Week 2 Chapter 9

Inflammation and Immunity

The Immune System

Cells of the Immune System

Source: http://www.biologymad.com/

Components of the Immune System

Immunity: protection from infectious disease
Involves coordinated response of cells and molecules Protection provided two lines of defense:

1. Innate defenses
Require no previous exposure to effectively respond to antigen NK cells Phagocytic cells
Neutrophils Macrophages

2. Specific defenses
Respond more effectively to 2nd exposure Highly restricted in ability to recognize antigens B and T lymphocytes

Types of immunty
Non-specfic (Doesn't identify enemy) Specific (identify enemy)

Physical Barriers - Skin - Normal Flora -Mucous membrane

Inflammation -Neurtrophils -NK cell -Monocyctes (Macrophages)

Immune response -T lymphocytes (identifies ad kills with a toxic) -B Lymphocytes (identifies and kills with an antibody)

Components of the Immune System

Skin and mucous membranes Mononuclear phagocyte system Bone marrow
Monocytes and macrophages Site of hematopoiesis from stem cells Site of B cell and NK cell maturation Spleen; houses many macropheges Thymus gland Lymph nodes and lymphatics Tonsils, Peyer patches in GI tract (MALT)
T cell maturation and selection

Lymphoid system

Mononuclear Phagocyte System (Cont.)

Fig 9-1

SECONDARY LYMPHOID ORGANS (CONT.)

Lymph Nodes Contain large numbers of B cells, T cells, and macrophages Lymph fluid flows through for immune cells to filter, detect, and react to foreign material

Found primarily in neck, groin, axillae, thorax, abdomen

Spleen Located under diaphragm on left side of body Largest lymphoid organ Macrophages filter out foreign substances and old red blood cells Lymphocytes contact blood-borne antigens (then may migrate to other lymphoid organs) Peyer Patches (Intestine) Produce antibodies to microorganisms that invade mucosal tissue

Lymphoid System (Cont.)

Fig 9-3

COMPONENTS OF THE IMMUNE SYSTEM (CONT.)

Leukocytes
Mediate

inflammation and immunity Locate and eliminate pathogens and foreign molecules

Chemical mediators
Aid

leukocytes

Complement Kinins Clotting

factors (helps to stop blood vessel bleeding) Cytokines (activate gene controlled cell death)

LEUKOCYTES
Primary effector cells of immune system Formed from stem cells in bone marrow Neutrophils Eosinophils Basophils and mast cells Monocytes and macrophages Dendritic cells Lymphocytes

Natural killer cells T Lymphocytes B Lymphocytes

Leukocytes Contd
Neutrophils Are the early responders to infection Phagocytosis (eat pathogen) and also release chemicals to destroy micro orgs

Attracted to areas of inflammation and bacterial products by chemotactic factors (complement, cytokines) Basophils and Mast Cells; release cytokins Basophils in circulation, mast cells in connective tissues Have receptors for IgE (immunoglobilin)

Can cause damage to normal tissue

When bind allergen, degranulate and begin inflammatory response ~ allergic reactions, also chronic inflammation

Mediator

Vasodilation

Increased permeability

pain

other

Histamine

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Major mediator of inflammation. Produces the effect of inflmtn

Bradykinins
prostaglandins

Enhance effects of the mediators. They often targeted in turns of eliveating the inflammation

Mediator: a molecule that works in the process Histamine: is a very strong vasodilator Brady: when they form they re also strong vasodilators, they induce pain they bind directly to the pain receptors +: Yes -: Nothig

LEUKOCYTES CONTD
Monocytes

Immature macrophages that circulate in bloodstream; become macrophages when enter tissue Large 2phagocytes; can ingest several times as many microorganisms than neutrophils May proliferate at site of inflammation Cell surface covered with variety of receptor proteins

Macrophages; developed from monocytes

e.g. Fc receptors bind to constant fragment of Abs which aid phagocytosis (opsinization coating with anti bodies and proteins of the bacteria)

Release cytokines

Promote inflammation, activate other WBCs

Antigen presentation

MONOCYTES AND MACROPHAGES

Fig 9-7 Fig 9-9

Summary function of marcophages

1. They are powerful phagocytes 2. Are predominant in the inflammation 3. Important secretory function !!!Without looking at the previous slides explain in detail what these three points mean!!!!!!!

LYMPHOCYTES
Three major types NK cells: function in innate immunity Released into circulation Important in killing tumor and virally infected cells without previous exposure T cells: responsible for specific adaptive immunity Mature in thymus Two major classes T helper cells: have CD4 proteins Cytotoxic T-cells: have CD8 proteins B cells: responsible for specific adaptive immunity Remain in bone marrow during maturation Recognize Ag with B cell receptor (BCR) Process and present Ag to T H Clone to produce Ab in response to Ag binding, cytokines and T H cell stimulation (require co-stimulation)

T and B Lymphocytes

Fig 9-12

Fig 9-15

Lymphocyte Maturation

Antibody Mediated Immunity B Cells Mature in Marrow Stem Cells of the Bone Marrow Released into blood, spleen, lymph

