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Blood Physiology - Lecture 3

Immune System (IS)

Dr. AM Zagrean

The Immune System

Immune organs

Central/ primary- bone marrow and

thymus- generation of lymphocytes

Peripheral/ secondary- trapping Ag+

specific (adaptive) immune responses

are initiated+ maintainance of

lymphocytes- lymph nodes, spleen,

GALT, MALT, BALT

Lymph node

Spleen

GALT, BALT, MALT

GALT= gut-associated lymphoid

tissues- tonsils, adenoids, appendix,

Peyer’s patches (small int)

BALT= bronchial-associated lymphois

tissue

MALT= mucosal- associated lymphoid

tissue

Lymph vessels

IMMUNITY

The body is continuously exposed to microorganisms (bacteria, viruses, fungi, parasites) at different levels: skin, mouth, respiratory passageways, eyes, intestinal tract, genital & urinary tracts

Immunity*: a condition of being able to resist a particular

disease especially through

preventing development of a pathogenic microorganism or

by counteracting the effects of its products

*Derives from the latin immunitas, meaning freedom from public service

(i.e., the military draft).

Overview of Immune System

In two words: specificity and memory

IS serves 3 major functions:

1. Protections from pathogens: microorganisms,

chemicals, foreign bodies – non-self, antigens

2. Removal of dead or damaged tissue and cells

3. Recognition and removal of abnormal cells

Every organism needs host defense.

Every organism needs to distinguish self from non-self.

Defense mechanisms can be toxic to self if not properly controlled.

Tolerance

Central- destruction of LT that recognize self

molecules in the thymus

Peripheral- LT that leave the thymus are relatively

safe, but not completely hypothesis

◦ Non-inflammatory environment

◦ Lack of costimulation- primary signal (binding to

TCR) needs a secondary signal (B7-CD28)

lack of second signal apoptosis of LT

◦ Some self molecules- hidden

◦ Death signals- Fas on LT and FasL on cells

interaction Fas-FasL death of LT

Steps in Immune System response

1. Detection & identification of non-self

2. Communication with other immune cells resulting in an

organized response

3. Recruitment of assistance and coordination of the

response among all participants

4. Destruction / suppression / removal / minimization of

spreading of the invader/non-self

Body defense…

FIRST LINE INNATE:

Non- specific physical and chemical barriers - physical barriers: skin, mucous membranes, epithelial linings & cilia

- chemical barriers: gastric secretion, tears, saliva, urine acids / pH extremes in stomach enzymes: lysozymes (tears,saliva,milk,mucus) high salt concentrations

SECOND LINE INNATE :

Non-specific immune responses:

- monocyte/macrophage system, neutrophils, NK, eosinophils and mast cells, interferons, and complement proteins…

- inflammatory response & fever

THIRD LINE ACQUIRED

Specific immune responses – T and B lymphocytes work like a team to destroy pathogens.

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Surface Barriers (First Line of

Defense) Skin, mucous membranes, and their

secretions make up the first line of defense

Keratin in the skin: ◦ physical barrier to most microorganisms

◦ resistant to weak acids and bases, bacterial enzymes, and toxins

Skin acidity (pH of 3 to 5) inhibits bacterial growth

Sebum contains chemicals toxic to bacteria

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Surface Barriers

◦ Stomach mucosae secrete concentrated HCl

and protein-digesting enzymes

◦ Saliva, tears, milk, mucus contain lysozyme

◦ Mucus traps microorganisms that enter the

digestive and respiratory system

◦ Mucus-coated hairs in the nose trap inhaled

particles

◦ Mucosa of the upper respiratory tract is

ciliated- cilia sweep dust- and bacteria-laden

mucus away from lower respiratory passages

19

Nonspecific immune responses

(Second Line of Defense) The body uses nonspecific cellular and

chemical devices to protect itself

1. phagocytes

2. natural killer (NK) cells

3. inflammatory response enlists macrophages, mast cells, WBCs, and chemicals

4. antimicrobial proteins in blood and tissue fluid- interferons and complement proteins

5. fever

Harmful substances are identified by surface carbohydrates unique to infectious organisms

I. Phagocytes: Produced throughout life by the bone marrow.

Scavengers, recycling – remove dead cells, microorganisms.

(phago="eating", cyte="cell").

Granulocytes: Neutrophils polymorph

Eosinophils

Basophils tissue mast cells

Monocytes tissue macrophages

II. Immunocytes- involved in specific immune response (3rd

line)

Lymphocytes: T and B (plasma cells)

Leukocytes (WBCs): “seek out and destroy” systems

- mobile units of the body's protective immune system

- transported in the blood to different parts of the body,

mostly to areas of infection and inflammation

- Leukocytes (functional classification):

Leukocytes (morphologic classification)

Granulocytes:

Neutrophils polymorph.

Eosinophils

Basophils

Primary/azurophilic granules are common to all granulocytes, appear in the promyelocyte stage and are obscured by the appearance of specific granules in the myelocyte stage. Contain myeloperoxidase and defensins.

Secondary secretory granules appear in the myelocyte phase; contain apolactoferrin and collagenase.

