1

Specific ImmunityTalaro Chapter 15

Elvis receives his polio vaccination during a 1956 March of Dimes campaign.www.marchofdimes.com

Dendritic cell (blue) communicates with four T lymphocytes (yellow).Talaro (5th ed.) page 445

2

Specific Immune Reaction Overview• Specific Immune Reaction Overview

– Characteristics of Specific Immunity– Humoral & Cellular Immune Response

• Lymphocyte Development & Differentiation• Cytokines• Major Histocompatibility Groups• Presenting of Antigens• Antibodies

– Immunoglobins (Igs)• Two Scenarios

– Humoral– Cellular

• Immunological Memory

3

Four Characteristics of the Immune System• Specificity

– Antigens are organisms or molecules that are specifically recognized as foreign by the immune system

– The sites on antigens that the immune system recognizes are the antigenic determinants or epitopes

– Each antigen typically has several different antigenic determinants.

– The host creates T cells and/or antibodies that are specific to the antigenic determinants

• T cells & Abs aid in the removal of the antigen

4

Epitope

Ab recognize andbind to a specific epitope

Proteins produced by the immune systemthat specifically binds to an epitope and initiates its removal of the antigen from the body

Proteins (enzymes, exotoxins, Abs, hormones)LipoproteinsGlycoproteinsNucleoproteins (pure DNA isn’t antigenic)Polysaccharides (bacterial capsules) & LPS

Foreign molecules less than 1,000 MW are not antigenic unless attached to a larger carrier molecule

5

Antigens

Viruses present various antigenic determinants.

Each determinant will stimulate a unique lymphocyte and Ab response.

Small molecules, simple molecules, and large but repetitive molecules can

evade the immune system.

Whole cells, viruses and complex molecules elicit the immune response.

6

• Diversity

– The human immune system can distinguish and respond to 10 million different antigenic determinants

• Distinguishing Self from Non-self

– Major Histocompatibility Complex

• Proteins on the surface of every cell

• Immunological Memory

– Once exposed to a pathogen, the immune system “remembers” and mounts future responses more rapidly

Characteristics of the Immune System

7

The Immune System• Humoral Immune Response

– Defense against extracellular pathogens

– Abs bind to antigens

– Makes antigens easy targets for phagocytes

• Cellular Immune Response

– Intracellular pathogens & cancer

– Bind & lyse abnormal cells

• The two responses operate in concert and share mechanisms

8

B Lymphocytes (B-Cells)- Lymphocytes that mature in bone marrow- Responsible for the production of antibodies and humoral (fluid) immunity

T Lymphocytes (T-Cells)- Lymphocytes that mature in thymus gland- Responsible for the cell-mediated immunity- Directed against a factor, such as a virus or mutation, that changes a normal cell into an abnormal cell

LymphocytesWBC (leukocytes) involved in the immune response. Two types: B cells & T cells. Lymphocytes secrete cytokines that regulate the activities of many other types of cells and are often present at sites of inflammation.

9

Lymphocytes develop from the same stem cell but undergo a sequential development that begins in the embryonic yolk sac and shifts to the liver and bone marrow. Diverge into two distinct types: B cells & T cells.

10

Immature lymphocytes cannot reactwith antigens.

Lymphocyte differentiation & immunocompetence are completed by late fetal or early neonatal period.

Mature B cells are found in the lymph nodes, spleen, gut associated lymphoid tissue. Have immunoglobin receptors & numerous microvillus projections.

Mature T cells are found in the lymphoid organs but pass between lymphatic & general circulation. 7 clusters of differentiation (CD) or receptors that recognize antigens bound on cells, MHC receptors, B cells, T cells and macrophages.

