Copyright 2009, John Wiley & Sons, Inc. Chapter 22: The Lymphatic System and Immunity

Copyright 2009, John Wiley & Sons, Inc.

Chapter 22: The Lymphatic System and Immunity


Immunity or Resistance Ability to ward off damage or disease through our

defenses 2 types of immunity Innate or nonspecific immunity – present at birth

(Table 22.1, p891) No specific recognition of invaders, no memory

component 1st and 2nd line of defenses

Adaptive or specific immunity Specific recognition of invaders with a memory

component


Lymphatic system structure and function Consists of lymph (liquid), lymphatic

vessels, structures and organs containing lymphatic tissue, red bone marrow

Functions of the lymphatic system1. Drain excess interstitial fluid

2. Transport dietary lipid

3. Carry our immune responses


Components of the Lymphatic System

See page 833 for potential problem


Lymphatic vessels and lymph circulation

Vessels begin as lymphatic capillaries Closed at one end

Unite to form large lymphatic vessels Resemble veins in structure but thinner

walls and more valves Passes through lymph nodes

Encapsulated organs with masses and B and T cells

Definitions: T Cells = lymphocytes that mediate celluar immunity;

including helper and cytotoxoic (aka T lymphocytes). Origin – Thymus.

B Cells = (aka B lymphocytes) oversee humoral (fluids) immunity; their descendants differentiate into antibody-producing plasma cells. Origin – Red Bone marrow.

Lymphocyte – agranular white blood cell via bone marrow maturing in lymphoid organs of the body

Pluripotent stem cells - can develop into most of the specialized cells and tissues of the body, are self-renewing (see page Blood Chapter)

Antibody (protein), Antigen (foreign substance)


Lymphatic capillaries

Slightly large diameter than blood capillaries Unique one-way structure Permits interstitial fluid to flow in but not out Anchoring filaments pull openings wider when

interstitial fluid accumulates Small intestine has lacteal for dietary lipid

uptake Chyle is lymph with lipids

Lymphatic Capillaries**Blood Osmotic Pressure** - High = low blood volume = via dehydration


Lymph trunks and ducts

Vessels unite to form lymph trunks Principal trunks are the lumbar, intestinal,

bronchomediastinal, subclavian and jugular Passes from lymph trunks into 2 main

channels (thoracic and right lymphatic ducts) before draining into venous blood

Routes for drainage of lymph



Formation and flow of lymph More fluid filters out of blood capillaries than

returns to them by reabsorption Excess filtered fluid – about 3L/day – drains into

lymphatic vessels and become lymph Important function of lymphatic vessels to return

lost plasma proteins to blood stream Contain valves Same 2 “pumps” aiding venous return also used

Skeletal muscle pump – milking action Respiratory pump – pressure changes during breathing


Relationship of the Lymphatic System to the Cardiovascular System


Lymphatic tissues and organs

2 groups based on function

1. Primary lymphatic organs Sites where stem cells divide and become

immunocompetent Red bone marrow and thymus

2. Secondary lymphatic organs Sites where most immune response occurs Lymph nodes, spleen, lymphatic nodules


Thymus and Medulla

Thymus Outer cortex composed of large number of T cells

Immature T cells migrate here from red bone marrow where they proliferate and begin to mature

Dendritic cells derived from monocytes (largest WBC) assist in T cell maturation

Specialized epithelial cells help educate T cells through positive selection – only about 2% survive

Macrophages (phagocyte derived from monocyte, free or fixed) clear out dead and dying cells

Medulla More mature T cells migrate here from cortex More epithelial cells, dendritic cells and macrophages

Thymus shrinks with age from 70g in infants to 3g in old age


Thymus



Lymph nodes Located along lymphatic vessels (~600) Scattered throughout body Stroma = supporting connective tissue

Capsule, trabeculae, reticular fibers and fibroblasts Parenchyma – functional part

Outer cortex – aggregates of B cells called lymphatic nodules (follicles) – site of plasma cell and memory B cell formation

Inner cortex – mainly T cells and dendritic cells (one type of antigen presenting cell)

Medulla – B cells, antibody producing plasma cells from cortex, and macrophages


Lymph Lymph flows through a node in 1 direction only

Enters through afferent lymphatic vessels Directs lymph inward Lymph enters sinuses (irregular channels) Into medulla Medullary sinuses drain into efferent lymphatic vessels Conveys lymph, antibodies and activated T cells out of the

node Lymph nodes function as a filter

Foreign substances trapped Destroyed by macrophages or immune response of

lymphocytes


Structure of a Lymph Node


Spleen

Largest single mass of lymphatic tissue in the body

Stroma – capsule, trabeculae, reticular fibers, and fibroblasts

Parenchyma White pulp – lymphatic tissue (lymphocytes

and macrophages) B cells and T cells carry out immune

function Red pulp…


Red Pulp

Red pulp – blood-filled venous sinuses and splenic (Bilroth’s) cords – red blood cells, macrophages, lymphocytes, plasma cells, and granulocytes. Functions: Macrophages breakdown ruptured, worn out or

defective blood cells Storage of up to 1/3 of body’s platelet supply Production of blood cells during fetal life