All cytoplasmic granules, primary or secondary, contain biologically active substances that are involved in inflammatory and allergic reactions

Agranulocytes

Monocytes

Lymphocytes: T and B, plasma cells

Cells of the immune system

Pluripotential

hematopoietic

stem cell

(PHSC)

PHSC

Colony

forming

unit

(CFU

GEMM)

Lymphoid

stem cell

(LSC)

CFU-B(last) CFU-E Erithrocytes

CFU-GM Granulocytes

Monocytes/Macrophages

CFU-M Megakaryocytes platelets

T Lymphocytes

B Lymphocytes

NK

Myeloid

stem

cell

(MSC)

Myelocyte series:

1, myeloblast;

2, promyelocyte;

3, megakaryocyte;

4, neutrophil (N) myelocyte;

5, young N metamyelocyte;

6, "band" N metamyelocyte;

7, polymorphonuclear neutrophil;

8, eosinophil myelocyte;

9, eosinophil metamyelocyte;

10, polymorphonuclear eosinophil;

11, basophil myelocyte;

12, polymorphonuclear basophil;

13-16, stages of monocyte formation.

Genesis of white blood cells. myeloblast lymphoblast

Leukocytes:

-No: ~ 4000 - 11000 WBCs / ml of blood

-Normally, WBCs in bone marrow are ~ 3x more then in circulating

blood (~ a 6-day supply of WBCs)

Leukocyte formula

Polymorphonuclear neutrophils 62% (50-70%)

approach, ingest & kill bacteria;

see Arneth count for average age of N (nuclei lobes #)

Blood N: 50% circulating at any instant, 50% remain marginated

/sidelined on vessel walls or sequestered in closed capillaries.

Polymorphonuclear eosinophils 2.3% (1-4%)

attack parasites that are too large to be engulfed

increased in allergic disease

Polymorphonuclear basophils 0.4% (0-1%)

release histamine & other inflammatory mediators

important in immediate-type hypersensitivity reaction

Monocytes 5.3% (2-8%)

Lymphocytes 30% (20-40%)

Leukocytes life span

Granulocytes:

BM/lymphoid tissue 4-8 hrs circulating 4-5 days in tissues (less time during infections, die after digesting bacteria)

Neutrophils ‘patrol tissues’ as they squeeze out of the capillaries (diapedesis); large numbers are released during infections.

Monocytes:

BM/lymphoid tissue 10-20 hrs circulating enlarge to form tissue macrophages long-lived: months (unless destroyed while performing phagocytic functions)

Lymphocytes

lymph/lymphoid tissue (re)circulating for a few hrs. diapedesis - back into the tissues re-enter the lymph return to the blood… and so on for weeks/months

Calculations based on the blood volume and the level and half-life of blood cells in

the circulation indicate that each day an adult produces ~100 billion leukocytes. This

rate can increase by a factor of 10 or more when the demand increases.

Eosinophils (E)

2 % of all the blood leukocytes

weak phagocytes, exhibit chemotaxis, not significant in protecting against

the usual types of infection.

produced in large numbers in people with parasitic infections

eosinophils attach parasites by way of special surface molecules and

release substances that kill many of the parasites:

(1) hydrolytic enzymes from their granules, which are modified lysosomes;

(2) highly reactive forms of oxygen lethal to parasites;

(3) highly larvacidal polypeptide called major basic protein.

E collect in tissues where allergic reactions occur, migrating there because

of an eosinophil chemotactic factor released by mast cells and basophils

E detoxify some of the inflammation-inducing substances released by the

mast cells and basophils

phagocytize and destroy allergen-antibody complexes, thus preventing

excess spread of the local inflammatory process.

Basophils (B) / tissue mast cells

- release heparin (prevent blood coagulation), histamine

(vasodilator, bronchoconstrictor), smaller quantities of bradykinin

and serotonin (both are vasodilator substances) inflammation

- role in some types of allergic reactions: present membrane

receptors for immunoglobulin E (IgE, reagins or sensitizing

antibodies) binding of specific antigen for the specific IgE

attached to mast cells / basophils causes these cells to rupture

and release exceedingly large quantities of histamine, bradykinin,

serotonin, heparin, slow-reacting substance of anaphylaxis, and a

number of lysosomal enzymes local vascular and tissue

reactions that cause allergic manifestations.

Chapter 21, Immune System 30

1. Phagocytes

Macrophages are the chief phagocytic cells

Free macrophages wander throughout a region in search of cellular debris

Kupffer cells (liver) and microglia (brain) are fixed macrophages

Neutrophils become phagocytic when encountering infectious material

Eosinophils are weakly phagocytic against parasitic worms

Mast cells bind and ingest a wide range of bacteria

Defense mechanisms of Neutrophils (N) & Macrophages (M)

N are doing this even in the circulating blood M mature in the tissues (larger than N, 60-80 mm) and fight here Seek and destroy invading bacteria, viruses, parasites… Margination Diapedesis

Amoeboid motion through tissue spaces ~ 40 mm/min Chemotaxis:

◦ N & M are attracted in the inflamed area by chemicals: V & B toxins, degenerative products of the inflamed tissues, complement complex components, reaction products from clotting, histamine