11

Brief Explanation of B CellsEach B cell makes a unique Ab on its surface

Specificity between theantigen & Ab

B cell divides

Production of Clones“clonal selection”

Some develop into effector or plasma cells

A few develop into memory cells that divide at a low rate

12

Brief Explanation of T CellsHelper T cells activate other T & B cells

(CD4 or TH)

Cytotoxic T cells destroy foreign or abnormal cells by secreting perforins that lyse cells

(CD8 or TC)

13

Cytokines• Soluble proteins

• Regulate immune system activities

• Cytokine network– A complex web of signals among all the cell types

of the immune system

• Cytokines have been named after their cells of origin, their function, and / or the order in which they were discovered

14

Common Examples of Cytokines• Interleukins (ILs)

– Signal among leukocytes– 27 different ILs

• Interferons (IFNs)– Antiviral proteins that may also acts as cytokines– IFN-secreted by TH cells

• Growth Factors– Stimulate stem cells to divide– Sufficient quantity of leukocytes

• Tumor Necrosis Factor (TNF)– Kill tumor cells & regulate immune response to inflammation– Macrophages & T cells

• Chemokines– Signal leukocytes to migrate to site of inflammation or infection– Activate other leukocytes

Major Histocompatibility ComplexCellular surface glycoproteinsSelf identifying labelsCoordinate interactions among lymphocytes & macrophages

These molecules are called human leukocyte antigens (HLA)

16

• Class I MHC proteins are present on the surface of every nucleated animal cell– Not present on RBC

• Class II MHC proteins are found mostly on the surface of B cells, macrophages, and other antigen-presenting cells – When an antigen is ingested by an antigen-presenting cell, it

is broken down and fragments are presented at the cell surface by class II MHC proteins

• Class III MHC proteins include some of the proteins of the complement system that interact with antigen–antibody complexes to cause lysis of foreign cells– Not surface proteins

17

Macrophage takes upan antigen by phagocytosis

Macrophage processes theantigen by breaking it intofragments

A class II MCH protein bindsthe processed antigen

The MHC “presents” the antigento a helper T cell

Antigen Presenting Cell

A closer look at this interaction

18

Interleukin-1 is secreted by APC to activate TH cells

IL-1

Interleukin-2 is produced by TH to activate B & T cells

19

Variable regions differ in the a.a. sequences at the antigen-binding site & are responsible for the diversity of Ab specificity

BivalentAntibodies / Immunoglobins

Fc

20

- Antibodies interact with the epitope of the antigen by shape/shape recognition (lock and key mechanism)

- Recognition depends on multiple noncovalent bonds between the antigen-binding site and epitope

- Antibodies work to eliminate antigens by either enhancing phagocytosis or inducing the complement protein cascade

21

• The variable regions differ in the amino acid

sequences at the antigen-binding site and are

responsible for the diversity of antibody specificity

• The enormous range of antibody specificities is

made possible by the recombination of numerous

versions of coding regions for the variable regions

22

The Genetic Basis of Antibody Diversity

• As B cells develop, their genomes become modified until the cell can produce only one specific type of antibody

• If we had a different gene for each antibody our immune systems are capable of producing, our entire genome would be taken up by antibody genes

• Instead, just a small number of genes that can recombine to generate multitudes of possibilities are responsible for the vast diversity of antibodies

23

The Genetic Basis of Antibody Diversity

• Each gene encoding an immunoglobin is in reality a “supergene” assembled from several clusters of smaller genes located along part of a chromosome

• During B cell development, these variable regions rearrange and join

• Pieces of DNA are deleted, and DNA segments formerly distant from one another are joined together

• Immunoglobulin genes are assembled from randomly selected pieces of DNA

random process

24

Figure 18.18 Heavy-Chain Genes

Variable region for heavy chain

Constant Region

Encoded by one V segment,one D segment & one Jsegment

Another pool of segmentsis used for the constant region

25

The Genetic Basis of Antibody Diversity• There are multiple genes coding for each of the four

kinds of segments in the polypeptide chain for the heavy chain in mice: 100 V, 30 D, 6 J, and 8 C regions

• Each B cell randomly selects one gene for each of the V, D, J, and C regions

• A similar process occurs for the light chain• Theoretically, there are 144,000 x 144,000 possible

combinations of light and heavy chains– 21 billion possibilities

26

Immunoglobin• There are five immunoglobulin classes are based on

differences in the constant regions of the heavy chain– Table 15.2

• IgG – Classic Y shape– Compose 85% of the total immunoglobulin content of the bloodstream

