Copyright © 2010 Pearson Education, Inc. Lymphatic System: Functions Returns interstitial fluid and leaked plasma proteins back to blood Together with

Copyright © 2010 Pearson Education, Inc.

Lymphatic System: Functions

• Returns interstitial fluid and leaked plasma proteins back to blood

• Together with lymphoid organs provide the structural basis of immune system

Copyright © 2010 Pearson Education, Inc. Figure 20.1

Lymphaticsystem:Lymph ductLymph trunkLymph node

Lymphaticcapillary

Bloodcapillaries

Lymphaticcollecting vessels, with valves

HeartArterial systemVenous system

Tissuefluid

Tissue cell Bloodcapillaries

Lymphaticcapillaries

(a) Structural relationship between a capillary bed of the blood vascular system and lymphatic capillaries.

Filaments anchoredto connective tissue

Fibroblast in looseconnective tissue

Endothelial cell

Flaplike minivalve

(b) Lymphatic capillaries are blind-ended tubes in which adjacent endothelial cells overlap each other, forming flaplike minivalves.

Copyright © 2010 Pearson Education, Inc. Figure 20.2a

Cervical nodesEntrance of rightlymphatic duct into vein

Internal jugular vein

Entrance of thoracicduct into vein

Thoracic duct

Cisterna chyli

Lymphaticcollecting vessels

Axillary nodes

Aorta

Inguinal nodes

Regionallymph nodes:

(a) General distribution of lymphatic collecting vessels and regional lymph nodes.

Drained by the rightlymphatic ductDrained by thethoracic duct


Lymphoid Cells

• Lymphocytes - warriors of immune system

• Two types

• T cells (T lymphocytes)

• B cells (B lymphocytes)


Lymphocytes

• T cells and B cells protect against antigens

• Anything the body perceives as foreign

• Bacteria and their toxins; viruses

• Mismatched RBCs or cancer cells

• Provides a proliferation site for lymphocytes

• Furnishes a surveillance vantage point


Macrophage

Medullary sinus

Reticular fiber

Lymphocytes

Reticular cells onreticular fibers


Afferentlymphaticvessels

Efferentlymphaticvessels

Capsule

Trabeculae

Hilum

Cortex• Lymphoid follicle

• Germinal center• Subcapsular sinus

Medulla:

• Medullary cord• Medullary sinus

Follicles

Trabecula

Subcapsularsinus

Capsule

Medullarycords

Medullarysinuses

(b) Photomicrograph of part of a lymph node (72x)(a) Longitudinal view of the internal structure

of a lymph node and associated lymphatics


Spleen

• Largest lymphoid organ

• Functions

• Site of lymphocyte proliferation and immune surveillance and response

• Cleanses the blood of aged cells and platelets and debris

Copyright © 2010 Pearson Education, Inc. Figure 20.6c

(c) Photograph of the spleen in its normal position in the abdominal cavity, anterior view.

Diaphragm

Spleen

Adrenalgland

Splenicartery

Pancreas

Leftkidney


Thymus

• Size with age

• Infants, in inferior neck

• Increases in size, most active during childhood

• Stops growing during adolescence and then gradually atrophies

• It functions strictly in T lymphocyte maturation


Cortex

Medulla

Thymic (Hassall’s)corpuscle


Tonsil

Tonsillar crypt

Germinal centersin lymphoid follicles

Pharyngeal tonsil

Palatine tonsilLingual tonsil


Immunity

• Resistance to disease

• Immune system has two parts

• Innate (nonspecific) defense system

• Adaptive (specific) defense system


Immunity

1. Innate defense system has two lines of defense

• First line of defense is external body membranes (skin and mucosae)

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

• Inhibit spread of invaders

• Inflammation is its most important mechanism



Immunity

2. Adaptive defense system

• Third line of defense attacks particular foreign substances

• Takes longer to react than the innate system

• Innate and adaptive defenses are deeply intertwined


Innatedefenses

Surface barriers• Skin• Mucous membranes

Internal defenses• Phagocytes• NK cells• Inflammation• Antimicrobial proteins• Fever

Humoral immunity• B cells

Cellular immunity• T cells

Adaptivedefenses

Copyright © 2010 Pearson Education, Inc. Figure 21.2b

Lysosome

Phagosome(phagocyticvesicle)

Acidhydrolaseenzymes

(b) Events of phagocytosis.