◦ Depends on the conc. gradient of the chemotactic substances ◦ Chemotactic signal is effective up to 100 mm away from the inflamed tissue

(50 mm is the average distance between tissue/cells and capillaries)

Diapedesis

Diapedesis First step- reversible binding of leukocytes

to vascular endoth- interaction SELECTIN-

sialyl-Lewisx (rolling but not anchoring)

Second step- strong interaction- induction

of ICAM-1 on the endoth interact with

integrin receptors (LFA1 and Mac-1)- due to

chemokines (IL8)

Third step- penetration

◦ Endoth junction

◦ Penetration of basement mb-

metalloproteinase

Forth step- migration through Ec matrix

Neutrophilia is caused by:

-transient - mobilization of

marginated/sequestered N

(secondary to adrenaline, exercise)

- release of stored N from BM (100 mature N

stored in the BM for every circulating N)

when stimulated by cortisol or

granulocyte-inducing factor derived from

dead leukocytes.

-stimulation of BM production

Chemotaxis

The above neutrophils were placed in a gradient of fMLP (n formyl methionine-

leucine- phenylalanine), a peptide chain produced by some bacteria.

Phagocytosis

The macrophage is using its internal cytoskeleton to envelop cells of the fungus

Candida albicans. After ingestion, the phagocyte kill microorganisms by some

means, such as the oxidative burst.

Phagocytosis Selectivity criteria:

- normal/self cells have smooth surface and protective protein coats that repel phagocytes

- through C3b molecules receptors, phagocytes (bearing ABs rec.) bind to C3b-AB complexes that coat the foreign structures (AG) = opsonization

N phagocytize 3-20 B before become inactivated/die (N attaches to B, projects pseudopodia around it fuse of pseudopodia enclosed chamber containing the phagocytized particle phagocytic vesicle inside the cytosol

M are more powerful phagocytes: engulf B and larger structures, ~ 100 /macrophage digest them and is possible to survive and function months or years after.

Phagocytic vesicles (phagosomes) fusion with lysosomes/ peroxisome/ cytoplasmic granules [contain proteolytic enzymes, lipases, bactericidal agents, oxidizing agents (O2

-, H2O2, OH-), myelo-peroxidase (form the bactericidal hypochlorite)] digestive vesicle

After ingesting a foreign invader, M “wear” pieces of it called epitops on their cell membrane receptors AG presenting cells (APC).

Opsonisation

Phagocytosis

Macrophages (M)

Also initiate specific immune

responses as they display

antigens from the pathogens

to the lymphocytes= antigen

presenting cells

Monocyte-macrophage (M-M) system.

Reticuloendothelial System

Reticuloendothelial system: M-M system

Some endothelial cells from BM, spleen, lymph nodes

Monocytes (immature cells in the blood enter the tissues, begin to swell macrophages, that become attached to the tissues and remain attached for months or even years when appropriately stimulated, they detach and become mobile macrophages that respond to chemotaxis/stimuli related to the inflammatory process a widespread M-M system in the body

When infection begins in the skin and subcutaneous tissue local inflammation ensues local tissue macrophages (histiocytes) divide and form more macrophages.

Microorganisms at tissue level if not locally destroyed, enter the lymph trapped by macrophages in the lymph nodes

Alveolar M in the lungs: integral components of the alveolar walls “giant cells” capsule around not digestible particles (tuberculosis bacilli, silica dust, carbon particles).

Kupffer cells lining the liver sinusoids: filtration system for the portal blood

Microglia in the brain

Large numbers of macrophages line the lymph sinuses, and if any

particles enter the sinuses by way of the lymph, the macrophages

phagocytize them preventing general dissemination throughout the body.

Lymph nodes

Spleen capillaries are highly porous, allowing whole blood to pass out

of the capillaries into cords of red pulp. The blood then gradually

squeezes through the trabecular meshwork of these cords and

eventually returns to the circulation through the endothelial walls of the

venous sinuses. Both trabeculae of the red pulp and the venous

sinuses are lined with a large number of macrophages.

Spleen

44

2. Natural Killer (NK) Cells

~ large granular lymphocytes

Attack and kill certain tumor cells and virus-infected cells

Act more rapidly than other lymphocytes (hours from primary viral infection)

Secrete anti-viral cytokines (gamma-interferon)

Lyse virus-infected cells before the virus can replicate

Bind to cells using an antibody “bridge”, then kill it by secreting a chemical (perforin) that makes holes in the cell membrane of the target cell. With enough holes, the cell will die, because water rushing inside the cell will induce osmotic swelling

Cell lysis does not depend on binding to MHC-AG complexes

NK cells- early host response to

viral infection First wave- IFN, TNFalpha, IL12

Second wave- NK

Control viral replication

Don’t eliminate the virus

Third wave- LT

Virus elimination


3. Inflammation: Tissue

Response to Injury The inflammatory response is

triggered whenever body tissues are injured ◦ Prevents the spread of damaging agents

to nearby tissues

◦ Disposes of cell debris and pathogens

◦ Sets the stage for repair processes

The four cardinal signs of acute inflammation are redness, heat, swelling, and pain

Inflammation

Steps:

