Specific acquired immunity The Immune Response Chapter 16 and 17 Nester 4th. Ed.

Specific acquired immunityThe Immune Response

Chapter 16 and 17

Nester 4th. Ed.

Characteristics of Specific Acquired Immunity (The Immune Response)

Recognizing self from non-self (foreign) Protects the body from specific non-self

organisms and substances It is an induced response; our body cells are

trained or taught to attack which things Typically a specific immune response against one

pathogen will be ineffective against a different pathogen, sometimes even a closely related but still different pathogen

Characteristics of Specific Acquired Immunity (The Immune Response)

Specific immunity is acquired (not innate)• response has memory• also called anamnestic or secondary response• quicker/more effective than primary at

subsequent exposures

Primary and secondary response

Figure 16.11

Lag period 10 days to 2 weeks

Specific Immunity

Also known as adaptive immunity or acquired immunity, active or passive

Normally comes into play when innate or non-specific immunity can't handle the problem.

Mechanisms of the Immune Response

Two types of specific immune responses; humoral and cell mediated

Humoral immunity• B-lymphocytes (develop in bone marrow)

proliferate and differentiated into plasma cells produces Y-shaped molecules called Antibodies

Cell mediated immunity• T-lymphocytes (mature in Thymus)

• Effector T cytotoxic cells

• Effector T helper cells

CellularImmunity

Effector T-helper cell

B cell

Extracellular antigen

Activates B cellsthat bind antigen

HumoralImmunity

CellularImmunity

B cell

HumoralImmunity

CellularImmunity

Proliferation and differentiationof activated B cell

Plasma cell

Memory cell+

B cell

HumoralImmunity

CellularImmunity

Plasma cellAntibodyproduction

Memory cell

B cell

HumoralImmunity

CellularImmunity

Antibodiesbind antigen

Memory cell

B cell

HumoralImmunity

CellularImmunity

Memory cell

Host cells routinelypresent samples ofcytoplasmic proteins.

B cell

HumoralImmunity

CellularImmunity

Memory cell

Effector T-cytotoxic cell

Stimulates effector T-cytotoxiccells that bind antigen

B cell

HumoralImmunity

CellularImmunity

Memory cell

Destroys infected host cells Those cells presenting viralproteins or other abnormalproteins that signify dangerare destroyed.

B cell

HumoralImmunity

CellularImmunity

Memory cell

Activates macrophages thathave engulfed antigen

Destroys infected host cells

Activated macrophage

Those cells presenting viralproteins or other abnormalproteins that signify dangerare destroyed.

Molecules involved in the Immune Response Antigens Antibodies Major Histocompatibility Complex

Molecules

Molecules involved in the Immune Response -Antigens

Any molecule that react specifically with an antibody or a lymphocyte.

Foreign to the host Immunogens are antigens that elicit an immune

response in a given situation High molecular weight-at least 10,000 daltons

Molecules involved in the Immune Response -Antigens

Complex molecules

• protein, polysaccharide - best Ag

• lipid, nucleic acid - not good at all

• lipoprotein, nucleic acid with protein - average Ag

Molecules involved in the Immune Response -Antigens Have antigenic determinants (epitopes)

• Antibody binds to antigenic determinant small region of antigen

• small portions of the whole antigen molecule• equivalent of 10-25 amino acids long• large antigens may have 100 or more epitopes• Figure 16.1

Molecules involved in the Immune Response -Antigens Hapten

• Small molecules with a molecular mass under 5000 dalton make poor antigens by themselves

• Small molecules (haptens) can become immunogenic when combined with a larger carrier protein

• small molecular weight • acts as an antigenic determinant• example -penicillin (350 Dalton)

Molecules involved in the Immune Response -Antigens Exogenous antigens

• By inhalation, ingestion, or injection (cell wall, flagella etc)

