per second during their life span of 4 to 5 days
•antibodies travel through the body in the blood or other body fluids
–first exposure antibodiesIgM, later exposures to the same antigen,IgG
attack
–antibodies bind to antigen, render it harmless, „tag it‟ for destruction
memory
some B cells differentiate into memory cells
immunoglobulin (Ig)
an antibodyis a defensive gamma globulin found in the blood plasma, tissue fluids, body secretions, and some leukocyte membranes
antibody monomer
the basic structural unit of an antibody
–composed of four polypeptide chains linked by disulfide (-S-S-) bonds
–two larger heavy chains about 400 amino acids long
•heavy chains have a hinge region where antibody is bent
–two light chains about half as long
–variable (V) region in all four chains
•gives the antibody its uniqueness
antigen binding site
formed from the V regions of the heavy and light chain on each arm
•attaches to the epitope of an antigen molecule
constant (C) region
has the same amino acid sequence within one person and determines mechanism of antibody action
Five Classes of Antibodies
named for the structure of their C region IgA IgD IgE IgG IgM
IgA
monomer in plasma; dimer in mucus, saliva, tears, milk, and intestinal secretions
•prevents pathogen adherence to epithelia and penetrating underlying tissues
•provides passive immunity to newborns
IgD
monomer; B cell transmembrane antigen receptor
•thought to function in B cell activation by antigens
IgE
monomer; transmembrane protein on basophils and mast cells
•stimulates release of histamine and other chemical mediators of inflammation and allergy
–attracts eosinophils to parasitic infections
–produces immediate hypersensitivity reactions
IgG
monomer; constitutes 80% of circulating antibodies
•crosses placenta to fetus, secreted in secondary immune response, complement fixation
IgM
pentamer in plasma and lymph
•secreted in primary immune response, agglutination, complement
fixation
Antibody Diversity
human immune system capable of as many as 1 trillion different antibodies
•accustomed to „one gene, one protein‟ thinking
•35,000 genes in human genome
somatic recombination
–DNA segments shuffled and form new combinations of base sequences to produce antibody genes
somatic hypermutation
–B cells in lymph nodules rapidly mutate creating new sequences
Humoral Immunity -Attack
4
neutralization
complement fixation
agglutination
precipitation
neutralization
–antibodies mask pathogenic region of antigen
complement fixation
–antigen binds to IgM or IgG, antibody changes shape, initiates complement binding which leads to inflammation, phagocytosis, immune clearance, or cytolysis
–primary defense against foreign cells, bacteria, and mismatched RBCs
agglutination
–antibody has 2-10 binding sites; binds to multiple enemy cells immobilizing them from spreading
precipitation
–antibody binds antigen molecules (not cells); creates antigen-antibody complex that precipitates, phagocytized by eosinophils
Humoral Immunity -Memory
primary immune response
immune reaction brought about by the first exposure to an antigen
–appearance of protective antibodies delayed for 3 to 6 days while naïve B cells multiply and differentiate into plasma cells
as plasma cells produce antibodies
the antibody titer (level in the blood plasma) rises
•IgM appears first, peaks in about 10 days, soon declines
•IgG levels rise as IgM declines, but IgG titer drops to a low level within a month
–primary response leaves one with an immune memory of the antigen
•during clonal selection, some of the clone becomes memory B cells
•found mainly in germinal centers of the lymph nodes
•mount a very quick secondary response
secondary (anamnestic) response
if re-exposed to the same antigen
–plasma cells form within hours
–IgG titer rises sharply and peaks in a few days
–response is so rapid that the antigen has little chance to exert a noticeable effect on the body
–no illness results
–low levels of IgM also secreted and quickly declines
–IgG remain elevated for weeks to years
•conferring long lasting protection
•memory does not last as long in humoral immunity as in cellular immunit
immune response may be:
–too vigorous
–too weak
–misdirected against wrong targets
hypersensitivity
an excessive immune reaction against antigens that most people tolerate
alloimmunity
reaction to transplanted tissue from another person
autoimmunity
abnormal reactions to one‟s own tissues
allergies
reactions to environmental antigens (allergens) –dust, mold, pollen, vaccines, bee and wasp venom, poison ivy and other plants, foods such as nuts, milk, eggs, and shellfish, drugs such as penicillin, tetracycline, and insulin
four kinds of hypersensitivity
based on the type of immune agents involved (antibodies or T cells) and their method of attack on the antigen
Type I
acute (immediate) hypersensitivity –very rapid response
Type II and Type III
subacute –slower onset (1 –3 hours after exposure)
•last longer (10 –15 hours)
•Types I, II, and III are quicker antibody mediated responses
Type IV -
delayed cell-mediated response
Type I (acute) Hypersensitivity
- includes most common allergies
- IgE-mediated reaction that begins within seconds of exposure
- usually subsides within 30 minutes, although it can be severe to fatal
Type I (acute) Hypersensitivity
signs
•clinical signs include:
–local edema, mucus hypersecretion and congestion, watery eyes, runny nose, hives, and sometimes cramps, diarrhea and vomiting
•examples: food allergies and asthma–local inflammatory reaction to inhaled allergens
Type I (acute) Hypersensitivity
anaphylaxis
–immediate, severe reaction Type I reaction
–local anaphylaxis can be relieved with antihistamines
Type I (acute) Hypersensitivity
anaphylactic shock