-vasodilation of local blood vessels excess local blood flow

-chemotaxis

-margination of N

- permeability of the capillaries … diapedesis…leakage of fluid into interstitial space, including fibrinogen

-clotting of the fluid in the interstitial spaces

-migration of large number of G & M, also fibroblasts

-swelling of the tissue cells

-release of histamine, BK, serotonin, PG, CK / lymphokines , TNF activate M-M system hours phagocytosis (in still-living cells)

‘Walling-off’ effect of inflammation tissue spaces and the lymphatics in the inflamed area are blocked by fibrinogen walling-off process delays the spread of bacteria or toxic products

Neutrophilia 25,000 /ul; increased prod of G & M in BM…

• Tissue response to injury, that helps prevent spread of pathogen and

promotes healing


Inflammation Response

Begins with a flood of inflammatory chemicals released into the extracellular fluid

Inflammatory mediators (chemicals) : ◦ Include kinins, prostaglandins (PGs),

complement, and cytokines

◦ Are released by injured tissue, phagocytes, lymphocytes, and mast cells

◦ Cause local small blood vessels to dilate, resulting in hyperemia


Inflammatory Response:

Vascular Permeability Chemicals liberated by the

inflammatory response increase the

permeability of local capillaries

Exudate (fluid containing proteins,

clotting factors, and antibodies):

◦ Seeps into tissue spaces causing local

edema (swelling), which contributes to the

sensation of pain


Inflammatory Response: Edema

The surge of protein-rich fluids into

tissue spaces (edema):

◦ Helps to dilute harmful substances

◦ Brings in large quantities of oxygen and

nutrients needed for repair

◦ Allows entry of clotting proteins, which

prevents the spread of bacteria= “walling

off” the AG


Flowchart of Events in

Inflammation

Figure 21.2

Macrophage and Neutrophil Responses During Inflammation

Tissue macrophage is a 1st line of defense against infection.

M arrive within minutes/already present in the tissue, enlarge rapidly and begin

their phagocytic actions.

Neutrophil invasion of the inflamed area is a 2nd line of defense.

Within the first hour or so after inflammation begins, large numbers of N begin

to invade the inflamed area from the blood: chemotaxis, N margination N

diapedesis, immediately begin their phagocytic actions.

Within a few hours after the onset of acute severe inflammation, the number of

neutrophils in the blood increases from 4000 - 5000 to 15,000 - 25,000 / ml

(neutrophilia), because of inflammation products that reach the bone marrow

(stored neutrophils…)

Second macrophage invasion into inflamed tissue is a 3rd line of defense.

Monocytes enter the inflamed tissue (slower process requiring several days to

become effective), then enlarge to become macrophages (~ 8 hours to enlarge

and to develop tremendous quantities of lysosomes. After days - weeks, these

M become the dominant phagocytic cells of the inflamed area.

Increased production of G & M by the BM Is a 4th line of defense resulting

from stimulation of the granulocytic and monocytic progenitor cells of the

marrow 3 - 4 days before newly formed granulocytes & monocytes mature…

Control of BM production of granulocytes and monocyte-macrophages in

response to multiple growth factors released from activated macrophages in an

inflamed tissue. G-CSF, granulocyte colony-stimulating factor; GM-CSF,

granulocyte-monocyte colony-stimulating factor; IL-1, interleukin-1; M-CSF,

monocyte colony-stimulating factor; TNF, tumor necrosis factor.

54

4. Antimicrobial Proteins

Enhance the innate defenses by:

◦ Attacking microorganisms directly

◦ Impare microorganisms’ ability to

reproduce

The most important antimicrobial

proteins are:

◦ Interferon

◦ Complement proteins

Complement proteins

More than 25 plasma proteins and cell membrane proteins

Various intermediates act as opsonins, chemotaxins, trigger

degranulation of mast cells

Complement cascade terminates with the formation of membrane

attack complex, a group of lipid-soluble proteins that insert in the

membrane of pathogens and form pores that allow Na+ and H2O

to pass osmotic swelling cell lyses

Complement proteins, are mainly enzyme precursors, normally present

among the plasma proteins in the blood as well as among the proteins that

leak out of the capillaries into the tissue spaces.

More important: 11 proteins designated C1 through C9, B, and D.

The enzyme precursors are normally inactive, but they can be activated

mainly by the classical pathway initiated by an AG-AB reaction

Complement proteins

There are three major pathways

of complement activation, two

initiated by microbes in the

absence of antibody (alternative

and lectin pathways) and the

third initiated by certain isotypes

of antibodies (IgM, IgG1, IgG2)

attached to antigens, called the

classical pathway

Effects of complement proteins/complement cascade end products

1.Opsonization and phagocytosis: C3b strongly activates phagocytosis by

both neutrophils and macrophages, causing these cells to engulf the bacteria to

which the antigen-antibody complexes are attached; enhances the number of

bacteria that can be destroyed by many hundredfold.

2.Lysis: MAC (membrane attack complex) lytic complex, a combination of

multiple complement factors designated as C5b6789, with a direct effect of

rupturing the cell membranes of bacteria or other invading organisms.

