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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.