Cell Mediated Immunity T Cells Mature in Thymus

Identify Antigens

Macrophages carry foreign cells to T Helper cells T Helper cells (Th) produce proteins

B Cells Replicate to form Plasma cells B Memory Cells

Release Antibodies

Secrete Interleukins Replicate Cytotoxic (killer) T (Tc) Cells Effector Tc Cells Tm Memory Cells

Secrete lymphokines Stimulates Phagocytosis

CHEMICAL MEDIATORS OF IMMUNE FUNCTION

Complement
Complement

cascade Membrane attack complex (MAC) Opsinization

Kinins (bradykinin)
Vasodilation,

permeability, pain

Clotting factors Cytokines and chemokines

Coordinate

and enhance both innate and specific immune defenses

Complement

INNATE DEFENSES AND INFLAMMATION

Three purposes of inflammatory response
1.
2.

3.

Neutralize and destroy invading and harmful agents Limit spread of harmful agents to other tissue Prepare damaged tissue for repair

Five Cardinal Signs of Inflammation Redness Swelling Heat Pain Loss of function

Inflammation Continued
Tissue Injury Release of Histamine, Bradykinin and PGs Vasodilatio n Heat and Redness Capillary Permeability Capillaries leak fluid and protein (exudate) Pain and Swelling Blood clot walls-off injured area Chemotaxi s Release of Leukocytosis inducing factor Increased WBCs in blood

neutrophils and monocytes migrate to injured area

Phagocytosis by neutrophils and macrophages

Increased metabolic rate, oxygen and nutrient delivery

Healing

Inflammation
Increased vascular permeability Emigration of leukocytes

Emigration or diapedesis Chemotaxis

Phagocytosis; clean up dead cells Healing Mediators

Histamine Bradykinins Prostaglandins (PGs)

Fig 9-19

CARDINAL EVENTS OF INFLAMMATION

PROSTAGLANDINS
Prostaglandins (PGs) are fatty acids produced from the phospholipid derivative arachidonic acid The enzyme cyclooxygenase (COX) converts arachidonic acid into difft PGs, each with their own biological activities Two difft COX enzymes have been characterized: COX I produces PGs that regulate blood flow to the kidneys and stimulate mucous production in the digestive tract COX II produces PGs that are involved in pain, inflammation, fever and uterine contractions Aspirin and other NSAIDs inhibit both COX I and COX II renal and gastrointestinal abnormalities along with the antiinflammatory, anti-fever and analgesic effects Hence, some current anti-inflammatory drugs are being developed that are specific COX II inhibitors e.g. celebrex, Valdecoxib Other anti-inflammatory drugs that are active in the PG pathway include steroids that inhibit the release of arachidonic acid from phospholipid stores

Innate Defenses and Inflammation (Cont.)

Types of Inflammation Acute
Short in duration, lasting less than 2 weeks Involves a discrete set of events

Chronic

More diffuse Extends over longer period May result in scar tissue formation or deformity Granulomas
Gould

INFLAMMATION MANIFESTATIONS
Inflammatory Exudates Transport leukocytes and antibodies Dilute toxins and irritating substances Transport nutrients for tissue repair Types

Serous exudate
Serosanguineous

drainage

Fibrinous exudate Purulent exudate

abscess

Hemorrhagic exudate

Systematic Manifestations of Inflammation

Localized
Occur with acute and chronic inflammation Can lead to systemic involvement

Systemic
Fever, neutrophilia, lethargy, muscle catabolism

Erythrocyte sedimentation rate (ESR) The systemic effects responses are generated by cytokines released by WBCs:
Fever, neutrophilia, lethargy, muscle catabolism

Erythrocyte sedimentation rate (ESR)

Specific Adaptive Immunity

Specific immune system capable of
Recognizing foreign invaders with specificity Destroying foreign invaders Retaining memory of the encounter

Allows for more effective defense (adaptive) to be achieved after subsequent exposure

MHC CLASS I PRESENTATION

Nucleated cells continuously produce MHC I proteins (on the rough endoplasmic reticulum (ER) where
they)

combine with peptide fragments in cytoplasm for presentation on cell surface MHC I -peptide complexes inspected by TCcells Binding of TC-cells to MHC I-antigen complex triggers release of enzymes and perforins which lyse the target cell Produce immune response

Abnormal proteins

MHC I peptide antigens have intracellular origin Viral protein common source of foreign MHC I

MHC Class I Presentation Contd

MHC CLASS II PRESENTATION

MHC II Proteins

Present antigens obtained from extracellular sources Extracellular antigens must first be ingested by antigen-presenting cell

Antigen presenting cell degrades Ag into fragments in endocytic vesicle MHC II proteins form complexes wit Ag from phagosome on way to plasma membrane T helper cells detect MHC II antigen complexes

MHC Class II Presentation (Cont.)

T Helper Cells

+) (CD4

Recognize antigen in association with MHC II molecules CD4 protein necessary to enable T helper cells to bind to MHC II protein; T-cell receptors recognize specific antigen presented T-cell receptors bind to corresponding antigen and generate signaling cascade in T helper cell cytoplasm
Fig 9-31

Cytotoxic T Cells (CD8+)

Recognize antigen displayed in association with MHC I protein CD8 protein needed for MHC I binding
TCR specifically recognizes presented antigen

Binding
Triggers cytokine release need costimulation by IL-2 cytokines and costimulators usually present on surfaces of presenting and responding cells

Activated cytotoxic T cells

Proliferate into memory cells and effector cells

Cytotoxic T Cells (CD8+) (Cont.)