• Complementation activation• Neutralize toxins• Opsonization

– FC binds to phagocytes

– Cross the placenta– Leave blood vessels and enter tissues

• IgM– Pentamer – More efficient at complement activation, neutralization and

agglutination– Produced as a first response by plasma cells– FC binds to B cells

27

28

Macrophage has receptorsfor constant region of Ab

Binding of Ab to receptorinitiates phagocytosis

OpsonizationCovered by complement proteins or Ab

29

Some Review Before Moving On…

Two General parts of Immune Response…

1) Cell mediated immunity – deals with destruction of cells… infected or tumor or injured cells

2) Humoral or Ab-mediated immunity – deals with production of Ab

30

Some Review Before Moving On…

Lymphoid Tissue…characterized by two types

Primary: Bone Marrow Thymus Gland

Secondary: Lymph Nodes, Spleen, Tonsils, Appendix (?)

31

Review of Cells of Immune System

Ag-Presenting Cells- APCs

Include macrophages and some other lymphocytes

32

T-Cells

5 Types

1) TD cells: D = Delayed-type hypersensitivity, involved in allergic reactions and inflammation

2) Natural Killer Cells (NK Cells): Responsible for cell killing (many consider these not T cells and are sometimes called null cells)

33

T-Cells

3) TC cells: Cytotoxic T cells – Responsible for cell killing

4) TH cells: Helper T cells – two typesa) TH1 Cells: Stimulate TC cells and so part of Cell-mediated immune response; Stimulate macrophages, Involved in inflammation

b) TH2 Cells: Stimulate B cells – leading to Ab production so part of humoral immune response

34

T-Cells

5) TS Cells: Supressor (or regulatory) T cells – Supresses immune response of other cells… very important. Two types…a) One with CD4 receptor

b) One with CD8 and CD25 receptors

Some are using these to combat autoimmune diseases

35

CD (Cell-Associated Differential) Receptors

Two main types (for us)

1) CD4: On TH cells and TD cells and some TS cells

2) CD8: TC cells and some TS cells

36

Major Histocompatibility Complex Proteins

Found in all vertebrate animals Collectively called Human Leukocyte Antigens

(transplantation problems)Two Types:

1) Class I MHC – found on surfaces of all nucleated cells 2) Class II MHC – found on B lymphocytes macrophages, and dendritic cells (all of which are APCs)

37

B Cells

B Cells Give rise to 2 to two types of cells…

1) Plasma Cells – cells that produce antibodies

2) Memory cells - slow growing cells that will produce antibodies when same Ag in reintroduced to host

38

Additional Information of Immunoglobulins

5 Classes: 1) IgG (80%): Found in extracellular fluid, blood and lymph, crosses placenta

2) IgM (6%): First Ab to appear after immunization, bind complement strongly; found in blood and lymph, and on the surfaces of B lymphocytes (as a monomer)

39

Additional Information of Immunoglobulins

3) IgA (dimer) (13%): Known as major secretory Ab, found in all kinds of secretions including saliva, colostrum, serum; is a monomer in serum and dimer in everything else

4) IgD (1%): Minor circulating Ab found in blood and lymph and lymphocyte surfaces; very heat labile; no known function but abundant of surface of memory B cells…

40

•Additional Information of Immunoglobulins

5) IgE (0.002%): Involved in allergic reactions, binds to mast cells; found in blood and lymph only

Know term valence… valence

41

Opsonization

Definition: Enhancement of phagocytosis by antibody or complement binding

When Ab binds to an Ag on surface of cell, the cell is more likely to be phagocytized…

When complement binds this Ab-Ag complex, it is even more likely to be phagocytized

42

Superantigens –e.g., Staphylococcus aureus Toxins (TSS toxins)

Proteins capable of eliciting a very strong immune response because they activate more T cells than that activated in a “normal” immune response…

43

Other Terms…

1) Natural Active Immunity-

2) Artificial Immunity –

3) Passive Immunity-a) General passive immunity- advanatges and

disadvantages

b) Maternal Passive Immunity- good for about 6 months

Two Scenarios

45

Phases of the Humoral Immune Responses (Part 1)

