IMMUNE SYSTEM

Dr. Vince Scialli

BSC 1086

Rev. 7-18-08IMMUNOLOGY

NON-SPECIFIC

DEFENSES

LECTURE 4

Rev. 5-15-08 IMMUNE SYSTEM

Specialized body defense systemMade up of billions of cells ~ MOSTLY lymphocytes

Provides specific resistance to disease ~ IMMUNITY1. Microorganisms ~ pathogens & parasites

Bacteria

Viruses

Fungi

Parasites

2. Foreign tissue cells & Foreign Proteins AllergensBlood transfusions

Tissue transplants

3.Cancer CellsTypes of Immune Protection1. Innate ~ Natural ~ Local Non-specific Body DefensesIntact surface membranes ~ barriers to entry

Specialized cells & chemicals ~ mucous, NK

phagocytes

2. Acquired ~ Adaptive ~ Specific Defense System

Antibodies

Immune Modulators ~ interferons & cytokinesNON-SPECIFIC BODY DEFENSES

Barriers to entry ~ Prevents foreign invasion & infectionMechanisms of Protection1.Surface Membrane Barriers ~ first line of defensePrevent Pathogens from entering the body

Skin ~ HairDermal Secretions ~ sweat, sebum

Mucous Membranes

2.Internal Cellular & Chemical Defenses ~ second linePhagocytes ~ remove foreign debrisMacrophages

Neutrophils

Monocytes

Eosinophils

Natural Killer Cells ~ surveillance ~ T-cellsInterferons ~ increase resistance against virusComplement ~ destroys invader cell walls

Attract Phagocytes

Stimulate Inflammation

Inflammatory Response ~ many effectsFever ~ mobilizes defenses

Accelerates Repairs ~ Inhibits pathogensSURFACE MEMBRANE BARRIERS

First Line of Defense - Nonspecific defenses

Provide mechanical barrier for entry of pathogens

Produce chemical substances ~ enhance defense effects

SKIN ~ microorganisms CANNOT penetrate intact skin

Keratinized Epithelial Cells Keratin ~ resistant to toxins & enzymes produced

by bacteria

Sebum from sebaceous glands

Toxic to bacteria

pH of skin ~ 3 to 5 (acid) ~ Inhibits bacterial growth Most bacteria need alkaline mediaMUCOUS MEMBRANES ~ mucosa

Protective membranes ~ contain goblet cells

Line body passageways exposed to outside

Digestive Tract

Respiratory TractPROTECTIVE MECHANISMSDigestive Tract

Mucous ~ produced by mucous membranes in

intestine traps bacteria

Saliva ~ from salivary glands ~ in oral cavity

Contains Lysozyme ~ destroy bacteria

Lacrimal secretion ~ tears contains Lysozyme

Other Digestive Secretions ~ kills bacteria

HCl in Stomach . . . Proteolytic Enzymes in Intestine

Respiratory Tract

Mucous ~ produced by mucous membranes in

trachea & nose traps bacteria

Cilia ~ of upper respiratory tract & trachea trap dust

& bacteria ~ cough into mouth and swallow

Fine mucous-coated hairs ~ inside nose traps particles when inhaled ~ stimulates sneezing reflex

Urogenital System

Normal urine is slightly acid ~ pH < 7.0

Prevents bacterial growth ~ urinary acidifiersVaginal secretions are very acid ~ inhibits bacteria

CELLULAR & CHEMICAL DEFENSES

Second Line of Defense ~ Nonspecific defenses

PHAGOCYTES

Engulf & destroy pathogens & foreign debris ~ pac-man Attack invaders that cross epithelial barriers ~ clean upEnhanced by complement or antibodies which attach to bacteria & provide binding surface for phagocyteMicrophage ~ small ~ usually circulate in blood

Leave blood ~ move into damaged tissue

Neutrophils ~ abundant WBC ~ become phagocytic

Attack bacteria and other foreign

Eosinophils ~ Weak phagocytes ~ attack Parasitic

Mast Cell ~ phagocytic cell ~ releases histamineMacrophage ~ large ~ most important type of phagocyte

