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MICR 201 Microbiology for Health Related Sciences

Lecture 10: Adaptive ImmunityEdith Porter, M.D.

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Lecture outline

Concept of immunity▪ Innate immunity ▪ Adaptive immunity

Humoral and cellular adaptive immunity Antigens and antibodies B cells and humoral immunity Effects of antigen-antibody binding T cells and cellular immunity Antigen presenting cells Cytokines Immunological memory

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Overview of host defenses

First Line of Defense Second Line of Defense

• NK cells

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Concept of immunity

INNATE IMMUNITY

Functional at birth Rapid responses:

preformed or available within hours after infection

Limited specificity: pattern recognition via toll like receptors

Widely present in nature including in plants, invertebrates and vertebrates

ADAPTIVE IMMUNITY

Acquired, available within days

High specificity Memory In higher

vertebrates

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Humoral and cellular immunity

Humoral immunity Transferable with serum Highly specific Mediated by antibodies and

lymphocytes who produce these antibodies

These types of lymphocyte mature in the bone marrow and are called B lymphocytes (B cells)

Cellular immunity Mediated by lymphocytes that

mature in the thymus and are called T lymphocytes (T cells)

T cells orchestrate the immune response

The thymus is located in mediastinum

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Lymphocytes

http://www.aamdsglossary.co.uk/i/c/1_2_lymphocytes.jpg

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Differentiation of B and T cells

B for Bone marrow

T for Thymus

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The lymphatic system

PRIMARY LYMPHATIC TISSUE

Lymphocyte formation and maturation

Bone marrow Thymus

SECONDARY LYMPHATIC TISSUE

Antigen contact Spleen Lymph nodes Peyer’s patches Mucosa associated

lymphatic tissue (MALT)

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Main tasks of lymphocytes Recognize foreign agents (antigen)

Lymphocytes carry specific antigen receptors on their surface

B-cell receptor, T-cell receptor Block and eliminate foreign agents

Through antibodies By activating host defense cells via cytokines By destroying infected host cells that have

been taken over by infectious agents

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Antigen

Substances that causes the body to produce specific antibodies

Any molecule that can be recognized by and bound to an antibody (“antibody generating”) or a T cell

Typically proteins and carbohydratesEpitop (or antigenic determinant) is

part of the antigen and is the specific region with which an antibody interacts

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Antigenic Determinants

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Example: Penicillin

Haptens A molecule too small to stimulate antibody formation

by itself When combined with a larger carrier molecule it can

initiate antibody production Once antibodies are generated, hapten can be

recognized by itself

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Antibodies

Globulin proteins (immunoglobulins or Ig)

Made in response to an antigen A bacterium or virus has many

antigenic determinants against which antibodies can be made

Bi-functional One portion binds specifically to

particular structures called antigen The other part interacts with host cells

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Antibody structure

2 heavy chains 2 light chains Connected with

disulfide bridges Variable regions in

heavy and light chains: bivalent antigen binding sites, mediate specificity

Constant regions on heavy chain mediate effector function

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Antibody classes

Each class shares the constant region of the antibody molecule but has many different variable regions

Each class interacts with different types of host cells

Differ in their effector function 5 classes:

IgG IgM IgA IgD IgE

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Monomer 80% of serum antibodies Fix and activate complement (classical

pathway) In blood, lymph, intestine Cross placenta Opsonin (enhance phagocytosis);

neutralize toxins & viruses; protect fetus & newborn

IgG antibodies

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Pentamer 5-10% of serum antibodies First Ig of an immune response Fix and activate complement (classical

pathway) In blood, lymph, on B cells Agglutinates microbes

IgM antibodies

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Dimer10-15% of serum antibodies In secretions (milk!!)Protection of mucosa

Mucosal pathogens like Haemophilus or Neisseria secrete IgA proteases

IgA antibodies

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Monomer0.2% of serum antibodiesMainly on B cells Maturation sign