Structure of the Spleen


Lymphatic nodules

Not surrounded by a capsule Scattered throughout lamina propria

(connective tissue) of mucous membranes lining GI, urinary, reproductive tract

Mucosa-associated lymphatic tissue (MALT) of respiratory tract

Most small and solitary Some larger – tonsils, Peyer’s patches,

appendix


Innate immunity

First line of defenses: Skin and mucous membranes Provide both physical and chemical barriers Physical barriers

Epidermis – closely packed, keratinized cells Periodic shedding

Mucous membranes Mucus traps microbes and foreign substances

Nose hairs trap and filter Cilia of upper respiratory tract propel trapped particles

up and out


Innate Immunity Fluids

Lacrimal apparatus of eye Washing action of tears Lysozyme breaks down bacterial cell walls – also present in

saliva, perspiration, nasal secretions, and tissue fluids Saliva washes mouth Urine cleanses urinary system Vaginal secretions defecation vomiting

Chemicals Sebaceous (oil) glands secrete sebum – protective film, acid Perspiration, gastric juice, vaginal secretions – all acidic


Second line of defenses: Internal defenses Antimicrobial substances

1. Interferons Produced by lymphocytes, macrophages, and fibroblasts

infected by viruses Prevents replication in neighboring uninfected cells

2. Complement Proteins in blood plasma and plasma membranes “complement” or enhance certain immune reactions Causes cytolysis of microbes, promotes phagocytosis,

contributes to inflammation


Internal Defenses

3. Iron-binding proteins Inhibit growth of bacteria by reducing available

iron

4. Antimicrobial proteins (AMPs) Short peptides that have a broad spectrum of

antimicrobial activity Can attract dendritic cells and mast cells that

participate in immune responses


Internal Defenses Natural Killer (NK) cells

Lymphocyte but not a B or T cell Ability to kill wide variety of infected body cells and

certain tumor cells Attack any body cell displaying abnormal or unusual

plasma membrane proteins Can release perforin (makes perforations) or granzymes

(induce apoptosis) Phagocytes

Neutrophils (type of WBC) and macrophages (from monocytes)

Migrate to infected area 5 steps in phagocytosis


Phagocytosis of a microbe

1 MicrobeCHEMOTAXIS

Phagocyte

Phases of phagocytosis

1


MicrobeCHEMOTAXIS

Pseudopod

Phagocyte

ADHERENCE2

1 MicrobeCHEMOTAXIS

Lysosome

Pseudopod

Phagocyte

ADHERENCE INGESTION2 3


1 MicrobeCHEMOTAXIS

Lysosome

Digestiveenzymes

Pseudopod

Phagocyte

ADHERENCE INGESTION

Plasmamembrane

DIGESTION

2 3

4


1 MicrobeCHEMOTAXIS

Lysosome

Digestiveenzymes

Pseudopod

Phagocyte

ADHERENCE INGESTION

Plasmamembrane

DIGESTION

KILLINGResidual body(indigestiblematerial)

Digested microbein phagolysosome

2 3

4

5



Inflammation

Nonspecific, defensive response of body to tissue damage

4 signs and symptoms – redness, pain, heat and swelling

Attempt to dispose of microbes, prevent spread, and prepare site for tissue repair

3 basic stages Vasodilation and increased blood vessel permeability Emigration Tissue repair


Vasodilation and increased permeability of blood vessels

Increased diameter of arterioles allows more blood flow through area bringing supplies and removing debris

Increased permeability means substances normally retained in the blood are permitted to pass out – antibodies and clotting factors

Histamine – released due to injury via mast cells (cell in areolar connective tissue), platelets, and Basophil (type of WBC)

Kinins – polypeptides, that VD and promote chemotaxis prostaglandins (PGs) – chemotaxis and enhance response of 1st two. leukotrienes (LTs) – chemotaxis, phagocyte attachment, via basophils. complement - similar to above traits and can also kill some bacteria.

