Lymphatic and Immune Systems
Lymphatic and Immune Systems
Maintain fluid balance
Protect body from infection and disease
Functions of Lymphatic System
Immunity
fluids from all capillary beds are filtered
immune cells stand ready to respond to foreign
cells or chemicals encountered
Lipid absorption
Lacteals in small intestine absorb dietary lipids
Fluid recovery
absorbs plasma proteins and fluid (2 to 4 L/day)
from tissues and returns it to the bloodstream
interference with lymphatic drainage leads to severe
edema
Lymph and Lymphatic Capillaries
Lymph
clear, colorless fluid, similar to plasma but
much less protein
Lymphatic capillaries
closed at one end
tethered to surrounding tissue by protein
filaments
endothelial cells loosely overlapped
allow bacteria and cells entrance to lymphatic
capillary
creates valve-like flaps that open when interstitial
fluid pressure is high, and close when it is low
Lymphatic Capillary
Lymphatic Vessels
Larger ones composed of 3 layers
tunica interna: endothelium and valves
tunica media: elastic fibers, smooth muscle
tunica externa: thin outer layer
Valve in a Lymphatic Vessel
Route of Lymph Flow
Lymphatic capillaries
Collecting vessels: course through many lymph
nodes
Lymphatic trunks: drain major portions of body
Collecting ducts :
right lymphatic duct receives lymph from R arm, R
side of head and thorax; empties into R subclavian
vein
thoracic duct - larger and longer, begins as a
prominent sac in abdomen called the cisterna chyli;
receives lymph from below diaphragm, L arm, L side
of head, neck and thorax; empties into L subclavian
vein
The Fluid Cycle
Lymphatic Drainage of
Mammary and Axillary Regions
Drainage of Thorax
Mechanisms of Lymph Flow
Lymph flows at low pressure and speed
Moved along by rhythmic contractions of
lymphatic vessels
stretching of vessels stimulates contraction
Flow aided by skeletal muscle pump
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
Lymphatic Cells
Natural killer (NK) cells
responsible for immune surveillance
T lymphocytes
mature in thymus
B lymphocytes
activation causes proliferation and differentiation
into plasma cells that produce antibodies
Antigen Presenting Cells
macrophages (from monocytes)
dendritic cells (in epidermis, mucous membranes and
lymphatic organs)
reticular cells (also contribute to stroma of lymph organs)
Lymphatic Tissue
Diffuse lymphatic tissue
lymphocytes in mucous membranes and CT
of many organs
Mucosa-Associated Lymphatic Tissue (MALT):
prevalent in passages open to exterior
Lymphatic nodules
dense oval masses of lymphocytes,
congregate in response to pathogens
Peyer patches: more permanent
congregation, clusters found at junction of
small to large intestine
Lymphatic Organs
At well defined sites; have CT capsules
Primary lymphatic organs
site where T and B cells become
immunocompetent
red bone marrow and thymus
Secondary lymphatic organs
immunocompetent cells populate these
tissues
lymph nodes, tonsils, and spleen
Lymph Node
Lymph nodes - only organs that filter lymph
Fewer efferent vessels, slows flow through
node
Capsule gives off trabeculae, divides node
into compartments containing stroma (reticular
CT) and parenchyma (lymphocytes and APCs)
subdivided into cortex (lymphatic nodules) and
medulla
reticular cells, macrophages phagocytize foreign
matter
lymphocytes respond to antigens
lymphatic nodules-germinal centers for B cell
activation
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
Lymph Node
Fig. 21.12 a and b
Tonsil
Covered by epithelium
Pathogens get into tonsillar crypts and
encounter lymphocytes
Location of Tonsils
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 pharynx
Thymus
Thymus
Capsule gives off trabeculae, divides
parenchyma into lobules of cortex and medulla
Reticular epithelial cells
form blood thymus barrier in cortex
isolates developing T lymphocytes from foreign antigens
secretes hormones (thymopoietin, thymulin and thymosins)
to promote development and action of T lymphocytes
Very large in fetus; after age 14 begins involution
in elderly mostly fatty and fibrous tissue
Histology of Thymus
Spleen
Parenchyma appears in fresh specimens
as
red pulp: sinuses filled with erythrocytes
white pulp: lymphocytes, macrophages;
surrounds small branches of splenic artery
Functions
blood production in fetus
blood reservoir
RBC disposal
immune reactions: filters blood, quick to
detect antigens
Spleen
Defenses Against Pathogens
Nonspecific defenses - broadly effective, no
prior exposure
first line of defense
external barriers
second line of defense
phagocytic cells, antimicrobial proteins,
inflammation and fever
Specific defense - results from prior exposure,
protects against only a particular pathogen