1 Phagocyteadheres to pathogens or debris.

2 Phagocyte formspseudopods that eventually engulf the particles forming a phagosome.

3 Lysosome fuseswith the phagocytic vesicle, forming a phagolysosome.

4 Lysosomal enzymes digest the particles, leaving a residual body.

5 Exocytosis of thevesicle removes indigestible andresidual material.


Inflammatory Response

• Cardinal signs of acute inflammation:

1. Redness

2. Heat

3. Swelling

4. Pain

(And sometimes 5. Impairment of function)


Tissue injury

Release of chemical mediators(histamine, complement,kinins, prostaglandins, etc.)

Vasodilationof arterioles

Increased capillarypermeability

Local hyperemia(increased blood

flow to area)

Locally increasedtemperature increasesmetabolic rate of cells

Leaked protein-richfluid in tissue spaces

Leaked clottingproteins form interstitialclots that wall off area

to prevent injury tosurrounding tissue

Temporary fibrinpatch forms

scaffolding for repair

Healing

Capillariesleak fluid

(exudate formation)

Attract neutrophils,monocytes, andlymphocytes to

area (chemotaxis)

Release of leukocytosis-inducing factor

Leukocytosis (increased numbers of whiteblood cells in bloodstream)

Leukocytes migrate toinjured area

Margination (leukocytes cling to

capillary walls)

Diapedesis (leukocytes pass through

capillary walls)

Phagocytosis of pathogensand dead tissue cells

(by neutrophils, short-term;by macrophages, long-term)

Area cleared of debris

Pus may form

Signs of inflammation

Initial stimulus

Physiological response

Result

Innate defenses Internal defenses

Possible temporarylimitation of

joint movement

Heat Redness Pain Swelling


Phagocyte Mobilization

• Neutrophils, then phagocytes flood to inflamed sites


Innatedefenses

Internaldefenses

Leukocytosis.Neutrophils enter bloodfrom bone marrow.

Margination.Neutrophils clingto capillary wall.

Diapedesis.Neutrophils flatten andsqueeze out of capillaries.

Chemotaxis.Neutrophilsfollow chemicaltrail.

Capillary wallBasementmembraneEndothelium

Inflammatorychemicalsdiffusingfrom theinflamed siteact as chemotacticagents.

1 2 3

4


Antimicrobial Proteins

• Interferons (IFNs) and complement proteins

• Attack microorganisms directly

• Hinder microorganisms’ ability to reproduce


Spontaneous activation

Stabilizing factors (B, D, and P)

No inhibitors on pathogensurface

Alternative pathway

Enhances inflammation:

Insertion of MAC and cell lysis(holes in target cell’s membrane)

Complementproteins(C5b–C9)

Pore

Membraneof target cell

+

+

stimulates histamine release,increases blood vessel permeability, attracts phagocytes by chemotaxis, etc.

complex

Opsonization:

+

coats pathogensurfaces, which enhances phagocytosis

Antigen-antibody complexClassical pathway


Fever

• Systemic response

• Leukocytes secrete pyrogens

• Pyrogens reset the body’s thermostat upward

• High fevers are dangerous because heat denatures enzymes

• Benefits of moderate fever

• Causes the liver to sequester iron and zinc

• Increases metabolic rate, speeds up repair


Adaptive Defenses

• Adaptive immune response

• Is specific

• Is systemic

• Has memory

• Two separate overlapping arms

1. Humoral (antibody-mediated) immunity

2. Cellular (cell-mediated) immunity


Antigens

• Substances that can mobilize the adaptive defenses and provoke an immune response

• Most are large, complex molecules not normally found in the body (nonself)


Antigenic determinantsAntigen-bindingsitesAntibody A

Antibody BAntibody C

Antigen


Self-Antigens

• Protein molecules (self-antigens) on the surface of cells

• Antigenic to others in transfusions or grafts

• Example: MHC proteins

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


Cells of the Adaptive Immune System

• Two types of lymphocytes

• B lymphocytes (B cells)—humoral immunity

• T lymphocytes (T cells)—cell-mediated immunity

• Antigen-presenting cells (APCs)

• Do not respond to specific antigens


1

2

3

Red bone marrow: site of lymphocyte origin

Secondary lymphoid organs: site ofantigen encounter, and activation to becomeeffector and memory B or T cells

Primary lymphoid organs: site ofdevelopment of immunocompetence as B orT cells

Lymphocytes destined to become T cellsmigrate (in blood) to the thymus and develop immunocompetence there. B cells develop immunocompetence in red bone marrow.