IgD antibodies

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Monomer~0.002% of serum antibodiesMainly on mast cells, basophils,

and activated eosinophilsAllergic reactions; defense

against parasitic worms

IgE antibodies

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Bone marrow gives rise to B cells (B-lymphocytes)

Naïve but mature B cells migrate to secondary lymphatic tissue and become exposed to antigen

B cells recognizes epitopes with antigen specific B cell receptor

Each B-cell expresses a unique B cell receptor on its surface

B-cell receptor is actually the antibody produced by a particular B cell

B cells

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Clonal selection and expansionIncreased antibody productionPlasma cell or memory cell

development

Consequences of antigen recognition by B cells

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Clonal selection and differentiation of B cells

A clone originates

from a single cell

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Effector function of antibodies

Begin after antigen-antibody complex has been formed

Aggluntination Opsonization

Enhanced phagocytosis Complement activation

Opsonization and enhanced opsonophagocytosis via c3b

Microbial lysis through C5b-C9n Inflammation through C5a, C3a, C4a

Neutralization Toxins Viruses

Antibody dependent cytotoxicity Eosinophils: secrete toxic granules onto helminths NK cells: induce apoptosis of virus infected cells

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Effector functions of antibodies

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Anti-helminthic cytotoxicity of eosinophils

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Natural killer cells

Large granular lymphocyte-like cells Part of first line of defense (innate immunity) Activated by interferons (produced by virus infected

cells) and other cytokines Target altered host cells

Virus infected Infected with intracellular organism Tumor cells

Induce cell suicide (apoptosis) Cells covered with antibodies (antibody dependent

cytotoxicity) Direct sensing of altered cells

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The kiss of death

After NK cell have recognized their target they release their large granules containing Pore-forming

toxins Enzymes that

induce suicide of target cell

Tumor Cell

NK-Cell

t0

t60’

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After differentiating in the thymus, T cells migrate to lymphoid tissue

T cells become activated effector T cells when stimulated by an antigen

T cells respond to digested antigens via T-cell receptor

T cells recognize antigen only when presented by other cells on special molecules Major histocompatibility complex (MHC)

Some effector T cells become memory cells

T-cell mediated immunity

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T-cell antigens

Short contiguous amino acid (aa) sequence

Processed antigens Antigen must have

been unfolded and degraded

Primary aa structure Only when bound to

a specialized antigen presenting molecule (MHC)

APC

MHC

T-Ly

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MHC molecules

Major Histocompatibility Complex Same as HLA (human leukocyte antigen) Determine compatibility of donor and recipient in

transplantation Every individual as a unique set of MHC molecules Within an individual all cells are equipped with the same set Have a peptide binding groove onto which antigen can be

loaded MHC I: peptides newly synthesized and degraded in cytoplasma

(endogenous) MHC II: peptide fragments generated in phagolysosome

(exogenous)

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Classification of T cells

Depends on surface molecules on T cells that determine the interaction with MHC molecules and their type of response Cytokine release Sending trigger to target cell to commit

cell suicideT helper cellsCytotoxic T cells (“T killer cells”)Regulatory T cells

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T-helper cells

Express the surface molecule CD4 Recognizes exogenous digested antigen

presented on MHC type II molecule Interact with antigen presenting cells

Macrophages Dendritic cells B-cells

Respond with secretion of cytokines and activate immune cells

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Antigen presenting cells

Express MHC II Highly specialized in uptake of

foreign antigen, degradation and presentation to T helper cells via MHC II

Macrophages and dendritic cells Take up antigen via phagocytosis

B cells Bind antigen with surface

antibody and internalize the complex

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The CD4 : MHC II Interaction

Ag Presenting Cell

MHC IIDigested Ag

Microbe

CD4TCR

TH Cell

Cytokines

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T helper cells in action

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T helper cell subclasses

TH1 Secrete the cytokine IFNg▪ Activates macrophages▪ Promotes IgG antibody production in B cells