3.Agglutination: complement products change the surfaces of the invading

organisms (AGs), causing them to adhere to one another, thus promoting

phagocytosis.

4.Neutralization of viruses: complement enzymes and end products attack

the structures of some viruses.

5.Chemotaxis: fragment C5a initiates chemotaxis of neutrophils & macrophage

6. Activation of mast cells and basophils: fragments C3a, C4a, and C5a

activate mast cells and basophils release of histamine, heparin, and several

other substances into the local fluids role in inflammation and allergy.

7. Inflammatory effects: complement products contribute to local

inflammation, by increased blood flow, increased capillary leakage of proteins,

coagulation of interstitial fluid proteins walling-off effect

59

Genes that synthesize IFN are activated

when a host cell is invaded by a virus

Interferon molecules leave the infected

cell and interact with neighboring cells

Interferon stimulates the neighboring

cells to activate genes for PKR- protein

kinase R (an antiviral protein) PKR nonspecifically blocks viral replication in the

neighboring cell

Interferon (IFN)

60

Interferon (IFN)

Figure 21.4

61

Interferon Family Interferons are a family of related proteins

each with slightly different physiological effects

Lymphocytes secrete gamma () interferon, but most other WBCs secrete alpha () interferon

Fibroblasts secrete beta () interferon Interferons also activate macrophages and

mobilize NKs FDA-approved IFN is used as treatment for

different conditons


Abnormally high body temperature in

response to invading microorganisms

The body’s thermostat is reset

upwards in response to pyrogens,

chemicals secreted by leukocytes and

macrophages exposed to bacteria and

other foreign substances

5. Fever

POSITIVE

• indicate a reaction to infection

• stimulate phagocytosis

• slow the bacterial growth

– increases body temperature beyond the tolerance of some bacteria

NEGATIVE

• extreme heat enzyme

denaturation and

interruption of normal

biochemical reactions

> 39° C (103°F) is dangerous

> 41°C (105°F) could be fatal and

requires medical attention

Fever is induced by pyrogens:

endogenous (IL-1, IL-6, TNFa)

exogenous (bacterial lipopolysaccharide – LPS)

activ of arachidonic ac. pathway PGE2hypothalamic action

Positive/ negative effects of fever


The adaptive immune system is a

functional system that:

◦ Recognizes specific foreign substances

◦ Acts to immobilize, neutralize, or destroy

foreign substances

◦ Amplifies inflammatory response and

activates complement

Adaptive (Specific) Defenses (Third Line of Defense)


The adaptive immune system is

antigen-specific, systemic, and has

memory

It has two separate but overlapping

arms

◦ Humoral, or antibody-mediated (B Cell)

immunity

◦ Cellular, or cell-mediated (T Cell)

immunity

Adaptive Immune Defenses

Types of Specific (acquired) Immunity

I. Naturally Acquired Immunity: Obtained in the course of daily life.

A. Naturally Acquired Active Immunity:

◦ Antigens or pathogens enter body naturally.

◦ Body generates an immune response to antigens.

◦ Immunity may be lifelong (chickenpox or mumps) or temporary (influenza or intestinal infections).

B. Naturally Acquired Passive Immunity:

◦ Antibodies pass from mother to fetus via placenta or breast feeding

◦ No immune response to antigens.

◦ Immunity is usually short-lived (weeks to months).

◦ Protection until child’s immune system develops.

II. Artificially Acquired Immunity: Obtained by receiving a

vaccine or immune serum.

1. Artificially Acquired Active Immunity:

◦ Antigens are introduced in vaccines (immunization).

◦ Body generates an immune response to antigens.

◦ Immunity can be lifelong (oral polio vaccine) or temporary (tetanus toxoid).

2. Artificially Acquired Passive Immunity:

◦ Preformed antibodies (serum) are introduced into body by injection. Snake antivenom injection from horses or rabbits.

◦ Immunity is short lived (half life three weeks).

◦ Host immune system does not respond to antigens.

Basic Types of Acquired Immunity

Humoral immunity or B-cell immunity - develops

circulating antibodies capable of attacking the invading

agent

Cell-mediated immunity or T-cell immunity - formation of

large numbers of activated T lymphocytes that are

specifically crafted in the lymph nodes to destroy the

foreign agent

Both types of acquired immunity are initiated by

antigens


Two types of lymphocytes

◦ B lymphocytes – oversee humoral

immunity

◦ T lymphocytes – non-antibody-producing

cells that constitute the cell-mediated arm

of immunity

Antigen-presenting cells (APCs):

◦ Do not respond to specific antigens

◦ Play essential auxiliary roles in immunity

Cells of the Adaptive Immune System

INDUCTION OF AN IMMUNE RESPONSE

Foreign invaders - viruses, bacteria, allergens, toxins and parasites- constantly bombard our body.

Antigens (Antibody Generators…)

• Antigens are distinguished as non-self and elicit immune

responses

• For a substance to be antigenic, it usually must have a high

molecular weight, 8000 Da or greater.

• The process of antigenicity usually depends on recurrent

molecular groups, called epitopes, on the surface of the

large molecules.