• E.g. dust and pollen etc. Endogenous antigens

• Altered self antigens• E.g. denaturation of proteins

• Addition of viral antigens to cells• Viruses, protozoa and fungi which multiply

inside the host cells

Molecules involved in the Immune Response - Antibodies Immunoglobulins

• glycoproteins• recognize epitopes of antigens

• Figure 16.1

• 5 classes - meaning types• IgM, IgG, IgA, IgD, IgE

• Table 16.1 - Each class has a function

Molecular weight

Disulfide bonds

Crystallizable

Variable amino acids

Antigen binding site

Class of antibody

Figure 16.3, Page 397

Molecules involved in the Immune Response - Antibodies Generic structure - Y

• Figure 16. 3• Figure 16. 4• heavy chains- constant region and variable region• light chains- constant region and variable region• hinges• Constant region of heavy chain defines the class

of immunoglobulin

Molecules involved in the Immune Response - Antibodies Generic structure

• Variable regions of the light and heavy chains together determines the specificity of antibody to antigen

• disulfide bridges• Fab• Fc• antigen binding site

Molecules involved in the Immune Response - Antibodies

• complementarity• Figure 16.5• antigen binding site of antibody and specific

antigenic epitope• Fit must be precise• Bonds hold the antibody and antigen are

non-covalent, weak and have short range

Protective Outcome of Antibody-Antigen Binding (Figure 16.5)

Precipitation by precipitin Agglutination by agglutinin Opsonization by opsonin- Complement-fixation and activation Immobilization and prevention of

adherence Neutralization Antibody Dependent Cellular Cytotoxicity

Toxin or virus coated with antibody is prevented from interacting with a healthy cell

Antibodies + antigen = clumps for phagocytic cells e.g. IgM

Antigen + antibod trigger classical pathway of complement cascasde

Multiple IgG molecules bind to a cell, cell becomes target for destruction by natural killer cells

NK cells deliver granules containing protease and perforin

Compliment system

Regulatory proteins halt the process inactivate C3b

Regulatory proteins are not associated with microbial surfaces

C3a and C5a→induce changes in endothelial cells and mast cells →↑ vascular permeability

C5a attracts phagocytes

C3b binds to foreign material called opsonized, C3b called opsonins

Immunoglobulin G (IgG) Accounts for about 80% to 85% of the total

serum immunoglobulin Is a single Y shape - 2 antigen binding sites Is found in circulation Is the first and most abundant circulating

class produced during the secondary response

Reaches high levels and has a long half- life 21 days

Is part of long term immunity

Functions of IgG

Works best against infectious agents that reach the blood

Types of reactions• agglutination• precipitation• neutralization• opsonization • complement fixation and activation

Functions of IgG

Crosses the placenta from the mother to provide immunity for the new born• (Fig 16.7)

Premature infants have a problem with infection since they do not get this passive transfer of immunity

Also present in colostrum

Infant antibodies3 to 6 months

Immunoglobulin M (IgM)

Accounts for 5% to 13% of circulating antibodies

Is the first Ab produced during primary response to an antigen

Is made of 5 Y shapes - pentamer• joined with a J chain and disulfide bridges• 10 antigen binding sites• Is found in circulation only- too big to get out

Function of IgM

good for agglutination and precipitation• phagocytes pick up large agglutinated clumps

more efficiently

best at activating complement (classical pathway)

removes microorganisms early in the course of an infection

only Ab made against polysaccharide Ag’s

Immunoglobulin A (IgA) Accounts for 10% to 13% of antibodies Is in monomer form in circulation Is in dimer form on mucous membranes called

secretory IgA (sIgA)• Produced by plasma cells –B cells reside in the

mucosal-associated lymphoid tissue (MALT)• Composed of two monomeric antibody subunits

connected by a J-chain• Found on mucous membranes of genitointestinal,

genitourinary and respiratory tracts• Found in saliva, tears and breast milk• Ab is transported to the surface of the mucosal lining• Secretory component helps keep enzymes from

degrading the Ab

Functions of IgA

inhibits adherence of microorganisms to host cells

prevents colonization and therefore infection

Neutralizes toxins and viruses protects the breast-fed infant’s GI tract from

infection

Immunoglobulin D (IgD)

Accounts for less than 1% of all serum immunoglobulins

Is in monomer form Binds to B-cells by its Fc end May be involved in the maturation of B-

Immunoglobulin E (IgE)