third line of defense
immune system
External Barriers
Skin
toughness of keratin
dry and nutrient-poor
defensins: peptides, from neutrophils attack
microbes
lactic acid (acid mantle) is a component of
perspiration
Mucous membranes
stickiness of mucus
lysozyme: enzyme destroys bacterial cell walls
Subepithelial areolar tissue
tissue gel: viscous barrier of hyaluronic acid
hyaluronidase: enzyme used by pathogens to spread
Leukocytes and Cutaneous Defenses
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
Neutrophils
Phagocytize bacteria
Create a killing zone
degranulation
lysosomes discharge into tissue fluid
respiratory burst
toxic chemicals are created (O2.-, H2O2,
HClO)
Eosinophils
Phagocytize antigen-antibody
complexes
Antiparasitic effects
Promote action of basophils, mast
cells
Enzymes block excess inflammation,
limit action of histamine
Basophils
Aid mobility and action of WBCs by
release of
histamine (vasodilator)
blood flow to infected tissue
heparin (anticoagulant)
prevents immobilization of phagocytes
Monocytes
Circulating precursors to macrophages
Specialized macrophages found in
specific localities
dendritic cells
epidermis, oral mucosa, esophagus, vagina,
and lymphatic organs
microglia (CNS)
alveolar macrophages (lungs)
hepatic macrophages (liver)
Lymphocytes
Circulating blood contains
80% T cells
15% B cells
5% NK cells
Antimicrobial Proteins
Interferons
Complement system
Interferons
Secreted by certain cells invaded by
viruses
generalized protection
diffuse to neighboring cells and stimulate
them to produce antiviral proteins
activate natural killer cells and macrophages
destroy infected host cells
stimulate destruction of cancer cells
Complement System
Complement (C) proteins in blood that
must be activated by pathogens
Pathways of complement activation: C3
split into C3a and C3b
classical pathway
requires antibody; specific immunity
alternate pathway
nonspecific immunity
lectin pathway
nonspecific immunity
Complement System
Mechanisms of action
enhanced inflammation
phagocytosis
promoted by opsonization
cytolysis
membrane attack complex forms on target cell
immune clearance
RBCs carry Ag-Ab complexes to macrophages
in liver and spleen
Complement Activation
Fig. 21.15
Membrane Attack Complex
Complement proteins form ring in plasma
membrane of target cell causing cytolysis
Immune Surveillance
NK cells
destroy bacteria, transplanted cells, cells
infected by viruses, and cancer cells
release perforins and granzymes
Action of NK cell
Fig. 21.17
Inflammation
Defensive response to tissue
injury
1. limits spread of pathogens, then
destroys them
2. removes debris
3. initiates tissue repair
Cytokines
. small proteins regulate inflammation
and immunity; include
interferons, interleukins, tumor necrosis
factor, and chemotactic factors
Inflammation
Suffix -itis denotes inflammation of
specific organs
Cardinal signs
redness (erythema) caused by hyperemia
( blood flow)
swelling (edema) caused by capillary
permeability and filtration
heat caused by hyperemia
pain caused by inflammatory chemicals
(bradykinin, prostaglandins) secreted by
damaged cells, pressure on nerves
Inflammation
Three major processes
1. mobilization of body defenses
2. containment and destruction of
pathogens
3. tissue clean-up and repair
Mobilization of Defenses
Kinins, histamine, and leukotrienes are secreted
by damaged cells, basophils and mast cells
stimulates vasodilation that leads to hyperemia
causes redness and heat
local metabolic rate, promotes cell multiplication and
healing
dilutes toxins, provides O2, nutrients, waste removal
stimulates permeability of blood capillaries
allows blood cells, plasma proteins (antibodies, complement
proteins, fibrinogen) into tissue
clotting sequesters bacteria, forms scaffold for tissue repair
Mobilization of Defenses
Leukocyte
Deployment
margination
selectins cause
leukocytes to
adhere to blood
vessel walls
diapedesis
(emigration)
leukocytes
squeeze between
endothelial cells
into tissue space
Containment and Destruction of
Pathogens
Fibrinogen now in tissue clots, trapping pathogens
Heparin prevents clotting at site of injury
pathogens are in a fluid pocket surrounded by clot
Chemotaxis
leukocytes are attracted to chemotactic chemicals
Neutrophils are quickest to respond
phagocytosis
respiratory burst
secrete cytokines for recruitment of macrophages
and neutrophils
macrophages and T cells secrete colony-stimulating
factor to stimulate leukopoiesis
Tissue Cleanup
Monocytes the primary agents of
cleanup arrive in 8 to 12 hours, become
macrophages,
Edema venous flow, lymphatic flow
that favors removal of bacteria and
debris
Formation of pus
mixture of tissue fluid, cellular debris, dying
neutrophils and microbes
Tissue Repair