Derived from monocytes ~ large WBCs

Monocytes enter tissue & become enlarged

Free Macrophages ~ wander through tissue

Fixed Macrophages ~ stationary

Kupffer cells & Microglia CELLULAR & CHEMICAL DEFENSES

Natural Killer Cells ~ NK Cells

Immune Surveillance Cells ~ Police ~ Army

Constant monitoring of normal tissue by NK cells

Recognize & destroy abnormal or foreign cells

Large granular lymphocytes in blood & lymph

T-lymphocytes ~ from thymus

Non-specific ~ kill viruses, bacteria & malignant cells

Help fight cancerEarly Protection ~ Act before immune system is activated

Action is NON-phagocytic

First ~ Disrupt the membranes of those cells

they attack

Second- release cytolytic chemicals ~ PerforinCause breakdown of cytoplasm of cell foreign or abnormal cell being attacked ~ lysis

Antimicrobial Proteins

Enhance bodys ability to defend against invaders

Two MOST important:

Interferon & Complement

Interferon ~ produced by virus infected cells

Anti-viral ~ anti-microbial proteinCytokine ~ Produced by lymphocytes, macrophages, virus infected cells & other immune cellsPrevents viruses from multiplying in other normal adjacent body cellsActivates macrophages . . . Stimulates natural killer cellsComplement Anti-microbial circulating proteinComplement Activation ~ Complement FixationActivated after binding to antibody-covered antigens complexFIXES on bacteria surfaces & makes bacteria more susceptible to body defenses

Marks bacteria for phagocytosisIntensifies inflammatory & immune response

Enhances phagocytosis by phagocytesStimulates mast cells & basophils to release histamine & heparin

Attracts neutrophils & other WBCs to areaLyses microorganisms~ destroys microorganism

CELLULAR & CHEMICAL DEFENSES

Inflammation ~ Inflammatory Response

Tissue response to injury or breakdown

Response triggered in an area where injury occurs

Trauma

Heat or Burn

Irritating Chemicals

Infection ~ viral, bacteria, parasitic, fungiSigns or symptoms of inflammation

Four Cardinal Signs

Swelling

Redness ~ hyperemia

Pain

Heat

Impairment of Function (5th sign) ~ sometimesFunctions of Inflammation

1. Prevents spread of damaging agents

2. Disposal of cellular debris & pathogens

3. Helps to prepare for repair & regeneration4. MUST occur prior to the healing process

INFLAMMATORY PROCESS ~ Overview1. Vasodilation & Increased Vascular Permeability

Chemical Mediators ~ released from tissue

Histamine & HeparinKinins ~ plasma proteinsProstaglandins ~ attract platelets & swellingComplement ~ marks invadersLymphokines ~ cytokinesExudate formation ~ Pus or Purulent Exudate

Local edema

Pus ~ Purulent Exudate

Pain

2. Phagocyte Mobilization ~ army moves inLeukocytosis ~ increased WBC countMargination ~ neutrophil pavementing in vesselsDiapedesis ~ neutrophil emigration into tissueChemotaxis ~ macrophages remove cellular debrisREAD ABOUT INFLAMMATION DETAIL IN NOTES . . .

NOT COVERED IN LECTUREINTERNAL CELLULAR & CHEMICAL DEFENSES

FEVER

Increased body temperature common during pathogenic infection > 99.2 oFPyrogens ~ produced by macrophages & leukocytes

following pathogenic exposure

Stimulate febrile response ~ increase temperatureEffects of Fever ~ Good & Bad

Increase metabolic rate of tissue cells

Faster immune response & tissue repair

Inhibit some viruses & bacteria

NOT very comfortable

IMMUNOLOGY

SPECIFIC

DEFENSES

LECTURE 5 & 6

IMMUNE SYSTEM

Specific Body Immunity ~ Adaptive Immunity ~ AcquiredThird Line of Defense . . . A Very Specific Defense

Immune system recognizes something as foreignBody responds to immobilize, neutralize or remove foreign substancesProperties of Acquired Immunity1. Specificity ~ NOT general ~ NOT localImmunity recognizes & is directed against a particular foreign substance

Antigen ~ foreign substance ~ NOT SELF2. Versitle & Systemic

Not restricted to location of infection ~ systemic

Can respond to millions of different antigens

Tolerance ~ NO normal response to self

3. Memory

After initial exposure to an antigen . . .Sensitization ~ it remembers Immune system responds stronger the second time aroundFORMS OF IMMUNITY

