The Lymphatic System and Immunity: Chpt. 22

Pathogen:Fungus:

Bacteria

Virus

Immunity:

Consists of:1. network of lymphatic vessels2. lymph:

similar to interstitial fluid

3. lymphatic tissues & organs

4. Lymphocytes, phagocytes &

Functions of Lymphatic System:1. Production, maintenance, and distribution of lymphocytes

2. Return of fluid and solutes from interstitial fluid

3. Transport of hormones, nutrients

Distribution & Structure of Lymph Vessels - form a 1-way system1. Lymphatic Capillaries (lacteal):

similar to systemic blood capillaries except lymphatic capillaries are more

lacteals also have thinner walls

are found near systemic capillaries

endothelial cells overlap and leave “flaps” which open when fluid P> in interstitial space allowing interstitial fluid to enter lymph. cap

Proteins and large debris (including bacteria, viruses and cancer cells) easily enter lymph vessels

However, lymph takes detours through lymph nodes

2. Small Lymphatic Vesselscollect lymph from lymphatic capillaries transport to larger lymphatic vessels

larger lymphatic vessels have valves to prevent backflow of lymph

often found near arteries and veins

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superficial and deep lymphaticssuperficial in subcutaneous layerdeep near deep arteries/veins of skeletal muscles

lymphangitis:

3. Lymphatic Trunks: collect lymph from the lymphaticsmajor trunks – Lumbar

Intestinal

Bronchomediastinal

R,L Subclavian

R,L Jugular

Trunks drain lymph into 1 of 2 ducts:1. Right Lymphatic Duct: collects lymph from the ,

, and trunks

2. Thoracic Duct: largestbegins as an enlarged sac termed the Cisterna Chyli located at L1 which collects lymph from the and trunks.

As thoracic duct runs superiorly, accepts lymph from the , , and trunks.

Each duct empties lymph into the subclavian veins (R and L)

lymphangitis: inflamed lymphatic vessels

Lymph Transport:∙ low pressure

∙ lymph moves one-way

∙skeletal muscle contractions, pressure changes thorax during breathing

∙ valves

∙ arterial pulses

∙ lymphedema: lymph cannot drain due to blockage in limblimb becomes swollen – higher risk of infection in area

Lymphoid Cells:• account for 20-30% of all circulating leukocytes (WBCs)• 3 types of lymphocytes:

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1. T cells (thymus-dependent) – 80% of circulating lymphocytesprovide cell-mediated immunity or cellular immunity

cytotoxic T cells – attack foreign cells & virus infected cellshand-to hand combat

helper T cells – stimulate T & B cells

suppressor T cells –

2. B cells (bone marrow-derived) – 10-15% of circulating lymphocytesprovide antibody-mediated immunity or humoral immunity

when encounter antigen become activated & form 2 types of clones (sensitive to the antigen)plasma cells and memory cells

plasma cells make antibodies (immunoglobulins) to attack the antigen

memory cells:

3. NK cells (natural killer or large granular) – 5-10% of circulating lymphocytesprovide immunological surveillance – “police”

Note: lymphocytes circulate in blood, bone marrow, spleen, thymus and lymph tissue.Lymphocyte lifespan 4 - 20 years – new lymphocytes made in bone marrow and lymph tissue

4. Macrophages:

5. Dendritic cells: “Antigen Presenting Cells”

Lymphopoiesis: occurs in bone marrow, thymus and peripheral lymph tissue

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Lymph Tissues• connective tissue with lymphocytes• lymphoid or lymphatic nodules densely packed in connective tissue of respiratory, digestive and urinary tracts

• examples includeMALT (mucosa-associated lymphatic tissue): Peyer's patches and appendix

Tonsilsring of lymph. tissue around entrance to pharynx (throat) pharyngeal tonsil or adenoid:palatine tonsils: throatlingual tonsils: back of tongue

Lymph Organs1. Lymph nodes: bean shaped

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filter and purify lymph before it enters blood (removes 99% of antigens)

Each node has a fibrous capsule, a cortex, & a medulla

Cortex contains dendritic cells, macrophages and T cells

Medulla mostly contains B cells and plasma cells

Lymph enters lymph nodes via afferent lymph vessels & exits via efferent vessels.