Is in monomer form Barely detectable in blood Bound to mast cells and basophils by its Fc

end Is not free in circulation Bound cells releases a mixture of potent

chemicals histamine, cytokines etc that contributes to inflammatory response

Functions of IgE

IgE has beneficial effects.• IgE binds to parasitic worms

• they are then expelled from the GI tract

• IgE is the second line of defense at mucous membranes

• if org. gets past the IgA in the surface, IgE gets it in the tissue

Functions of IgE

IgE has beneficial effects.• IgE and IgG function in ADCC

• antibody dependent cellular cytotoxicity

• eosinophils bind IgE and IgG by their Fc fragments

• the Ab variable ends bind to the parasites• eosinophils release anti-microbial proteins• eosinophils have a peroxidase-halide anti-

microbial system

Major Histocompatibility Complex Molecules

Major histocompatibility antigens First time in humans these antigens were

identified on leukocytes and were named human leukocyte antigens (HLA)

Major histocompatability complex (MHC) clusters of genes

In humans MHC is located on each copy of chromosome 6

Major Histocompatibility Complex Molecules

Major Histocompatibility Complex (MHC) is a set of molecules displayed on cell surfaces that are responsible for lymphocyte recognition and “antigen presentation”

MHC molecules control the immune response through recognition of "self" and "non-self" and, consequently, serve as targets in transplantation rejection

Class I and Class II MHC molecules

Molecules of the Immune Response-Major Histocompatibility Complex Molecules (Fig 16.16)

MHC class I molecules

• are on all nucleated cells

• not on RBC’s

• interact with Ag fragments of 8-10 amino acids long

• present Ag to T-cytotoxic lymphocytes (CD8 cells)

(surface protein cluster of differentiation)

• Endogenous antigens

MHC class II molecules• are on macrophages, B

cells and dendritic cells• interact with Ag

fragments of 12-25 amino acids long

• present Ag to T-helper lymphocytes (CD4 cells)

• Exogenous antigens

Antigen binding groove Exogenous antigens

Endogenous antigens

Molecules of the Immune Response-Major Histocompatibility Complex Molecules Cluster of genes

• on chromosome 6• code for histocompatibility antigens

• on surfaces of many cell types

• in humans, called human leukocyte antigens (HLA)

• involved in transplant rejection

Also called the HLA gene cluster

Molecules of the Immune Response-Major Histocompatibility Complex Molecules

Human leukocyte antigens (HLA) • Proteins located on the surface of

white blood cells which play an important role in our body's immune response to foreign substances

• Vary from person to person• These antigens are also used to determine the

suitability of a match between a donor and a recipient. Patients and potential donors have their white blood cells tested for three antigens - HLA-A, -B and –DR

• Each individual has two sets of these antigens, one set inherited from each parent.

Molecules of the Immune Response-Major Histocompatibility Complex Molecules

Other reasons for importance of MHC molecules• cell to cell contact needed for an immune

response• recognition of self or foreign substance (non-

self)• accept self• dispose of foreign material

Tissues involved in the Specific Immune Response- Lymphoid System

Lymphatic vessels

Lymphoid tissues

Tissues involved in the Specific Immune Response- Lymphoid Tissues

Primary Lymphoid organs• bone marrow

• thymus

Secondary lymphoid organs• Organs

• adenoids

• tonsils

• spleen

• lymph nodes

• Diffuse tissues• MALT

• SALT

Cells Involved in the Specific Immune Response Macrophages Lymphocytes

Cells Involved in the Specific Immune Response - Macrophages Non specific cells that are involved in the

killing of bacteria and the phagocytosis of garbage in the tissues

In the specific immune response they are important due to their role in the processing and presenting of antigens to the lymphocytes.