TH2 Secrete the cytokine IL4▪ Promotes IgE production in B cells▪ Pro-allergic

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Cytotoxic T cells

Express the surface molecule CD8Recognizes endogenous antigen

presented on MHC type I molecule Can interact with any nucleated cell

Respond with secretion of perforin and granzyme Kill target cells via apoptosis in a

highly specific manner

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The CD8 : MHC I Interaction

Any Nucleated Cell

MHC IEndogenous Ag

EndogenousAg

CD8TCR

CTL

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CTL mediated cytotoxicity

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Treg and TH3Differentiate from T helper cellsTurn off immune response when Ag no

longer presentUse inhibitory cytokines (IL10)

Regulatory T cells

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Summary for cell mediated immunity

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Principals cells in the adaptive immune response

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Summary for cytokines

Cytokine Source Effect

Interleukin-1 Macrophages Activates TH cells, induces fever

Interleukin-2 Activated lymphocytes Activates lymphocytes, NK cells

Interleukin 4 TH2 cells IgE production

Interleukin 6 Monocytes, macrophages Acts on liver, acute phase response

Interleukin-8 (CXCL8)

Epithelial cells, macrophages, neutrophils

Activates and attracts neutrophils

Interleukin 10 TH3 cells Inhibitory

Interleukin-12 Activated macrophages, TH1 Activates NK cells

Interferon a and b Any virus infected cell Induce antiviral activity

Interferon g TH1 cells Activates macrophages

Tumor necrosis factor a

Monocytes, macrophages Activates phagocytes, NK cellsCytotoxic for tumor cells

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Superantigens

Activate simultaneously up to 20% of all TH cells

Cause an intense immune response due to release of cytokines from host cells (“cytokine storm”)

Fever, nausea, vomiting, diarrhea, sunburn-like rash, shock, death

Examples : Toxic Shock Syndrome Toxin

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Immunological memory

Once lymphocytes have encountered their specific antigen they undergo clonal expansion

Some of these cells develop further into memory cells Can circulate for many years

Upon re-contact with the same antigen they quickly proliferate and resume effector function▪ B cells: antibody production▪ T cells: cytokine production (TH, Treg) and cytotoxicity

(CTL)

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Example: Primary and secondary immune responses to an antigen

IgM is always the first antibody

IgG follows IgM IgG level does not go

back to baseline Re-exposure to the same

antigen will lead to an augmented and accelerated immune response with higher residual antibody levels

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Types of adaptive immunity

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Important to remember

Key players in adaptive immunity Antibodies B-cells T-cells

Lock- key principle: Ag-Ab B cells make antibodies 5 Types of antibodies : IgM (first), IgG (placenta), IgD (maturation), IgA

(mucosa), IgE (allergies) Antibodies can agglutinate, activate complement, promote phagocytosis,

neutralize and initiate cell lysis by NK cells T cells recognize digested antigen when presented to them on MHC

molecules Main effector T-cells

Helper T-cells: strengthen defense cells Cytotoxic T-cells: kill infected cells Regulatory T cells: down regulate immune response

Cytokines serve cell-to-cell communication

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Check your understanding 1) What type of immunity results

from vaccination? A) Innate immunity B) Naturally acquired active immunity C) Naturally acquired passive

immunity D) Artificially acquired active

immunity E) Artificially acquired passive

immunity

3) What type of immunity results from recovery from mumps?

A) Innate immunity B) Naturally acquired active immunity C) Naturally acquired passive

immunity D) Artificially acquired active

immunity E) Artificially acquired passive

immunity

15) The antibodies found in mucus, saliva, and tears are

A) IgG. B) IgM. C) IgA. D) IgD. E) IgE.

26) The best definition antibody is A) A serum protein. B) A protein that inactivates or kills an

antigen. C) A protein made in response to an

antigen that can combine with that antigen.

D) An immunoglobulin. E) A protein that combines with a

protein or carbohydrate.