• Most effective are large and complex:

• proteins

• polysaccharides

• also, glycoproteins and glycolipids

Lymphocytes (L) and Acquired Immunity (AI)

AGs diversity L specificity

L are distinguished by their specific membrane

receptors- antibodies

Each unique type of L, along with all the other

identical cells, forms a clone.

A clone of L is a group of L specific to one AG

First step- clonal selection

Lymphocytes and Acquired Immunity

Initially there are only a few naïve L

Naïve L are activated after AG exposure = clonal expansion

The newly formed L in the clone differentiate into

- effector cells, short-lived cells that create the immune response

- memory cells, with longer-lives, continue to reproduce, and with a second or subsequent exposure to the same AG, activate, creating a more rapid and stronger secondary response to the AG.

Lymphocytes and Acquired Immunity

There are 3 main types of Lymphocytes:

LB (mature in bone marrow, concentrate in lymph nodes & spleen)

- secrete AB

LT (mature in thymus) – cellular immunity

B and T cells mature then circulate in the blood and lymph. Circulation

ensures they come into contact with pathogens and each other

Natural killer (NK) cells - attack & destroy infected cells

Origin of lymphocytes


Red bone marrow

1

2

3

Immunocompetent,

but still naive,

lymphocyte

migrates via blood

Mature (antigen-activated)

immunocompetent lymphocytes

circulate continuously in the

bloodstream and lymph and

throughout the lymphoid organs of

the body.

Key: = Site of lymphocyte origin

= Site of development of immunocompetence

as B or T cells; primary lymphoid organs

= Site of antigen challenge and final

differentiation to activated B and T cells Immature

lymphocytes Circulation in

blood 1

1 Lymphocytes destined to become T

cells migrate to the thymus and develop

immunocompetence there. B cells

develop immunocompetence in red

bone marrow.

Thymus

Bone marrow

Lymph nodes,

spleen, and other

lymphoid tissues

2 2 After leaving the thymus or bone

marrow as naive immunocompetent

cells, lymphocytes “seed” the lymph

nodes, spleen, and other lymphoid

tissues where the antigen challenge

occurs.

3 3

Activated

immunocompetent

B and T cells

recirculate in blood

and lymph

Immunocompetent B or T cells

Figure 21.8

I. Humoral (Antibody-Mediated) Immunity

◦ Involves production of antibodies against foreign

antigens

◦ B cells that are stimulated will actively secrete

antibodies and are called plasma cells.

◦ Antibodies are found in extracellular fluids (blood

plasma, lymph, mucus, etc.) and the surface of B

cells.

◦ Defense against bacteria, bacterial toxins, and

viruses that circulate freely in body fluids, before

they enter cells.

◦ Also cause certain reactions against transplanted

tissue.

LB – B cells

Develop in BM

Secrete AB/Ig

Mature LB insert AB molecules in their membrane ABs become surface receptors mark the members of each clone ◦ There are ~10 million different B-lymphocytes, each of which make a

different antibody. The huge variety is caused by genes coding for ABs changing slightly during development.

Activation of a LB clone in response to AG exposure some cells differentiate in plasma cells =effector LB cell

- do not have AB proteins bound in their mb

- synthesize & secrete ~ 2,000 molec. of AB/sec.

memory cells of the clone remain, to respond: - rapidly and amplified to a next AG exposure (divide...)

- the enhanced secondary response is used in immunizations.

there are a small group of clones of each type of LB

http://www.sanidadanimal.info/inmun/images/fig2.gif

HUMMORAL IMMUNE RESPONSE

1. AGs are presented to the B-cells by macrophages/AG-presenting cells (APC)

2. AG-binding to ABs on B cells activates B cells

3. B cell activation- Thelper costimulatin

One B cell surface is covered with 100,000 AB molecules through Fc ends. Fab regions are free to bind AG from ECF

AG binding activates LB, that differentiate into

-plasma cells: releases AB that travel to the blood, lymph, lining of gut and lungs. The number of plasma cells goes down after a few weeks. ABs stay in the blood longer but eventually their numbers go down too.

-memory cells: divide rapidly as soon as the antigen is reintroduced. When the pathogen/infection infects again it is destroyed before any symptoms show.


Stimulated B cell growth forms clones

bearing the same antigen-specific

receptors

A naive, immunocompetent B cell is

activated when antigens bind to its

surface receptors and cross-link

adjacent receptors

These activating events, plus T cell

interactions, trigger clonal selection

Clonal Selection


Clonal Selection

Figure 21.9


Secreted antibodies:

◦ Bind to free antigens

◦ Mark the antigens for destruction by

opsonisation

Clones that do not become plasma

cells become memory cells that can

mount an immediate response to

subsequent exposures of the same

antigen

Fate of the Clones


Primary immune response – cellular

differentiation and proliferation, which

occurs on the first exposure to a

specific antigen

◦ Lag period: 3 to 6 days after antigen

challenge

◦ Peak levels of plasma antibody are

achieved in 10 days

◦ Antibody levels then decline

Immunological Memory


Secondary immune response – re-

exposure to the same antigen

◦ Sensitized memory cells respond within

hours

◦ Antibody levels peak in 2 to 3 days at

much higher levels than in the primary

response

◦ Antibodies bind with greater affinity, and

their levels in the blood can remain high

for weeks to months

Immunological Memory


Primary and Secondary Humoral

Responses

Figure 21.10

What are ABs? ABs are Y-shaped proteins secreted by plasma cells

- 4 polypeptide chains, 2 light & 2 heavy, identical for the same AB, held

together by disulphide bridges

-2 arms: Fab regions, contain variable AG-binding sites that confer AB

specificity. The seqence of amino acids in the variable region determines the

shape of the binding site.