Inflammation


Emigration of phagocytes

Depends on chemotaxis Neutrophils predominate in early stages but

die off quickly Monocytes transform into macrophages

More potent than neutrophils Pus – pocket of dead phagocytes and

damaged tissue


Adaptive immunity

Ability of the body to defend itself against specific invading agents

Antigens (Ags) – substances recognized as foreign and provoking an immune response

Distinguished from innate immunity by Specificity Memory


Maturation of T cells and B cells

Both develop from pluripotent stem cells originating in red bone marrow B cells complete their development in red bone marrow T cells develop from pre-T cells that migrate from red

bone marrow to the thymus 2 types - Helper T cells (CD4 T cells) and cytotoxic T cells

(CD8 T cells)

Immunocompetence – ability to carry out adaptive immune response Have antigen receptors to identify specific antigen

Mechanisms of Antigen Entrance Enters Skin - Lymph vessels – L. Nodes

Lymph nodules Enter mucus membrane – M.A.L.T. Enters blood – Spleen



Cell-mediated and antibody-mediated immunity





2 types of adaptive immunity

Cell-mediated Cytotoxic T cells directly attack invading antigens Particularly effective against intracellular pathogens, some

cancer cells and foreign tissue transplants Antibody-mediated (B cells stay in secondary LT)

B cells transform into plasma cells making antibodies (Abs) or immunoglobulins

Works against extracellular pathogens in fluids outside cells Helper T cells aid in both types

2 types of immunity work together


Clonal selection

Process by which a lymphocyte proliferates and differentiates in response to a specific antigen Clone – population of identical cells all recognizing the same

antigen as original cell Lymphocyte undergoes clonal selection to produce

Effector cell – active helper T cell, active cytotoxic T cell, plasma cell; all die after immune response

Memory cell – do not participate in initial immune response, respond to 2nd invasion by proliferating and differentiating into more effector and memory cells, long life spans (decades)


Antigens

Antigens have 2 characteristics Immunogenicity – ability to

provoke immune response Reactivity – ability of

antigen to react specifically with antibodies it provoked

Entire microbes may act as antigen

Typically, just certain small parts of large antigen molecule triggers response (epitope or antigenic determinant)



Diversity of antigen receptors

Human immune system able to recognize and bind to at least a billion different epitopes

Result of genetic recombination – shuffling and rearranging of a few hundred versions of several small gene segments

Major Histocompatibility Complex Antigens MHC or human leukocyte antigens (HLA) Normal function to help T cells recognize foreign or self Class I MHC (MHC-I) – built into all body cells except

RBCs Class II MHC (MHC-II) – only on antigen presenting cells

(APC)


Pathways of antigen processing

B cells can recognize and bind to antigens T cells must be presented with processed

antigens Antigenic proteins are broken down into peptide

fragments and associated with MHC molecules Antigen presentation – antigen-MHC complex

inserted into plasma membrane Pathway depends on whether antigen is outside or

inside body cells


Exogenous and Endogenous Antigens Exogenous antigens – present in fluid outside

body cells Antigen-presenting cells (APCs) include dendritic

cells, macrophages and B cells to… Ingest antigen, process, place next to MHC-II

molecule in plasma membrane, and present to T cells

Endogenous antigens – antigens inside any body cells Infected cell displays antigen next to MHC-I


Exogenous Antigens

Phagocytosis orendocytosis ofantigen

APCs present exogenous antigens in association with MHC-II molecules

Antigen-presentingcell (APC)

MHC-IIself-antigen

Antigenpeptidefragments

Key:

Exogenousantigen

1 Phagocytosis orendocytosis ofantigen

Digestion ofantigen intopeptide fragments

Phagosomeor endosome



MHC-IIself-antigen


Key:

1

2

Exogenousantigen






Synthesis of MHC-II molecules

MHC-IIself-antigen


Key:

Endoplasmicreticulum

1

3

2

Exogenousantigen






Packaging of MHC-IImolecules into a vesicle


MHC-IIself-antigen


Key:


1

4

3

2

Exogenousantigen






Vesicles containing antigenpeptide fragments andMHC-II molecules fuse



MHC-IIself-antigen


Key:


1

5

4

3

2

Exogenousantigen



Antigen peptidefragments bind toMHC-II molecules







MHC-IIself-antigen


Key:


1

5

6

4

3

2

Exogenousantigen



Antigen peptidefragments bind toMHC-II molecules







MHC-IIself-antigen


Key:


Vesicle undergoesexocytosis andantigen–MHC-IIcomplexes are insertedinto plasma membrane

1

5

6

7

4

3

2

Exogenousantigen

Endogenous Antigens


Cell-mediated immunity Activation of T cells

First signal in activation T-cell receptors (TCRs) recognize and bind to a specific

foreign antigen fragments that are presented in antigen-MHC complexes

CD4 and CD8 proteins are coreceptors Second signal required for activation

Costimulation – 20 known substances (cytokines, plasma membrane molecules)

May prevent immune response from occurring accidentally Anergy – recognition without costimulation (in both B and T cells)

leads to prolonged state of inactivity


Activation and clonal selection of helper T cells

Most that display CD4 develop into helper T cells (aka CD4 T cells)

Recognize exogenous antigen fragments associated with MHC-II molecules on the surface of an APC

After activation undergoes clonal selection Makes active helper T cells and memory helper T cells Active helper T cells secrete variety of cytokines