Innate Immunity

Genetically Determined at Birth ~ species specific

NO prior exposure to foreign substance needed

Acquired Immunity

Produced by PRIOR EXPOSURE

Develop own or receive antibodies to foreign substance

Acquired Passively ~ Passive Immunity

Produced by transfer of antibodies from another

person or another source

Induced ~ Receive antibodies directly

Tetanus anti-toxin . . . Snake anti-venom

Natural ~ Receive antibodies from mother ~ milk

Acquired Actively ~ Active Immunity

Make OWN antibodies in response to antigens

Induced ~ Develops from artificial exposure

Vaccines

Acquired ~ from exposure to environment

Natural exposure/recoveryMECHANISMS OF ACQUIRED IMMUNITYCell Mediated Immunity ~ occurs within cellsFrom t-cells ~ T-lymphocytesDefends against abnormal pathogens or antigens within cells

Humoral Immunity ~ occurs outside cellsAntibody Mediated Immunity ~ classicalDefends against abnormal pathogens or antigens in body fluids outside cellsAntibodies produced by B-lymphocyte plasma cellAntibodies circulate freely in bloodCirculating antibodies bind to a pathogen or toxins produced by pathogen -----> neutralizationNeutralization ~ marks foreign substance for destruction, removal by phagocytes, or complementSpecific Body Defense Involves the Immune Response

Cell-mediated Immunity

Antibody Mediated ImmunityLong Term Immunity ~ memoryCELLS OF THE IMMUNE SYSTEM

T - LYMPHOCYTES ~ T-cells ~ Controls Immune System

From hemocytoblasts stem cells in bone marrow

Migrate to thymus & mature

Develop immunocompetence in thymus

Sub-populations:Cytotoxic T-cells ~ NK cells

T-helper cells

T-suppressor cells

Memory cells

Recognize foreign antigens & respondNon-antibody producing ~ stimulate cell-mediated immunity

Activated by macrophages ~ cytokinesMigrate to blood, lymph nodes, spleen & other organs of lymphatic system in ready position ~ memory

B - LYMPHOCYTES ~ B-cells

From hemocytoblasts stem cells in bone marrow

Important in humoral immunity ~ antibody mediated

Sub-populations:Plasma Cells ~ become antibodies

Memory cells

Migrate to blood, lymph nodes, spleen & other organs of lymphatic system in ready position ~ memoryANTIGENS ~ Ag

Substances recognized as foreign by body ~ NOT SELF

Usually large complex molecules

Proteins ~ strongest & MOST COMMON antigens

SOME Lipids . . . Nucleic Acids . . . Polysaccharides

Provoke immune response specific to foreign substance

Antigenic Determinant ~ portion recognized as foreign

Complete Antigens

Immunogenic ~ Protective & Neutralizing ~ GOOD

Stimulate a proliferation of specific B-lymphocytes to produce specific antibodies ~ lock & key fit

Reactive ~ Anaphylaxis & Hypersensitivity ~ BAD

React with specific lymphocytes & IgE antibodies

Partial Antigens ~ Haptens >>> ALLERGY

Small foreign particles NOT immunogenic by themselves

Become immunogenic antigens & reactive when linked to other body proteins in some people

Poison ivy

Animal dander Detergents Penicillin Cosmetics

Pollens Grasses & Weeds

Household Products FoodsThus . . . allergic in some individuals & not in others

MACROPHAGES ~ antigen presenting cells

Arise from Monocytes

Distributed throughout lymphoid organs

Engulf foreign particles ~ phagocytosisAntigen Presenting Cells ~ APCPresent antigenic determinants on surfaces of pathogen recognized as foreign

Present to T-cells Stimulates engulfment by macrophage

Secrete Cytokines

Chemicals which mediate cellular immunity

Activate T-cells to become phagocytic

Enhance Inflammatory response

Stimulate B & T-cell proliferation

Stimulate immature helper T-cells

Secrete bactericidal chemicals ~ kill bacteria

EG:

Interferons, interleukins, etc.

Antigen Presentation

T-cells MUST be activated by exposure to antigen

Antigen-Presenting Cells ~ Macrophages ~ APCs

Macrophages respond to activated T-cells

Release lysosomes ~ lyse foreign invader

Presents marked antigen on surface for destruction

MHC Proteins ~ Self Antigens ~ produced by SELF

MHC = major histo-compatability complex

Proteins on our own cells ~ Mark Self as NOT foreign

Only identical twins have same MHC proteins

If cells infected by foreign invader . . .