Cells Involved in the Specific Immune Response - Macrophages Antigen Processing

• To a Cytotoxic T cell• To a Helper T cell

Cells Involved in the Specific Immune Response - Lymphocytes Development of Lymphocytes

Clonal selection

Specific response of lymphocytes to an antigen

This process gives rise to a population of clones of the original cell ‘Clonal selection”

Clonal Selection of Lymphocytes

See Figure 16.8tp://highered.mcgraw-hill.com/sites/0072919248/student_view0/chapter16/animations.html#

Development of Lymphocytes

Descriptive terms for lymphocytes• Immature lymphocytes

• not fully developed their antigen specific receptors

• Naïve lymphocytes • have antigen receptors but have not yet encountered

the antigen

• Activated lymphocytes • have bound to antigen and have received signals

from another cell regarding danger and able to proliferate

Development of Lymphocytes

Descriptive terms for lymphocytes

• Effector lymphocytes • descendents of activated lymphocytes that

are armed with the ability to produce specific cytokines, endowed with effector functions TH and TC

• Memory lymphocytes • long-lived descendents of activated

lymphocytes, responsible for the speed and effectiveness of the secondary response

B lymphocytes and the Antibody Response

Molecules on the outside of B lymphocytes• B cell receptors (BCR), MHC Class II

molecules and MHC I molecules Response to T-dependent antigens Response to T-independent antigens Characteristics of the primary immune response Characteristics of the secondary immune

response

1) B cell receptor binds to antigen

Antigen

B cell receptor

1) B cell receptor binds to antigen 2) B cell internalizes antigen

Antigen

B cell receptor

3) B cell degrades antigen into peptide fragments, then presents them in the groove of MHC class II molecules that reside on the B-cell surface.

Antigen

B cell receptor

Antigen fragment presentedby MHC class II molecule

4) If the T-cell receptor of an effector T-helper cell binds to one of the fragments, then cytokines are delivered to the B cell, initiating the process of clonal expansion.

3) B cell degrades antigen into peptide fragments, then presents them in the groove of MHC class II molecules that reside on the B-cell surface.

Cytokine delivery

Antigen

T-cell receptor

B cell receptor

Antigen fragment presentedby MHC class II molecule T cells antigen-specific

receptors

B lymphocytes and the Antibody Response Response to T-dependent antigens

• Antigens are generally proteins• Antigen binds to a B-cell receptor• B-cell needs to respond• Before that B-cell requires confirmation by an

effector T-helper cell that antigen truly merit a response

• B-cell begin dividing and differentiating and finally producing antibodies

B lymphocytes and the Antibody Response Response to T-independent antigens

• Stimulate an antibody response by activating B cells without the aid of effector T cells

• E.g. polysaccharides (capsules of Streptoccocus pneumoniae and Hemophilus influenzae) that have numerous identical evenly spaced epitopes

• Lipopolysaccharide (LPS) outer membrane of Gram-negative bacteria

• Clusters of B-cells receptors binds the antigen simultaneously, which leads to B-cells activation without T-helper cells

Lipopolysaccharide also functions as a T-independent antigen

B lymphocytes and the Antibody Response

Characteristics of the primary immune response• Lag period (10 days to 2 weeks)

• Affinity maturation

• B-cells that binds to an antigen most tightly and for longest duration are most likely to proliferate

• Class switching

• Under the direction of cytokines, some B cells become programmed to produce antibodies other than IgM. Most commonly switch to IgG production

• Memory cells• Memory B cells persist in the body for years and in

sufficient numbers

B lymphocytes and the Antibody Response Characteristics of the secondary immune

response• Memory B cells are responsible for swift and

effective response• IgG immunoglobulins• IgG antibody can circulate in body for years

allowing protection against specific antigens

Characteristics of secondary response• Memory cells responsible for swift effective

reaction of secondary response• Often eliminate invaders before noticeable harm is

• Vaccine exploits phenomenon of immunologic memory

• Some memory B cells will differentiate into plasma cells

• Results in rapid production of antibodies

B Lymphocyte and Antibody Response

T-Lymphocytes

T lymphocytes• Molecules on the outside of all T cells

-T-cell receptors TCR’s, MHC Class I

molecules• Types of T cells

• Tc cells (cytotoxic) - CD8

• Th cells (helper) - CD4

• T memory cells

T-Lymphocytes

T lymphocytes• T Cell Receptors (Figure 16-15)