Blood platelets and endothelial cells in
injured area secrete a cytokine, PDGF,
that stimulates fibroblasts to multiply
and synthesize collagen
Facilitated by hyperemia that provides
materials needed and heat that
increases metabolism
Fibrin clot may provide a scaffold for
repair
Pain limits use of body part allowing for
repair
Fever
Defense mechanism: does more good than
harm
promotes interferon activity
accelerating metabolic rate and tissue repair
inhibiting pathogen reproduction
A cytokine, interleukin 1, called a pyrogen
secreted by macrophages, stimulates anterior
hypothalamus to secrete PGE which resets body
thermostat higher
> 105F may cause delirium, 111F- 115F, coma-death
Stages of fever
onset, stadium, defervescence
Course of a Fever
Specific Immunity
Specificity and memory
Cellular immunity: cell-mediated (T
cells)
Humoral immunity: antibody mediated
(B cells)
Passive and Active Immunity
Natural active immunity (produces memory cells)
production of ones own antibodies or T cells as a
result of infection or natural exposure to antigen
Artificial active immunity (produces memory
cells)
production of ones own antibodies or T cells as a
result of vaccination
Natural passive immunity (through placenta,
milk)
temporary, fetus acquires antibodies from mother
Artificial passive immunity (snakebite, rabies,
tetanus)
temporary, injection of immune serum (antibodies)
Antigens
Trigger an immune response
Complex molecules
> 10,000 amu, unique structures
proteins, polysaccharides, glycoproteins,
glycolipids
Epitopes (antigenic determinants)
stimulate immune responses
Haptens
too small, host macromolecule must bind to
them to stimulate initial immune response
Lymphocytes
Specific immunity depends on
lymphocytes
Life Cycle of T cells
Stem cells in red bone marrow
Mature in thymus
thymosins stimulate maturing T cells to
produce antigen receptors
immunocompetent T cell has antigen
receptors in place
Deployment
nave T cells colonize lymphatic tissue and
organs
Negative Selection of T cells
Immunocompetent T cells must be able
to
1. bind to RE cell
2. not react to self antigens
Failure results in negative selection via
. clonal deletion: destruction of offending T
cells
. anergy: inactive state, alive but
unresponsive
Leaves body in a state of self-tolerance
Only 2% of T cells succeed
Positive Selection of T cells
Immunocompetent T cells that are able
to
1. bind to MHC on RE cell
2. not react to self antigens
divide rapidly and form clones of T cells
with identical receptors for a specific
antigen
. these cells have not encountered target
antigens, constitute nave lymphocyte pool
Deployment - cells ready to leave
thymus
B Lymphocytes (B cells)
Sites of development
other fetal stem cells remain in bone
marrow
B cell selection
B cells should not react to self antigens
or suffer clonal deletion or anergy
Self-tolerant B cells form B cell clones
synthesize antigen receptors, divide rapidly,
produce immunocompetent clones
Antigen-Presenting Cells (APCs)
Function depends on major
histocompatability complex (MHC)
proteins
act as cell ID tag
B cells and macrophages, display
antigens to T cells
Antigen Processing
Interleukins
Chemical messengers between
leukocytes
Used by lymphocytes and APCs to
communicate
Cellular Immunity
T cells attack foreign cells and
diseased host cells; memory of Ag
Three classes of T cells
1. Cytotoxic T cells (Tc cells) carry out
attack
2. Helper T cells: help promote Tc cell
and B cell action and nonspecific
defense mechanisms
3. Memory T cells: provide immunity
from future exposure to antigen
TC cell Recognition
Antigen presentation
MHC-I proteins
found on nearly all nucleated body cells
display peptides produced by host cells
TC cell activation
1. binding of cytotoxic T cells (CD8 cells) to
abnormal peptides on MHC-I and
2. costimulation via a cytokine
. triggers clonal selection: clone of identical
T cells against cells with same epitope
TH cell Recognition
Antigen presentation
role of MHC-II proteins
found only on antigen presenting cells
display only foreign antigens
stimulate helper T cells (CD4 cells)
TH cell Activation
1. binding of helper T cells (CD4 cells)
to epitope displayed on MHC-II of APC
2. costimulation via a cytokine
3. triggers clonal selection
T cell Activation
Attack Phase: Role of Helper T Cells
Secretes
interleukins
attract neutrophils,
NK cells,
macrophages
stimulate
phagocytosis
stimulate T and B
cell mitosis and
maturation
Coordinate
humoral and
cellular immunity
Attack Phase: Cytotoxic T Cells
Only T cells directly attack enemy
cells
Lethal hit mechanism
docks on cell with antigen-MHC-I protein
complex
1. releases perforin, granzymes - kills target
cell
2. interferons - decrease viral replication