MHC proteins sense foreign proteins ~ warning flagMHC proteins become marked by foreign protein

Body MUST get rid of marked MHC complex before it causes harm

Self MHC Antigens are antigenic to other persons

Blood Transfusion ~ ABO blood type

Tissue or Organ Transplants

Could be recognized as foreign in autoimmune diseaseCELL MEDIATED IMMUNITY

Defends against abnormal cells & pathogens inside cells

Involves T-lymphocytes ~T-cellsNeeded where humoral immunity is ineffective or slowWhen pathogens attack quickly & replicate Target cells infected with viruses, bacteria, parasites & cancerous cells ~ all have abnormal foreign protein (not self) Types of T- lymphocytes ~ T-cells ~ many & diverseCytotoxic ~ Killer T-Cells ~ NK CellsKill invaded, damaged or cancerous cells ~ perforinHelper T Cells ~ the master switch

Promote development of other T-cells

Also stimulate B-cells to produce antibodies

Suppressor T Cells ~ the regulatorRelease chemicals which inhibit T & B-cellsEnd immune response ~ turn off Memory T-Cells ~ the ready positionTrigger differentiation into cytotoxic T-cells upon repeated exposure to same foreign antigen

CELL MEDIATED IMMUNITY

Antigen engulfed by Macrophage ~ becomes APC

Activates immature Helper T-cells

Antigen displayed on surface of infected cell ~ marked MHC

Activates immature Cytotoxic T-cells

Helper T Cells ~ the master switch

Become primed & activated by APC & MHC

APC ~ antigen presenting cells ~ macrophages

MHC ~ major histocompatability complex ~ markedRelease cytokines & lymphokines that attract other types of WBCs to infection site

Interferons & Interleukins

Stimulate proliferation of mature B & T cells ~ MAJORT- cells ~ cell mediated immunity

B-cells ~ humoral immunity & antibody productionEnhance nonspecific defense system & inflammationHIV (Aids Virus) ~ inhibits Helper T-Cells

Causes massive immunodeficiency

Cytotoxic T-cells ~ NK cells ~ the weapon Only T-cell that can attack & kill other cells Attack & lyse invading foreign protein ~ MHC markedRelease PERFORIN ~ kills target cell

Roam through body via blood and lymph ~ mobileSearch for MHC cells displaying foreign antigens Target infected cells (virus & bacteria), foreign cells, & cancer cells

NK Cell Lethal Hit Mechanism

1. Killer T-cell docks to target cell ~ APC ~ Macrophage2. PERFORIN is released from T-cell & inserted into target cell plasma membrane3. Killer T- cell detaches

4. PERFORIN molecules cause cell membrane lysis5. Other lethal mechanisms:

DNA fragmentation in target cells

Slow destruction of tumor cellsStimulation of macrophagesMemory T-Cells

Remain in reserve to differentiate into cytotoxic T-cells

Differentiation occurs immediately after a second attack

Overwhelms attacking organism before it can become established

Memory B-Cells

Remain in reserve to differentiate into plasma cells

Differentiation occurs immediately after a second attack

Very rapid antibody response occurs

Overwhelms attacking organism & neutralizes it before it can become established

Suppressor T-Cells ~ the regulatorRegulatory cells which inhibit activity of B & T-cellsStop immune response after foreign antigens have been destroyedSuppression occurs slowly

HUMORAL IMMUNE RESPONSE ~ Antibodies

Antibody Mediated Immunity ~ Humoral Immunity

Very specific antibody response to an antigen challenge

Formation of Antigen-Antibody Complex

ANTIGEN ~ Antigenic Determinates

Portion of antigen recognized as foreign

Could be many antigenic determinates on an antigen

Determines the immunogenicity of antigens

Stimulates production of Antibodies

ANTIBODIES ~ Immunoglobulins ~ Ig

Proteins produced by B-lymphocytes & plasma cells

Attach to antigenic determinants on antigen

Antibody Structure

Four chains arranged in a Y or T shape

Two short light & two long heavy chains

Tips are Variable . . . Heavy Chains are Constant

Specialized Binding Sites ~ very specific

For Antigens . . . Complement . . . Macrophage ACTIVE IMMUNITY ~ body response to antigen challenge

1.Naturally Acquired ~ antibodies self produced

Exposure to bacteria, viruses or other pathogens

2.Artificially Acquired ~ antibodies self produced

Induced from vaccines or vaccination

PASSIVE IMMUNITY ~ immediate but temporary ~ NO ANTIBODIES

PRODUCED

Antibodies received directly from an external source

Antibodies in mothers milk or in serum infusion

Tetanus Anti-toxin antibodies

Snake Anti-venom antibodiesAntigen-Antibody Complex Formation ~ STEPS1. Antigen Challenge ~ Primary ChallengeFirst encounter between B-lymphocytes & invading foreign substance ~ the antigen