Immunocompetent but still naive lymphocytes leave the thymus and bone marrow. They “seed” the lymph nodes, spleen, and other lymphoid tissues where they encounter their antigen.

Antigen-activated immunocompetent lymphocytes (effector cells and memory cells) circulate continuously in the bloodstream and lymph and throughout the lymphoid organs of the body.

Redbone marrow

Bone marrow

Thymus

Lymph nodes,spleen, and otherlymphoid tissues

Immaturelymphocytes

Adaptive defenses Humoral immunityCellular immunity


Clonal Selection

1. B cell is activated when antigens bind to its surface receptors

2. Bound antigen enters cell

3. Stimulated B cell grows to form a clone of identical cells bearing the same antigen-specific receptors(T cells required to help B cells achieve full activation)


Fate of the Clones

• Most clone cells become plasma cells

• secrete antibodies at rate of 2000 per second for 4 - 5days

• Secreted antibodies

• Circulate in blood or lymph

• Bind to free antigens

• Mark the antigens for destruction

Copyright © 2010 Pearson Education, Inc. Figure 21.11 (1 of 2)

Primary response(initial encounterwith antigen)

Antigen bindingto a receptor on aspecific B lymphocyte (B lymphocytes with non-complementary receptors remain inactive)

Proliferation toform a cloneActivated B cells

Plasma cells(effector B cells)Secretedantibodymolecules

Memory B cell—primed to respond to same antigen

Adaptive defenses Humoral immunity

Antigen


Immunological Memory

• Primary immune response

• Occurs on first exposure to specific antigen

• Lag period: three to six days

• Peak levels of antibody reached in 10 days

• Antibody levels then decline


Immunological Memory

• Secondary immune response

• Occurs on re-exposure to same antigen

• Sensitized memory cells respond within hours

• Antibody levels peak in 2 – 3 d at higher levels

• Antibodies bind with greater affinity

• Antibody level remain high for weeks to months


Primary response(initial encounterwith antigen)

Antigen bindingto a receptor on aspecific B lymphocyte(B lymphocytes withnon-complementaryreceptors remaininactive)

Proliferation toform a cloneActivated B cells

Plasma cells(effector B cells)

Secretedantibodymolecules

Memory B cell—primed to respondto same antigen

Clone of cellsidentical toancestral cells

Subsequentchallenge by same antigenresults in more rapid response

Secondary response(can be years later)

MemoryB cells

Plasmacells

Secretedantibodymolecules


Antigen


Time (days)

Anti-bodiesto A

First exposureto antigen A

Second exposure to antigen A;first exposure to antigen B

Anti-bodiesto B

Primary immuneresponse to antigenA occurs after a delay.

Secondary immune response toantigen A is faster and larger; primaryimmune response to antigen B issimilar to that for antigen A.


PassiveActive

Humoralimmunity

Artificiallyacquired

Injection ofimmune serum (gamma globulin)

Naturallyacquired

Antibodiespass from mother tofetus via placenta; or to infant in her milk

Artificiallyacquired

Vaccine;dead or attenuated pathogens

Naturallyacquired

Infection;contact with pathogen


Antigen-bindingsite

Stemregion

Hingeregion

Light chainconstant regionDisulfide bond

Light chainvariable region

Heavy chainconstant region

Heavy chainvariable region

(a)


Inactivates by

Antigen Antibody

Fixes and activates

Enhances Enhances Leads to

Phagocytosis

Chemotaxis

Histaminerelease

Inflammation Cell lysis

Agglutination(cell-bound antigens)

Precipitation(soluble antigens)

Neutralization(masks dangerousparts of bacterial

exotoxins; viruses)

Complement

Antigen-antibodycomplex



Monoclonal Antibodies

• Commercially prepared pure antibody

• Proliferate indefinitely and have the ability to produce a single type of antibody

• Used in research, clinical testing, and cancer treatment


Cell-Mediated Immune Response

• T cells defend against intracellular antigens

• Major types of T cells

• CD4 cells become helper T cells (TH)