There are fewer efferent vessels than afferent which

Largest lymph nodes found in the inguinal, axillary, submandibular & cervical regions of body

Hemocytoblast generates 2 main types of lymph stem cells –

1.) One group remains in bone marrow: produces immature B cells & NK cells

B cells migrate into lymph nodes, spleen & lymph tissue

NK cells circulate through peripheralTissues

2.) The other migrates to the thymus gland to form T cells

T cells develop in the thymus glandand then are released to the blood

travel to bone marrow, peripheraltissues, lymph tissues & lymphorgans

Sometimes the nodes are overwhelmed and become painful/swollenTonsillitis:

Lymphadenopathy: chronic or excessive enlargement of lymph nodes

Lymph nodes can also become secondary cancer sites (lymphoma)

2. Thymus Glandlocated in mediastinumgrows throughout childhood and is largest at puberty then atrophies

secretes hormones (thymosins) cause T lymphocytes to become immunocompetent

3. Spleensoft, blood rich organ on lateral border of stomach (9-11th rib)largest lymphatic organ

Functions of the spleen:1. spleen cleanses blood: phagocytosis

2. Stores some iron from breakdown of RBCs

3. Initiates the immune response (immune surveillance) of B & T cells

4. Stores platelets

spleen surrounded by fibrous capsule

inside of spleen contains red pulp: regions containing macrophages & dendritic cells

white pulp: contains lymphocytes

Injury to spleen: impact on left abdomen can tear capsule

Splenectomy:

Immunity:

Defenses: Nonspecific vs. SpecificNonspecific: same response to any threatSpecific: lymphocytes respond to antigens

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Nonspecific: (p. 776 figure 22-10): prevent entrance and/or limit spread of pathogens

1. Physical Barriers: keep organisms out of bodyskin: first line of defense

keratin and hair

sweat, sebaceous glands: secretions contain lysozyme and antibodies

mucus membranes in respiratory, digestive, urinary and reproductive tracts

HCl in stomach

2. Phagocytes:first line of cellular defenseattack & remove microorganisms before lymphocytes detect their presence

microphages: neutrophils and eosinophils normally in blood

leave blood and travel to injured/infected tissue

respond quickly

neutrophils become activated which increases metabolic rate (respiratory burst) and they produce nitric oxide & H2O2 to destroy engulfed pathogens.

also release cytokines to attract other neutrophils and macrophages to area

macrophages: larger, derived from monocytes (leukocyte)

Activated Macrophages:1. Adhere to pathogen & engulf it to destroy it in lysosome

Opsonization: complement or antibodies coat pathogen

2. bind to pathogen to "hold" it for other cells to help destroy it

3. release toxic chemicals (cytokines) to destroy pathogen (tumor necrosis factor, defensins)

fixed vs. free: fixed include Langherhans cells, microglia and kupffer cells

free or mobile: dust cells and those that circulate in blood

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Movement of microphages & free macrophages:• diapedesis – move through capillary walls out of blood

• chemotaxis

• adhesion: phagocyte must first attach to target

3. Immunological surveillance: cell (pg. 778 figure 22-11)natural killer (NK) cells: recognize and destroy abnormal cells (via antigens) in peripheral tissues

can destroy many types of cells

recognizes abnormal cell, adheres to it, produces and releases perforins (exocytosis) which destroys cell membrane of abnormal cell (rotates golgi apparatus to “aim” at cell and then releases perforin proteins)

4. Interferons (cytokines): alpha (), beta() and gamma () interferons

•small proteins released from activated lymphocytes, macrophages and cells infected with virus

•releases antiviral proteins to healthy cells – inhibit viral replication

•also stimulate NK cells and macrophages

5. Complement:• 11 plasma proteins

• once activated this system causes a complement cascade which eventually:1. forms MAC

2. release of histamine

3. attracts neutrophils and macrophages to area

4. facilitates phagocytosis – coating of complement proteins & antibodies makes it easier for phagocyte to adhere/engulfAssist with opsonization

6. Inflammatory Response:4 signs of inflammation:

vasodilation of blood vessels:

mast cells release histamine - increased permeability of blood vessels:

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leukotrienes & prostaglandins also released for inflammation

why beneficial? (see tissue notes)

7. Fever: temperature >37.2o C or 99o Fpyrogens: circulating proteins, toxins, antibody complexes cause hypothalamus to reset

temperature –

Endogenous pyrogens = interleukin-1 (IL-1) pyrogen released by active macrophagesa cytokine

beneficial because: increases metabolism, accelerates defensesinhibits some viruses and bacteria