Interleukin-2 (IL-2) needed for virtually all immune responses (which triggers t-cell proliferation) via positive feedback

Memory helper T cells are not active cells – can quickly proliferate and differentiate if the antigen appears again


Activation and clonal selection of a helper T cell



Activation and clonal selection of cytotoxic T cells

Most that display CD8 develop into cytotoxic T cells (CD8 T cells)

Recognize antigens combined with MHC-I Maximal activation also requires presentation of

antigen with MHC-II to cause helper T cells to produce IL-2

Undergoes clonal selection Active cytotoxic T cells (cause apoptisis) attack

body cells Memory cytotoxic T cells do not attack but wait for a

(of the same) antigen to appear again

Activation and clonal selection of a cytoxic T cell


Elimination of invaders Cytotoxic T cells migrate to seek out and destroy infected

target cells Kill like natural killer cells Major difference is T cells have specific receptor for particular

microbe while NK cells destroy a wide variety of microbe-infected cells

2 ways to kill cells Granzymes cause apoptosis

Phagocytes then destroy the invading microbes Perforin and / or granulysin causes cytolysis of the microbe

Immunological surveillance Tumor antigens displayed on cancerous cells targeted by

cytotoxic T cells, macrophages and natural killer cells


Activity of cytoxic T cells


Antibody-mediated immunity

Activation and clonal selection of B cells During activation, antigen binds to B cell receptor (BCRs) B Cell can respond to unprocessed antigen (no APC) Response much more intense when B cell processes

antigen from APC Antigen taken into B cell, combined with MHC-II, moved to

plasma membrane, helper T cell binds and delivers costimulation (interleukin-2 and other cytokines)

B cell undergoes clonal selection Plasma cells secrete antibodies Memory B cells do not secrete antibodies but wait for

reappearance of antigen


Activation and clonal selection of B cells


Chemical structure of the immunoglobin (IgG) class of antibody

Antibodies There are 5 classes of antibodies:

• IgG – a monomer with two antigen-binding sites Comprises 80% of total antibody Only class able to cross the placenta Provides long-term immunity against bacteria and

viruses, by enhancing phagocytosis, neutralizing toxins, and triggers compliment systems

• IgA – a dimer with four antigen-binding sites prevalent in body secretions like sweat, tears, saliva, breast

milk and gastrointestinal fluids Provides localized protection of mucous membranes

against B and V See Table 22.3


Antibody actions

Neutralizing antigen – stops bacterial toxins or viral adhesion

Immobilizing bacteria – cilia or flagella Agglutinating and precipitating antigen Enhancing phagocytosis Activating complement

Defensive system of over 30 proteins Destroy microbes by causing phagocytosis, cytolysis, and

inflammation Acts in a cascade – one reaction triggers another 3 different pathways to ass. activate C3 C3 then begins cascade that brings about phagocytosis,

cytolysis, and inflammation


Complement activation and results of activation

1

C3

C3b C3a

C5

1

Microbe

Mast cell

C3

Microbe

Mic

robe

C3b C3a

C5Histamine

INFLAMMATION:Increase of blood vesselpermeability and chemotacticattraction of phagocytes

PHAGOCYTOSIS:Enhancement of phagocytosisby coating with C3b

2

1

Microbe

Mast cell

C3

Microbe

Mic

robe

C3b C3a

C5

C5b C5a

Histamine



2

3

1

Microbe

Mast cell

C3

Microbe

Mic

robe

C3b C3a

C5

C5b

C6

C7C8

C9

C5b C6 C7 C8 C9

C5a

Histamine



CYTOLYSIS:Bursting of microbe due toinflow of extracellular fluid through channel formed by membrane attack complex C5-C9

Membrane attackcomplex formschannel

Microbialplasmamembrane

Channel

2

3

4


Immunological memory Thousands of memory cells

exist after initial encounter with an antigen

Next time antigen appears can proliferate and differentiate within hours

Antibody titer measure of immunological memory Amount of Ab in serum

Primary response Secondary response faster

and stronger


Self-recognition and self-tolerance Your T cells must have

Self-recognition – be able to recognize your own MHC Self-tolerance – lack reactivity to peptide fragments from

your own proteins Pre-T cells in thymus develop self-recognition via

positive selection – cells that can’t recognize your own MHC undergo apoptosis

Self-tolerance occurs through negative selection in which T and B cells that recognize self peptide fragments are eliminated Deletion – undergo apoptosis Anergy – remain alive but are unresponsive


Development of self-recognition and self-tolerance

Nova Science Now

http://www.pbs.org/wgbh/nova/body/replacing-body-parts.html

Thymus


Lymph node


Spleen


Documents

Copyright 2009, John Wiley & Sons, Inc. Chapter 22: The Lymphatic System and Immunity