TH cells bind to an antigen presented to it by an antigen-presenting macrophage

The activated TH cell produces and secretes IL-2 molecules, which attach to their own specific cell membrane receptor proteins

The TH cell divides to produce clones capable of interacting with B cells

These steps, called the activation phase, occur in the lymphatic tissues

IL-1

IL-2

46

Phases of the Humoral Immune Responses (Part 2)In the effector stage, an antigen of the same sort that was processed by the macrophage binds to a specific IgM receptor on the surface of a B cell

The B cell degrades the antigen and presents a piece of processed antigen in a class II MHC protein on its cell surface

One of the TH cells created in the activation stage recognizes the processed antigen and class II MHC protein on the surface of the B cell

The TH cell releases growth factor, which activate B cell proliferation and differentiation into plasma cells and memory cellsThe plasma cells secrete Abs

IL-4

IgM

47

Phases of the Cellular Immune Responses (Part 1)Like class II MHC molecules, class I MHC molecules also present processed antigen to T cells

Foreign protein fragments are bound by class I MHC molecules and carried to the plasma membrane, where TC cells can check them

If a TC cell binds to the MHC I–antigen complex, the TC cell is activated to proliferate and differentiate

If a cell has been infected by a virus, or has mutated, it may present protein fragments that are not normally found in the body

IL-2drives T cell division

48

Phases of the Cellular Immune Responses (Part 2)

In the effector stage, TC cells once again bind to the cells bearing MHC I–antigen complex and secrete perforin molecules create pores within the cell

This system helps rid the body of virus-infected cells. It also helps to destroy some cancer tumors

TC secrete granzymes that enterthe pores and induce apoptosisGranzymes are stored in cytoplasmic granules

49

Some develop into effector cells (plasma cells)

Memory (Fig 15.13) Each B cell makes a unique Ab on its surface

Specificity between theantigen & Ab

B cell divides

Production of Clonesclonal selection

A few develop into memory cells that divide at a low rate

50

First exposure to the antigenPrimary response: IgM & IgGSecondary response: IgG & IgM

Memory B cells differentiate into plasma cells and produce IgG

Latent PeriodAntigen concentrated in lymphoid tissue

Augmented response related to a prior stimulation of the immune system by antigens.

Persists 23 days

Persists 5 days

Produced by plasma cells

Body produces memory B cells

Memory B cells survive in lymphoid tissue

Memory cells will divide and differentiate into plasma cells without interaction with APC

51

Can there be B cells that make antibodies against host….?

Yes… this a is a big problem… but most are eliminated…

“Clonal Deletion”

52

Allergic (Hypersensitivity Reactions)

Anaphylaxis – can be local or systemic

4 Types:Type I: Immediate Hypersensitivity… occurs within minutes, IgE sensitization of mast cells that become degranulated (they release histamine and serotonin)… therby causing anaphylaxis… examples- bee sting reactions, hay fever

Treatment - antihistamines

53

Allergic (Hypersensitivity Reactions)

Type II: Cytotoxic Hypersensitivity – Mechanism involves IgG interaction with cell surface Ag

Occurs in hours… example is many drug allergies including that for penicillin

Type III: Immune Complex Hypersensitivity – Mechanism is IgG interaction with soluble or circulating Ag – Reaction takes hours…

Example : Systemic Lupus erythematosis (Lupis)Involves autoantibodies against soluble, circulating self-Ag. Ab bind

to proteins forming insoluble complexes and then complement becomes involved resulting in infallmation

54

Allergic (Hypersensitivity Reactions)

Type IV: Delayed-type hypersensitivity – Takes days to develop (maximum reaction is typically 24-48 hours)… Mechanism involves TH1 inflammatory cells… Ab not involved

Tissue damage due to inflammations by TH1 inflammatory cells that release cytokines that attract macrophages to go to affected area

Examples: Contact dermatitis (poison ivy) and the tuberculin test… Type I (juvenile) diabetes mellitus

55

Allergic (Hypersensitivity Reactions)

Autoimmune Diseases…

Caused by Types II, III, and IV