Immunity (specific resistance)Responds to specific antigens – with coordinated action of T and B cells

Cellular Immunity:T cells (lymphocytes) : provide cell-mediated immunity

directly kill cellsindirectly by releasing cytokines

Humoral Immunity: B cells (lymphocytes): provide antibody-mediated immunity

Antigens:Proteins, polysaccharides, lipids, nucleic acidsMobilize immune system

Complete Antigens:Immunogenicity: Stimulate antibody formationReactivity: react with activated lymphocytes & antibodies

Antigenic determinants:

Hapten: incomplete antigenUsually doesn’t trigger immune response unless attached to proteinPoison ivy & animal dander

Self-Antigens: MHC Proteins: glycoproteins

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MHC Class I: proteins in cell membranes of all nucleated cells

-peptide displayed is synthesized within the cell (endogenous)

-displays peptides from cellular protein recycling (T cells ignore normal peptides)

- if cell is infected it will display the protein and T cell will recognize it and be activated – abnormal peptides activate T cell

also occurs during organ rejection

alert T cells to pathogens hiding inside cell

MHC Class II: only in APC and lymphocytes

Engulf and break down (process) antigens which come form foreign antigens (exogenous) which are then presented on the cell membrane.

APC: responsible for activating T cells against foreign cells & proteins

Dendritic cells can migrate to lymph node to activate T cells

Tolerance: immune system doesn’t respond to some antigens – ignores self-antigens and nonharmful antigens

Forms of Immunity:

Innate:

Acquired: Active vs. Passive

Passive Immunity: • naturally acquired

• artificially acquired (induced)

Active Immunity:• naturally acquired

• artificially acquired (induced)

Specific Defenses and Immunity: T and B cells

T Cells: Cell-Mediated Immunityprotect against abnormal cells or pathogens inside of our cells

3 Types of T cells:1.) Cytotoxic: TC or CD82.) Helper T: TH or CD43.) Suppressor T: TS

1. Cytotoxic: TC or CD8directly attack foreign cells or cells infected with virusesuse physical and chemical methods

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BUT: must be activated first (this is done by antigen presentation through MHC proteins or HLAs)Note: must be costimulated to be activated

T cells respond to either class I or class II antigens (page 789 figure 22-19)CD8 cells activated by class I antigensCD4 respond to class II antigens

Once activated form killer T cells and memory T cellsKiller T cells release chemicals to destroy cell

perforins

lymphotoxin

activate genes to stimulate cell to die (apoptosis)

slow response time

Memory T cells: Produced with cytotoxic T cells

immediately form cytotoxic T cells if exposed to same antigen again

2. Suppressor TS

release suppression factors to limit the immune responseinhibit responses of T and B cells

Act after initial immune response

3. Helper: TH or CD4once activated divide to form: active helper T cells & memory helper T cells

Activated helper T cells release cytokines which:

1. stimulate production & maturation of killer T cells2. attract macrophages to area3. stimulate and attract NK cells4. stimulate B cell to make antibodies

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B Cells: antibody-mediated or humoral immunity

B cells attack antigen by producing specific antibodies

B cell must first be activated or sensitized (usually in lymph node) - Requires helper T cell

Once sensitized produces clones that will become:1. plasma cells: make and secrete antibodies against the antigen

(2000 molecules/second)

Antibodies released into interstitial fluid & circulate in blood or lymph2. memory cells: remain for second exposure to antigen

Immunoglobulins: antibodiesStructure: 2 heavy parallel polypeptide chains: heavy & light

Each chain has constant (stem) and variable region

Constant region determines antibody class

Antigen-antibody complex

5 classes: IgG, IgE, IgD, IgM and IgA

IgG: most numerous in plasma (accounts for aprx. 80%)protects against viruses, bacteria & toxinsMain antibody of secondary responseOnly one to cross the placenta

IgE: triggers release of histamine & inflammatory chemccals from mast cellsallergic reactions, asthmachronic parasitic infections in GI tract

IgM: first antibody secreted during primary response

IgA: found in saliva, mucus, tears

Complete antigen vs. hapten:Complete antigen binds to both antigen binding sites

Hapten: Small molecule that triggers immune response by linking to other protein (carrier) Dangers of Haptens

Antibodies produced will attack both hapten and its linked protein If carrier is “normal”

Antibody attacks normal cells For example, penicillin allergy, poison ivy, detergents, etc.