–severe, widespread acute hypersensitivity that occurs when an allergen is introduced to the bloodstream of an allergic individual
–characterized by bronchoconstriction, dyspnea (labored breathing), widespread vasodilation, circulatory shock, and sometimes death
–antihistamines are inadequate by themselves
–epinephrine relieves the symptoms by dilating bronchioles, increasing cardiac output, and restoring blood pressure
–fluid therapy and respiratory support are sometimes required
Type I (acute) Hypersensitivity
asthma
–most common chronic illness in children
allergic (extrinsic) asthma
is most common form
•respiratory crisis triggered by inhaled allergens
•stimulate plasma cells to secrete IgE
•binds to most cells in respiratory mucosa
•mast cells release a complex mixture of inflammatory chemicals
•triggers intense airway inflammation
asthma
effects
•bronchospasms within minutes
–severe coughing, wheezing, and sometimes fatal suffocation
asthma
treatment
•epinephrine and other β-adrenergic stimulants to dilate airway and restore breathing, and with inhaled corticosteroids to minimize inflammation and long term damage
Type II Hypersensitivity (Antibody-Dependent Cytotoxic)
•occurs when IgG or IgM attacks antigens bound to cell surfaces
–reaction leads to complement activation
–and lysis or opsonization of the target cell
–macrophages phagocytize and destroy opsonized platelets, erythrocytes, or other cells
•examples: blood transfusion reaction, pemphigus vulgaris, and some drug reactions
Type III Hypersensitivity (Immune Complex)
occurs when IgG or IgM form antigen-antibody complexes
–precipitate beneath endothelium of blood vessels and other tissues
–at site, activate complement and trigger intense inflammation
–examples: autoimmune diseases -acute glomerulonephritis and in systemic lupus erythematosus, a widespread inflammation of the connective tissues
Type IV Hypersensitivity (Delayed)
•cell-mediated reaction in which the signs appear 12 to 72 hour after exposure
–begins with APCs in lymph nodes display antigens to helper T cells
–T cells secrete interferon and cytokines that activate cytotoxic T cells and macrophages
–result is a mixture of nonspecific and immune responses
•examples: haptens in cosmetics and poison ivy, graft rejection, TB skin test, beta cell destruction that causes type I diabetes mellitus
autoimmune diseases
failures of self-tolerance
•immune system fails to distinguish self-antigens from foreign ones
–produces autoantibodies that attack the body‟s own tissues
three reasons why self-tolerance
cross-reactivity
abnormal exposure of self-antigens in the blood
self-reactive T cells
cross-reactivity
- some antibodies against foreign antigens react to similar self-antigens
- rheumatic fever -streptococcus antibodies also react with heart valves
abnormal exposure of self-antigens in the blood
- some of our native antigens are not exposed to blood
* blood-testes barrier isolates sperm from blood
self-reactive T cells
–not all are eliminated in thymus and are normally kept in check by regulatory T (TR) cells
Immunodeficiency Diseases
immune system fails to react vigorously enough
Severe Combined Immunodeficiency Disease (SCID)
–hereditary lack of T and B cells
–vulnerability to opportunistic infection and must live in protective enclosures
Acquired Immunodeficiency Syndrome (AIDS)
nonhereditary diseases contracted after birth
•group of conditions that involve and severely depress the immune response
•caused by infection with the human immunodeficiency virus (HIV)
nonhereditary diseases contracted after birth
•group of conditions that involve and severely depress the immune response
•caused by infection with the human immunodeficiency virus (HIV)
–HIV structure (next slide)
–invades helper T cells, macrophages and dendritic cells by “tricking” them to internalize viruses by receptor mediated endocytosis
–reverse transcriptase (retrovirus) uses viral RNA as template to synthesize DNA
•new DNA inserted into host cell DNA (may be dormant for months to years)
•when activated, it induces the host cell to produce new viral RNA, capsid proteins, and matrix proteins
•they are coated with bits of the host cell‟s plasma membrane
•adhere to new host cells and repeat the process
AIDS
by destroying THcells, HIV strikes at the central coordinating agent of nonspecific defense, humoral immunity, and cellular immunity
•incubation period ranges from several months to 12 years
•signs and symptoms
–early symptoms: flulike symptoms of chills and fever
–progresses to night sweats, fatigue, headache, extreme weight loss, lymphadenitis
–normal THcount is 600 to 1,200 cells/L of blood, but in AIDS it is less than 200 cells/L
–person susceptible to opportunistic infections (Toxoplasma, Pneumocystis, herpes simplex virus, cytomegalovirus, or tuberculosis)
–Candida (thrush): white patches on mucous membranes
–Kaposi sarcoma: cancer originates in endothelial cells of blood vessels causes purple lesions in skin
HIV Transmission
through blood, semen, vaginal secretions, breast milk, or across the placenta
•most common means of transmission
–sexual intercourse (vaginal, anal, oral)
–contaminated blood products
–contaminated needles
•not transmitted by casual contact
•undamaged latex condom is an effective barrier to HIV, especially with spermicide nonoxynol-9
Treatment Strategies
prevent binding to CD4 proteins of THcells
•disrupt reverse transcriptase to inhibit assembly of new viruses or their release from host cells
•medications
–none can eliminate HIV, all have serious side-effects
–HIV develops drug resistance
•medicines used in combination
–AZT (azidothymidine)
•first anti-HIV drug -inhibits reverse transcriptase
–protease inhibitors
•inhibit enzymes HIV needs to replicate
–now more than 24 anti-HIV drugs on the market