Perforins
Proteins manufactured in cytotoxic T cell Store in cytoplasm granules with granzymes

Granules (vesicles)
Bind to target cell, migrate to contact site, and release to target cell membrane

Antigen Recognition by B Cells

Activation requires help from T helper cell
Ag binding to B-cell receptor (variable region) necessary but not enough stimulus to produce effective B-cell clone B cell engulfs, processes, and presents antigen to T helper cells Initiates cell-to-cell contact between B and complementary T cell helper

Fig 9-37

Antigen Recognition by B Cells (Cont.)

Cell-to-cell binding interactions stimulate intracellular signaling pathways in B- and T-helper cell Promote clonal expansion and differentiation B cells need specific cytokines to proliferate and begin antibody synthesis
become plasma cells

On the subsequent exposure, the Memory Cells rapidly clone and produce many more antibodies
The Secondary response is greater than the Primary Response
Fig 9-44

ANTIBODY STRUCTURE (CONT.)

Five classes

Serve different immune functions During the course of an Ab response, can undergo class switching ~ specific cytokines

Still recognizes the same Ag Presence of one class over another indicates stage in course

IgG IgM IgA IgD IgE

Fig 9-41

 IgG
Most common type; Smallest; Easily escapes bloodstream to enter interstitial fluid. Protection and immunity, neutralizes. Can cross placenta.

IgM
10% of circulating immunoglobulins; Mostly found in intravascular pool; cannot penetrate capillary wall (pentamer); First to be produced on exposure to antigens or after immunization; Major antibody found on B-cell surfaces; Works best to activate complement. First responder.

 Ig A
Produced by plasma cells located in tissue under skin/mucous membranes Primarily found in saliva, tears, tracheobronchial secretions, colostrum, breast milk, and GI/GU secretions. Can cross placenta.

IgD
Found in tiny amounts in serum Located primarily on B cell membranes (with IgM); fxn not clearly understood Thought to be cellular antigen receptor that acts to stimulate B cell to: Multiply, Differentiate, Secrete other specific immunoglobulins

 IgE
Bound by Fc tail to receptors on basophil and mast cell surfaces Trace amounts identified in serum Helps in immunity against helminthic parasites; responsible for initiating inflammatory and allergic reactions Functions as signaling molecule Causes mast cell degranulation when antigen detected at mast cell surface Type 1 hypersensitivity

Antibody Functions
1. Precipitation 2. Agglutination 3. Neutralization 4. Opsonization 5. Complement activation Each arm of immunoglobulin Y structure can bind an antigenic epitope Allows antibodies and antigens to bind together into large insoluble complexes that precipitate out of body fluids
enhance function of innate phagocytic cells

Fig 9-43

What Antibodies do:

TYPES OF IMMUNITY
Specific Immunity can be acquired in four ways:
1. Active natural immunity: exposure to an antigen

stimulates specific immune cells to produce antibodies and memory cells 2. Active artificial immunity: a specific antigen is purposefully introduced into the body to stimulate the specific immune cells e.g. immunization (i.e. vaccination): dead or attenuated pathogens are 3. Passive natural immunity: antibodies are passed from introduced mother to infant in utero and in breast milk 4. Passive artificial immunity: injection of antibodies developed in one person or animal to another e.g. rabies antiserum, snake antivenom, hepatitis B treatment
Note the differences between active and passive immunity

VACCINES
Vaccine: an artificially introduced microbial antigen capable of inducing active immunity without causing disease A good vaccine: is highly immunogenic stimulates both Ab and cellular immunity (long-term) is safe and free of side effects is administered appropriately Vaccines are composed of either: live attenuated microorganisms inactivated (killed) microorgs modified exotoxins (toxoids) recombinant (genetically engineered) antigens
Organism Disease Vaccine Type

Bacterial Vaccine:
Corynebacterium diphtheriae Diphtheria Toxin

Clostridium tetani
Berdetella pertusis Haemophilus influenzae Streptococcus pneumoniae Neisseria meningitidis Salmonella typhi Vibro cholerae Bacillus anthracis

Tetanus
Whooping cough Menigitis Pneumonia Menigitis Typhoid fever Cholera Anthrax

Toxin
Killed organisms Capsular polysaccharide Capsular polysaccharide Capsular polysaccharide Killed or live organisms Killed organisms Killed organisms

Viral Vaccines:
Rubeola virus Mumps virus Rubella virus Varicella-zoster virus Poliovirus Influenza virus Hepatitis A virus Hepatitis B virus Rabies virus Variola virus Measles Mumps German measles Chickenpox Poliomyelitis Influenza Hepatitis A Hepatitis B Rabies Smallpox Live virus Live virus Live virus Live virus Live or killed virus Killed virus Killed virus Recombinant Killed virus Live virus

Compiled by Joe Gordon