B-cell lymphocytes ~ recognize antigen challenge

B-lymphocyte multiplies into army of sensitized B-cells

Sensitization ~ B-cell ActivationOccurs in spleen, lymph nodes or lymphoid tissue

2. Primary Response ~ a humoral antibody response

Differentiate into a specific antibody against the antigen

B-cells become Plasma Cells ~ Takes 3 - 6 days LAG

Secrete specific antibodies ~ last for 4 - 5 daysB-cells become Memory B - cells for future attacksREADY in case of a second invasion by antigen

3. Future Antigen Challenge ~ Secondary Challenge

The next time same antigen invades body by exposure

4. Secondary Response ~ Anamnestic ResponseMemory B - cells mount an immediate humoral response if specific antigen is ever encountered againSECONDARY RESPONSE ~ Anamnestic Response

Results in MANY MORE antibodies produced VERY RAPIDLY

Overwhelms secondary foreign invader

Memory B-cells provide body with IMMUNE MEMORY

Memory can last a life time ~ but decreases with age Secondary response involves an encounter of memory B-cells with a previous recognized antigenAnamnistic Antibody Response is . . .

1. Faster ~ immediate

Response occurs in only 2 - 3 days ~ NOT 5 - 7 days2. Stronger

Plasma level antibodies rise to much HIGHER levels

than the primary response3. Longer

Plasma antibody levels REMAIN HIGH for weeks to months ~ not 4 - 5 days4.More Effective

Antibodies bind with greater affinity to antigen as compared to primary response

Overwhelms the invading antigen or attacker

Antibody ClassificationHeavy chain structure determines way antibody is secreted & how it is distributed in body

Heavy Chain = Constant Segment

Five major classes

IgM early protecting antibody ~ first antibodies

IgA local immunity antibody ~ in glandular secretions

IgG MOST common in serum ~ 80%

IgD B-cell activation

IgE antibodies of allergic reactions ~ histamine

Mechanism of Antibody Action

Antibodies function to inactivate & tag foreign invaders1. Neutralization

Simple mechanism

Antibody blocks binding sites on virus or bacteria or on toxins secreted by pathogenic organismsPrevents toxins from binding to receptor sites on tissue cellsAntigen-antibody complex engulfed & phagocytized2. Agglutination ~ ABO BloodAntibodies bind to more than one antigen ~ clumpingAntigen-antibody complex become cross linked forming matrix or latticeMatrix engulfed & phagocytized

3. Precipitation

Antibodies cause soluble antigenic molecules to become cross-linked with other soluble antigenic moleculesAntigen-antibody complexes settle out of solution as precipitatesPrecipitates engulfed & phagocytized

4. Complement Fixation and Activation MOST COMMON of primary mechanism of antigen-antibody interactionAntibodies bind to antigenic determinant target sites on pathogenResults in complement fixation & activationChemicals released attracts macrophages & enhances inflammatory response & lysisComplement coated invaders attracted to B-lymphocytesIMMUNE SYSTEM IMBALANCES

Hypersensitivities & Allergy ~ COMMONIntense reaction to allergen AFTER an initial sensitivityInitial exposure ----> release of very reactive IgE antibody Second encounter with antigen results in antigen-antibody reaction with MOSTLY IgECommon foreign antigens:

Bee sting

Fire ants

Poison ivy

Animal dander

Symptoms caused by Histamine release from mast cells & basophils

Vasodilation of blood vessels

Constriction of bronchioles

Immediate hypersensitivity ~ anaphylaxis

IgE induced

Anaphylactic Shock ~ serious

Sub-acute hypersensitivity ~ less severe

IgM or IgG induced

Delayed hypersensitivity ~ cell mediated response ~ slow

Skin Allergy contact dermatitisOrgan Transplants

Graft Rejection of foreign organ transplant is COMMONDue to cell mediated response ~ cytotoxic T-cells attack foreign graftOrgans from others recognized as foreign ~ NOT SELFMust immunosuppress first ~ with cortisoneInfections are major complicationsImmunodeficiencies

Involves many syndromes AIDS

Body destroys its own Helper t-cells

Body CANNOT mount humoral or cell mediated response

Overwhelming infections fatal if not treated (antibiotics)Autoimmune Diseases

Body recognizes itself as foreign ~ NOT SELF

Mounts an immune response against self antigens ~ MHC

Auto-antibodies ~ antibodies against self

Examples:Graves Disease ~ anti-TSH antibody

Rheumatoid arthritis

Multiple Sclerosis

Immune System ~ Chapter 22 ~ 9/10/201413