and activates macrophages
3. tumor necrosis factor: kills cancer cells
Cytotoxic T Cell Function
Cytotoxic T cell binding to cancer cell
Destruction of Cancer Cell
Memory
Memory T cells
following clonal selection some T cells
become memory cells
long-lived; in higher numbers than nave
cells
T cell recall response
upon reexposure to same pathogen,
memory cells launch a quick attack
Humoral Immunity
Recognition
B cell receptors bind antigen, take in and
digest antigen then display epitopes on its
MHC-II protein
After costimulation by TH cell, divide
repeatedly, differentiate into plasma cells,
produce antibodies specific to that antigen
Attack
antibodies bind to antigen, render it
harmless, tag it for destruction
Memory
some B cells differentiate into memory cells
Humoral Immunity - Recognition
B cells and Plasma cells
Antibody Structure
Antibody Classes
By amino acid sequences of C region of
antibody
IgA: monomer in plasma; dimer in mucus, saliva, tears,
milk, intestinal secretions, prevents adherence to
epithelia
IgD: monomer; B cell membrane antigen receptor
IgE: monomer; on mast cells; stimulates release of
histamines, attracts eosinophils; immediate
hypersensitivity reactions
IgG: monomer; 80% circulating, crosses placenta to
fetus, 2 immune response, complement fixation
IgM: pentamer, 10% in plasma, 1 immune response,
agglutination, complement fixation
Antibody Diversity
Immune system capable of as many as 1
trillion different antibodies
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
Neutralization
antibodies mask pathogenic region of antigen
Complement fixation
antigen binds to IgM or IgG, antibody changes
shape, initiates complement binding; primary
defense against foreign cells, bacteria
Agglutination
antibody has 2-10 binding sites; binds to multiple
enemy cells immobilizing them
Precipitation
antibody binds antigen molecules (not cells);
creates antigen-antibody complex that precipitates,
phagocytized by eosinophil
Agglutination and Precipitation
Humoral Immunity Responses
Hypersensitivity (Allergy)
Excessive immune reaction against antigens
that most people tolerate - allergens
Type I Antibody mediated (IgE), acute
reaction
Type II Antibody mediated (IgG, IgM),
subacute
Type III Antibody mediated (IgG, IgM),
subacute
Type IV Cell mediated, delayed
Type I (acute) Hypersensitivity
Anaphylaxis
occurs in sensitized people
allergen caps IgE on mast cells, basophils
release inflammatory chemicals
Asthma
most common chronic illness in children
inhaled allergens, histamines, bronchiole
constriction
Anaphylactic shock
bronchiole constriction, dyspnea,
vasodilation, shock, death; treatmentepinephrine
Type II Hypersensitivity
(Antibody-Dependent Cytotoxic)
IgG or IgM
binds to antigens on cells;
complement activation and lyses or
opsonization
may bind to cell surface receptors
and either interferes with function or
over-stimulate cell
Type III Hypersensitivity
(Immune Complex)
IgG or IgM form widespread antigenantibody complexes
Complexes precipitate and trigger
intense inflammation
involved in acute glomerulonephritis and
in systemic lupus erythematosus
Type IV Hypersensitivity
(Delayed)
12 to 72 hour delay
APCs in lymph nodes display antigens
to helper T cells, which secrete
interferon and cytokines that activate
cytotoxic T cells and macrophages
Cosmetic and poison ivy allergies haptens
TB skin test
Autoimmune Diseases
Failure of self tolerance
cross-reactivity
abnormal exposure of self-antigens
changes in structure of self-antigens
Production of autoantibodies
Immunodeficiency Diseases
Severe Combined
Immunodeficiency
Disease
hereditary lack of T
and B cells
vulnerability to
opportunistic
infection
Immunodeficiency Diseases
AIDS
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
HIV Structure
AIDS
Signs and symptoms
early symptoms: flulike chills and fever
progresses to night sweats, fatigue,
headache, extreme weight loss,
lymphadenitis
normal TH count is 600 to 1,200 cells/L of
blood but in AIDS it is < 200 cells/L
person susceptible to opportunistic infections
(Toxoplasma, Pneumocystitis, herpes simplex
virus, CMV or TB)
thrush: white patches on mucous membranes
Kaposi sarcoma: cancer originates in endothelial
cells of blood vessels causes purple lesions in skin
Kaposi Sarcoma
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 TH cells
Disrupt reverse transcriptase, inhibit assembly
of new viruses or their release from host cells
Medications
none can eliminate HIV, all have serious side-effects
HIV develops resistance, meds used in combination
AZT azidothymidine
first anti-HIV drug, inhibits reverse transcriptase
Protease inhibitors
inhibit enzymes HIV needs to replicate
now more than 16 anti-HIV drugs