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Antibody Effects:1. Neutralization: bind to pathogen site so pathogen cannot bind to other cells

effective at preventing viral and toxin binding to host cells

2. Agglutination and precipitation: binds to several antigens and clumps them together

3. Activate complement

4. Attract phagocytes

5. Opsonization: antibodies surround/coat pathogen so phagocytes can grab and ingest it more easily

6. Stimulate inflammation: via mast cells

7. Prevent bacteria and viruses from adhering to cellsmainly IgA in saliva etc. prevents binding/entrance of pathogens

Primary vs. Secondary Responses to Antigen Exposure

Immunological competence: the ability to produce an immune response after exposure to an antigenForm antibodies (antibody titer)

Note: monoclonal antibodies used in research, clinical testing, treatment

Important Cytokines (pg. 799 table 22-3)1. Interleukins (IL-2 etc)

produces by leukocytes and macrophagesstimulate T and B cell activity

increase antibody productiontrigger fever and inflammation

2. Interferonsresistance to viral infections

stimulate NK cells and macrophages

3. Tumor necrosis factors (TNFs)slow tumor growth, can kill tumor cellscause fever, increase neutrophil production

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stimulate T cells activation

4. Perforin

5. Lymphotoxins

6. Leukotrienesstimulate inflammation

Response to Bacterial Infection

Defense Against Bacterial and Viral Pathogens

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Summary of Immune Response

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Clinical Aspects of the Immune System

1. Immunodeficiency diseases:

Severe combined immunodeficiency disease (SCID)

AIDS: - HIV infection

Immunosuppressive Drugs:

2. Autoimmune Disorders:B cells produce autoantibodies

Can be due to decreases suppressor T cells

Increased stimulation of helper T cells

Tissue damage

Examples: thyroiditis, rheumatoid arthritis, insulin-dependent diabetes mellitus, multiple sclerosis, lupus3. Allergies

excessive immune response to antigen (allergens)

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usually IgE antibody response

may be geneticresponse releases histamine, heparin, cytokines etc.

4 categories of allergic reactions:1.) Type I: immediate hypersensitivity

Rapid & severe response to antigen (allergen)

IgE binds to mast cells & triggers release of histamineincreased capillary permeability cause swelling (hives)smooth muscles contract in respiratory passageways - difficulty breathing

Can be local or systemicLocal: histamine: runny nose, watery eyes, itchy, hives

If allergen inhaled: bronchoconstrictionTx: antihistamine, benedryl, corticosteroids

Systemic

anaphylaxis: (pg. 801 figure 22-26) allergen activates mast cells throughout the body – when allergen is in the blood

vasodilation can be so great as to drop BP and cause anaphylactic shockbronchoconstriction restricts air flowTx: Epi

2.) Type II (subacute hypersensitivity): cytotoxic reactionsCaused by IgG and IgMSlower onset (1-3 hours, longer duration)Blood transfusion reaction

3.) Type III: immune complex disordersAntigens widely distributed throughout the bodyResults in numerous antibody-antigen complexes, can’t be removedCauses inflammation and cell lysis by neutrophilsGlomerulonephritis, systemic lupus erythematosus, and rheumatoid arthritis.

4.) Type IV: delayed hypersensitivitySlowest to appear (1-3 days)Caused by cytokines (antihistamines don’t work), corticosteroids helpAllergic contact dermatitis (caused by haptens: poison ivy, detergents, etc)Tine test for tuberculosis

Stress and the Immune System: caused by CRH and ACTH: glucocorticoidssecreted to limit response- chronic secretion interferes with immune function

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1. depression of inflammatory response:

2. decreased number and activity of phagocytes:

3. inhibition of interleukin secretion:

4. decreased production of antibodies

Aging and the Immune System Immune system diminishes with age, increasing vulnerability to infections and cancer

Thymic hormone production is greatly reduced T cells become less responsive to antigens Fewer T cells reduces responsiveness of B cells Immune surveillance against tumor cells declines

Nervous & Endocrine System adjust sensitivity of Immune System

How to have a healthy immune system:

Don’t be too clean!! The “hygiene hypothesis”

Rest/De-stress

Diet

Supplements

Laugh↑ number & activity of cytotoxic T cells that attack viral infected cells, cancer & tumor cells↑ number of NK cells↑ activated T cells↑ IgA↑ gamma interferon↑antibody formation↓ cortisol

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