- a stem region: Fc region, bind to immune cells

- a hinge region between the arms and the stem allow flexible positioning

of the arms

- IgM – 5 Y-shaped AB; IgA – formed from 1 to 4 AB molecules (polymers)

What are ABs?

- Immunoglobulins/globular glycoproteins secreted by plasma cells

- Separated by electrophoresis Ig G, A, E, M, D

- IgM: assoc with primary immune response

- IgG: up to 75% of adult ABs

produced in secondary immune response

maternal IgG cross placenta

- IgA: in external secretions of the body (saliva, tears, intestinal and bronchial mucus, breast milk)

disable pathogens before reaching internal environment

- IgE: assoc with allergic responses, combine with mast cells receptors and AGs to trigger mast cells degranulation

Different Immunoglobulins

How ABs work?

-opsonins (labels) to identify antigens for phagocytes

-antitoxins i.e. they block toxins for e.g. those causing

diphtheria and tetanus

-attach to bacterial flagella making them less active and easier

for phagocytes to engulf

-agglutination (clumping together) of bacteria making them

less likely to spread

-bind to and activate other immune cells; AB-bound AG is recognized by AB receptors

- AG-bound ABs activate complement, mast cells enhance inflammation

Type Number of

AG binding

sites

Site of action Functions

IgG 2 •Blood

•Tissue fluid

•CAN CROSS

PLACENTA

•Increase

macrophage activity

•Antitoxins

•Agglutination

IgM 10 •Blood

•Tissue fluid

Agglutination

IgA 2 or 4 •Secretions (saliva,

tears, small intestine,

vaginal, prostate,

nasal, breast milk)

•Stop bacteria

adhering to host cells

•Prevents bacteria

forming colonies on

mucous membranes

IgE 2 Tissues •Activate mast cells

HISTAMINE

•Worm response

Functions of antibodies


Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed

Two major populations of T cells mediate cellular immunity

◦ CD4 cells (T4 cells) are primarily helper T cells (TH)

◦ CD8 cells (T8 cells) are cytotoxic T cells (TC) that destroy cells harboring foreign antigens

Other types of T cells are:

◦ Suppressor T cells (TS)

◦ Memory T cells

Cell-Mediated Immune Response

T Cells and Cell Mediated Immunity

Cellular Components of Immunity:

◦ T cells are key cellular component of immunity.

◦ T cells have an antigen receptor that recognizes and

reacts to a specific antigen (T cell receptor).

◦ T cell receptor only recognizes antigens combined

with major histocompatability (MHC) proteins on the

surface of cells.

MHC Class I: Found on all cells.

MHC Class II: Found on phagocytes.

◦ Clonal selection increases number of T cells.

T Cells Only Recognize Antigen Associated

with MHC Molecules on Cell Surfaces


T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells

T cells are best suited for cell-to-cell interactions, and target: ◦ Cells infected with viruses, bacteria, or

intracellular parasites

◦ Abnormal or cancerous cells

◦ Cells of infused or transplanted foreign tissue

Importance of Cellular Response

LT – T cells must make direct

contact with their target cells

LT differentiate in the thymus, from immature precursor cells that migrate there from the BM, into cytotoxic T cells (TC), helper T cells (TH), and suppressor T cells

LT are responsible for cell-mediated immunity

-contact with APCs, using membrane T-cell receptors

(mature T-cells have receptors which have a very similar structure to ABs and are specific to one AG).

-binding AG (from APC or invaded cell body) to T-cell receptors, activates T cell

-activated LT divide to form:

cytotoxic T cell (killer T cells) destroy AG helper T cells secretes cytokines that enhance the immune response (help B cells divide, stim macroph.)

memory T cells, remain in body

LT can not bind to free-floating AGs as LB; only bind to AGs presented as part of a membrane protein complex (MHC)


Major roles in immunity are: ◦ To engulf foreign particles

◦ To present fragments of antigens on their own surfaces, to be recognized by lymphocytes

◦ Secrete soluble proteins that activate T cells

Major APCs are dendritic cells (DCs), macrophages, and activated B cells

Antigen-Presenting Cells (APCs)

MHC incorporate AG fragments

Membrane protein complexes present in all nucleated

cells, are responsible for the extracellular presentation of

processed AG fragments (AG is engulfed, digested, and

their fragments are combined with an MHC complex and

inserted into cell mb by exocytosis)

2 types of MHC

MHC class I molecules – in all nucleated cells

(LT that binds to MHC class I- AG complexes kill the cell to

prevent the pathogen from reproducing)

MHC class II molecules – found primarily on APCs


Endogenous antigens are:

◦ Degraded by proteases and enter the

endoplasmic reticulum

◦ Transported via TAP (transporter associated

with antigen processing)