T cell receptors, Figure 16.15, p 407

One antigen binding site

T-Lymphocytes

Types of effector T cells• T cytotoxic cells TC

• T helper cells TH

• T memory cells

T lymphocytes T cytotoxic cells (Figure 16.17)

• have the CD8 molecule on its outside surface • recognizes an antigen that is specific for the

shape of the TCR• has to have the antigen presented to it by an

antigen presenting cell (macrophage and B cell) in combination with a MHC class I molecule

• Release several pre-formed cytotoxins (perforin and proteases)

• Apoptosis, apoptotic cells are quickly removed by macrophages

T-Lymphocytes

Role of T cells different from B cells• T cells never produce antibodies• T cells armed with effectors that interact

directly with antigen• T cell receptor does not react with free antigen

– Antigen must be present by APC

Antigen recognition by T cells

T lymphocytes T cytotoxic cells (continued)

• Recognizes antigens on the outside of the cell• Endogenous antigens

– virus infected cells

– tumor cells

– tissue transplant cells

• Mechanisms of killing-Figure 16.18• apoptosis triggered by TC cell cytokines

• cytokines

Virally infected "self" cellpresents peptides fromcytoplasmic proteins in thegroove of MHC class I molecules

Effector T-cytotoxic cell recognizes viralantigens presented by infected "self" cell

Virally infected "self" cellpresents peptides fromcytoplasmic proteins in thegroove of MHC class I molecules

Effector T-cytotoxic cell recognizes viralantigens presented by infected "self" cell

Virally infected "self" cellundergoes apoptosis

Effector T-cytotoxic cell delivers preformedcytotoxins to the infected "self" cell and producescytokines that allows neighboring cells to becomemore vigilant against intracellular pathogens

Secretion of cytokines

Targeted deliveryof cytotoxins thatinduce apoptosis

T lymphocytes

T-helper cells (Figure 16.17)• Have the CD4 marker on the outside• Antigen is presented by a specialized group of

cells called antigen-presenting cells (APCs)• APCs have MHC class II molecules (B cells,

dendritic cells and macrophages)• Exogenous antigens

Role of TH cells in B cell activation

• If TH cell encounters B cell bearing peptide: MHC calls II complex

• TH cell responds by producing cytokines

• B cell is activated in response to cytokine stimulation

• B cell proliferates and undergoes class switching

• Also drives formation of B memory cells

T LymphocytesAntigen Recognition and Response

Role of TH cells in macrophage activation

• Macrophages routinely engulf invading microbes resistant to lysosomal killing

• TH cells recognize macrophage with engulfed microbes resistant to killing

• TH cells activate macrophages by delivering cytokines that induce more potent destructive mechanisms

T LymphocytesAntigen Recognition and Response

Macrophage engulfs materials

Macrophage degrades proteins inphagosome into peptide fragments

Peptide fragments fromengulfed material are presentedby MHC class II molecules

T-cell receptor

Peptide fragments fromengulfed material are presentedby MHC class II molecules

Secretion of cytokines

Effector T-helper cell recognizesa peptide being presented by themacrophage and respondsby activating the macrophage

Targeted deliveryof cytotoxins activatemacrophage

Activated macrophage

•Enlarges

•Cell metabolism increases

•Lysosomes increases

•Nitric oxide potent antimicrobial chemical

T lymphocytes Effector T-helper cell

• Th1

• Antigen presented by macrophages• Effector Th1• Outcome

– Macrophages activation– release wide variety of cytokines– stimulate natural killer cells– Increase production of monocytes in bone marrow– Recruit macrophages at the site– Make phagocytic cell to adhere or exist from blood

vessels• Th2

• Antigen presented by B cells• Active in the antibody response

T Lymphocytes

Antigen presentation by a macrophage to a T-helper Cell (Figure 16.19)

T lymphocytes

Role of Dendritic Cells in T-Cell Activation (Figure 16.20)

Activation of T cells

•Surface proteins

•Flashing red lights signifies danger

Natural Killer Cells Natural killer cells (NK cells)

• large, granular lymphocytes• lack markers of T or B lymphocytes

• probably related to T cells

• but lack TCR’s

• lack antigenic specificity

Natural Killer Cells

Natural killer cells (NK cells)• Antibody Dependent Cellular Cytotoxicity

(antibodies coat antigen, NK cells recognizes target by Fc receptors)