• CD8 cells become cytotoxic T cells (TC) that destroy cells harboring foreign antigens

• Other types of T cells

• Regulatory T cells (TREG)

• Memory T cells


Maturation

CD4cell

T cellreceptor

T cellreceptor

CD4

Helper T cells(or regulatory T cells)

Cytotoxic T cells

APC(dendritic cell)

APC(dendritic cell)

Activation Activation

Memorycells

CD8cell

CD8

Lymphoidtissues andorgans

Blood plasma

Thymus

Class I MHCprotein

Class II MHCprotein

Effectorcells

Adaptive defenses Cellular immunity

Immaturelymphocyte

Red bone marrow


T Cell Activation

• APCs migrate to lymph nodes to present their antigens to T cells

• T cell activation is a two-step process

1. Antigen binding

2. Co-stimulation


1 Dendritic cell engulfs an exogenous antigen, processes it, and displays its fragments on class II MHC protein.

2 ImmunocompetentCD4 cell recognizes antigen-MHC complex. Both TCR and CD4 protein bind to antigen-MHC complex.

3 CD4 cells are activated,proliferate (clone), and become memory and effector cells.

Viral antigen

Dendriticcell

Class lI MHCproteindisplayingprocessedviral antigenCD4 protein

Immunocom-petent CD4T cell

ActivatedhelperT cells

Helper Tmemory cell

T cell receptor(TCR)

Cloneformation

Adaptive defenses Cellular immunity


Roles of Helper T(TH) Cells

• Play a central role in the adaptive immune response

• Once primed by APC presentation of antigen, they

• Help activate T and B cells

• Induce T and B cell proliferation

• Activate macrophages and recruit other immune cells

• Without TH, there is no immune response


(a)B cell (being activated)

MHC II proteinof B cell displayingprocessed antigen

IL- 4 and othercytokines

Helper T cellCD4 protein

T cell receptor (TCR)

Activated helperT cell 1

2

TH cell binds with the self-nonself complexes of a B cell that has encountered its antigen and is displaying it on MHC II on its surface.

TH cell releases interleukins as co-stimulatory signals to complete B cell activation.

TH cell help in humoral immunity

Copyright © 2010 Pearson Education, Inc. Figure 21.19b

Class II MHCprotein

Class IMHC protein

APC (dendritic cell)

IL-2

CD4 protein

CD8 T cell

Helper T cell

CD8protein

(b)

1

2

Previously activated TH cell binds dendritic cell.

TH cell stimulates dendritic cell to express co-stimulatory molecules (not shown) needed to activate CD8 cell.

3 Dendritic cell can now activate CD8 cell with the help of interleukin 2 secreted by TH cell.

TH cell help in cell-mediated immunity


Roles of Cytotoxic T(TC) Cells

• Targets

• Virus-infected cells

• Cells with intracellular bacteria or parasites

• Cancer cells

• Foreign cells (transfusions or transplants)


Organ Transplants

• Four varieties

• Autografts: from one body site to another in the same person

• Isografts: between identical twins

• Allografts: between individuals who are not identical twins

• Xenografts: from another animal species


Prevention of Rejection

• Depends on the similarity of the tissues

• Patient is treated with immunosuppressive therapy

• Corticosteroid drugs to suppress inflammation

• Antiproliferative drugs

• Immunosuppressant drugs

• Many of these have severe side effects


Immunodeficiencies

• Congenital and acquired conditions that cause immune cells, phagocytes, or complement to behave abnormally


Acquired Immune Deficiency Syndrome (AIDS)

• Cripples the immune system by interfering with the activity of helper T cells

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


Autoimmune Diseases

• Immune system loses the ability to distinguish self from foreign

• Production of autoantibodies and sensitized TC cells that destroy body tissues

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


Anaphylactic Shock

• Systemic response to allergen that directly enters the blood

• Basophils and mast cells are throughout the body

• Systemic histamine releases may cause

• Constriction of bronchioles

• Sudden vasodilation and fluid loss from the bloodstream

• Hypotensive shock and death

• Treatment: epinephrine

Documents

Copyright © 2010 Pearson Education, Inc. Lymphatic System: Functions Returns interstitial fluid and leaked plasma proteins back to blood Together with