◦ Loaded onto class I MHC molecules

◦ Displayed on the cell surface in association with

a class I MHC molecule

Class I MHC Proteins


Class I MHC Proteins

Figure 21.15a


Class II MHC proteins are found only

on mature B cells, some T cells, and

antigen-presenting cells

A phagosome containing pathogens

(with exogenous antigens) merges

with a lysosome

Invariant protein prevents class II

MHC proteins from binding to peptides

in the endoplasmic reticulum

Class II MHC Proteins


Class II MHC proteins migrate into the

phagosomes where the antigen is

degraded and the invariant chain is

removed for peptide loading

Loaded Class II MHC molecules then

migrate to the cell membrane and

display antigenic peptide for

recognition by CD4 cells




Figure 21.15b


Provides the key for the immune system to

recognize the presence of intracellular

microorganisms

MHC proteins are ignored by T cells if they

are complexed with self protein fragments

Antigen Recognition


Major Types of T Cells

Figure 21.14

T Cells and Cell Mediated Immunity

Types of T cells

1. T Helper (TH) Cells: Central role in immune

response.

CD4+

Recognize antigen on the surface of antigen

presenting cells (e.g.: macrophage)+ MHCII

molecules

Activate macrophages

Induce activation of cytotoxic T cells

Stimulate B cells to produce antibodies by cytokine

production


TH cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors

TH cells stimulate B cells to divide more rapidly and begin antibody formation

B cells may be activated without TH cells by binding to T cell–independent antigens

Most antigens, however, require TH co-stimulation to activate B cells

Cytokines released by TH amplify nonspecific defenses

Helper T Cell


Regulatory cells that play a central role in

the adaptive immune response

Once primed by APC presentation of

antigen, they:

◦ Chemically or directly stimulate proliferation of

other T cells

◦ Stimulate B cells

Without TH, there is no immune response

Helper T Cells (TH)


Helper T Cells (TH)

Figure 21.17a

Types of T cells (Continued) 2. Cytotoxic T (Tc) Cells: Destroy target cells.

CD8+

Recognize antigens on the surface of all cells, in

association with MHC I molecules:

Kill host cells that are infected with viruses or bacteria.

Recognize and kill cancer cells.

Recognize and destroy transplanted tissue.

Release protein called perforin which forms a pore

in target cell, causing lysis of infected cells.

Undergo apoptosis when stimulating antigen is

gone.

Cytotoxic T Cells Lyse Infected Cells


TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells

They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized (clone)

Their targets include:

◦ Virus-infected cells

◦ Cells with intracellular bacteria or parasites

◦ Cancer cells

◦ Foreign cells from blood transfusions or transplants

Cytotoxic T Cell (Tc)


In some cases, TC cells: ◦ Bind to the target cell and release perforin into

its membrane In the presence of Ca2+ perforin causes cell lysis by

creating transmembrane pores

Other TC cells induce cell death by: ◦ Secreting lymphotoxin, which fragments the

target cell’s DNA

◦ Secreting gamma interferon, which stimulates phagocytosis by macrophages

Mechanisms of Tc Action


Mechanisms of Tc Action

Figure 21.18a, b


- capable of suppressing the functions of both cytotoxic and helper T cells

- prevent the cytotoxic cells from causing excessive immune reactions that might be damaging to the body's own tissues (regulatory T cells)

- plays an important role in limiting the ability of the immune system to attack a person's own body tissues, called immune tolerance

Suppessor T cell

T cells

helper T cells (TH)

◦ secrete cytokines: IL, interferons, colony-stimulating factors

cytotoxic T cells (TC)

◦ attack and destroy cells that display MHC class I-AG complexes

◦ release perforin along with granzymes apoptosis

◦ bind to ‘Fas’ receptors (death receptors) on cell surface

apoptosis

suppressor T cells

- capable of suppressing the functions of both cytotoxic and helper T

cells

- prevent the cytotoxic cells from causing excessive immune reactions

that might be damaging to the body's own tissues (regulatory T cells)

- plays an important role in limiting the ability of the immune system to

attack a person's own body tissues, called immune tolerance

Chemical signaling in immune system Antibodies: identify and target the pathogens Cytokines: communication molecules released in response to stimuli; act as

both local and long-distance signals; regulatory peptide that control cell develop, different and immune response; IL-1

Opsonins - acute phase proteins (liver proteins, act also as anti-protease molecules) - complement proteins (also cytolytic agent and mediator of inflammation) Chemotaxins Pyrogens: fever-producing substances Kinins Bradykinin (stimulates pain receptors; vasodilator) Histamine: initiate inflammation vasodilator and bronchoconstr. released by

mast cells Granzymes (cytotoxic enzymes that trigger cellular suicide) Interferons: proteins that inhibit viral reproduction; modulate immune

response Lysozyme: bactericidal enzyme MHC: membrane protein complexes used for cell recognition Membrane attack complex: a membrane pore protein made in the

complement cascade Perforin: membrane pore protein made by natural killer and cytolytic T cells T-cell rec: mb rec on LT that recognize and bind AG presented by MHC rec

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