• Release granules containing perforin and proteases directly to the target cell

• Recognize and destroy host cells without MHC class I molecules

Lymphocyte Development

Negative selection of Self-reactive B cells

Positive and negative selection of self reactive T cells

Negative selection of Self-reactive B cells• Process of eliminating lymphocytes including

B-cells that recognize “self” molecules• Called clonal deletion• Occurs in bone marrow and secondary

lymphoid organs• Apoptosis• Failure to eliminate such B-cells leads to

production of autoantibodies

Positive and negative selection of self reactive T cells• Positive selection

• Process that permits only those T cells that recognize MHC molecule to some extent to develop further

• Those T cells that show insufficient recognition fail positive selection and are eliminated

• Negative selection• T cells that recognize “self” peptide presented by

MHC molecules are also eliminated

Primary lymphoid organ(bone marrow)

Immature B cells

Primary lymphoid organ(thymus)

Immature T cells

Immature B cells

Immature T cells

Mature (naive) B cells

Secondary lymphoid organs

Mature (naive) T cells

Tissues

Immature B cells

Immature T cells

Tissues

Dendritic cellsgather antigen

Immature B cells

Immature T cells

Tissues

Travel to secondary lymphoidtissue, developing into antigen-presenting cells; co-stimulatorymolecules are expressed ifantigen represents microbialinvasion or tissue damage.

Immature B cells

Immature T cells

Tissues

Antigen presented by MHC Class Imolecules in the presence ofco-stimulatory molecules activatesnaive T-cytotoxic cells. Naive T-cytotoxic

(CD8) cells

Immature B cells

Immature T cells

Tissues

(CD8) cells

Antigen presented by MHC Class IImolecules in the presence ofco-stimulatory molecules activatesnaive T-helper cells

Naive T-helper(CD4) cells

Immature B cells

Immature T cells

Tissues

(CD8) cells

Activation, proliferation,development ofeffector T cell functions

Immature B cells

Immature T cells

Tissues

(CD8) cells

MemoryT-helper cellsEffectorT-helper cells

MemoryT-cytotoxic cellsEffectorT-cytotoxic cells

Immature B cells

Immature T cells

Tissues

(CD8) cells

Th2 Th1

Immature B cells

Immature T cells

Tissues

(CD8) cells

Th2 Th1

Free antigen

Immature B cells

Immature T cells

Tissues

(CD8) cells

Th2 Th1

Free antigenT-dependent antigens

Naive B cells

Immature B cells

Immature T cells

Tissues

(CD8) cells

Th2 Th1

Free antigenT-dependent antigens

Naive B cells Activation, proliferation, classswitching, affinity maturation

Activates B cellsthat present antigen

Tissues Secondary lymphoid organs

Antigen presented by MHC Class Imolecules in the presence ofco-stimulatory molecules activatesnaive T-cytotoxic cells.

T-dependent antigens

Naive T-cytotoxic(CD8) cells Activation, proliferation,

development ofeffector T cell functions

Activation, proliferation, classswitching, affinity maturation

Memory cells

Th2 Th1

Naive B cellsFree antigen

Immature B cells

Immature T cells

Plasma cells produce antibody; dependingon site of infection and duration of exposure,the class may be IgM, IgG, IgA, or IgE

Memory cells

Th2 Th1

Immature B cells

Immature T cells

Memory cells

Th2 Th1

Th 1 cells activate macrophages that presentantigen via MHC class II molecules; also producecytokines that orchestrate other responses

Immature B cells

Immature T cells

Memory cells

Th2 Th1

Th 1 cells activate macrophages that presentantigen via MHC class II molecules; also producecytokines that orchestrate other responses

Effector T-cytotoxic cells destroy cellsthat presented antigen via MHC class Imolecules; also produce cytokines thatallow neighboring cells to become morevigilant against intracellular pathogen.

Immature B cells

Immature T cells

Specific acquired immunity The Immune Response Chapter 16 and 17 Nester 4th. Ed.

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