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Properties and Overview ofImmune Responses

Abbas Chapter 1

David RobertsonJuly 19, 2011

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Immune Function

Defense against infectiousmicrobes

Microbial components

Other proteins

Vaccines, Allergy, Auto-immunity

General overview of the immune system.

Primary function:1. Defense against infectious microbes.2. Because microbes are processed before presentation, other, non-infectious proteins can also be presented to the immunesystem and cause a reaction.

Modulation of the immune system: variolation

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Broken down into innate and adaptive in terms of immune reaction and components.Not a pure division: NK cells, macrophages.

Innate immunity is more rapid on initial presentation, but also more generalAdaptive takes longer to respond but is more specific.

Innate immunity is in all multicellular organisms.

Adaptive is only in vertebrates.

Not pictured are cytokines, secretory molecules that:1. link the two systems and2. regulation3. feedback and enhancement

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Designed for immediate/rapidresponse

Same response every time -common pattern

recognition.

First Line - Epithelial barrier

Second Line - Cells

Innate Immunity

Innate immunity

1. Epithelial barriers (Immediate)2. APCs - Phagocytes, dendritic cells3. Complement cascade4. NK Cells5. Cytokines

Because the response is always the same, microbes have developed ways around them, necessitating the adaptive immuneresponse.

Epithelial barrier includes skin, airway, GIAntimicrobial efects, secreted oils, ciliary clearanceNon-specific, Mechanical

Once the epithelial border is breached there are two ways the innate immune fights infection: #1 inflammation

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Inflammation

Anti-viral

Innate Immunity

Inflammation APCs - Dendritic cells

Cytokines - TNF-, IL-1, IL-6

Cells - Neutrophils, monocytes,macrophages, NK cells, mast cells(TLRs)

Inflammation = Cell recruitment

APCs - Dendritic cells, macrophages. Process pathogens, recruit leukocytes through cytokines

Cytokines Promote inflammation, recruitment. Pyrogens. IL-6 promotes neutrophil proliferation, hepatic acute phase proteins,and B lymphocytes.

Phagocytes cells - Neutrophils, Monocytes mature into macrophages. These cells have surface receptors that recognize foreign/microbial components and produce reactive oxygen/nitrogen species. These receptors are germline encoded and do notundergo recombination.

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Innate Immunity

PAMPs - Pathogen associatedmolecular patterns

TLRs - Toll-like receptors

Mannose Scavenger

N-formyl methionyl

Pattern recognition receptors

PAMPs - Same receptor recognize a antigen shared across an entire family of microbesalso DAMPs - damage associated

TLRs - Leucine rich hooks, cystine flanking motif, TIR (Toll like IL-1 receptor) 9 kinds, each one recognize a diferent class of microbial components

Mannose - phagocytosis, recognizes microbial sugar residuesScavenger - recognize oxidized lipoproteins including LPS and lipoteichoic acidN formyl methionyl - Structure on all bacterial but almost no mammalian proteins

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Innate Immunity

Anti-Viral Functions

Type I interferons - INF-, INF-

Resistance, lymph sequestration,increase NK cell activity

#2 Function: Antiviral

Recognition of viral particles induces release of Type I interferonsEfects: 1. Induce resistance to viral infection 2. Lymphocyte sequestration in the lymph nodes 3. Upregulate NK cell activity

Used in the treatment of viral hepatitis (Hep C)

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Innate Immunity

Complement

Alternative Pathway

Increased C3 activity

Direct binding/activation

Loss of C3 inhibition

LPS directly binds to C3

C3 always has some natural activity, butMammalian cells have C3 inhibitors on cell surfaceMicrobes dont and C3 can bind there begin cascade

C3 deficiency leads to severe, recurrent infections with encapsulates organisms, particularly S. pneumo and H flu

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Cytokines

IL-6 - Promotes antibody secretion by B cells

IL-12 stimulates TH1 differentiation

IL-15 promotes survival of memory CD8+ T cells

IL-1, IL-6, IL-23 stimulate TH17 effector cells

Autocrine, Paracrine, Endocrine

Autocrine - act on selfParacrine - NearbyEndocrine - Remote

Already talked about TNF, IL-1, IL-6

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Though Im presenting this linearly adaptive immunity is being stimulated while the innate system tries to hold of infection.

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Adaptive Immunity

Specificity and diversity Specialization

Memory

Clonal expansion Contraction and homeostasis

Self tolerance

Major players here are the lymphocytes, though once again cytokines will play a key role

Using an army analogy, these guys are the specialists

Much more active process, and failure at any one of these steps will cause disease

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Adaptive Immunity

Epitope/Determinant

Specialization

Repertoire - 107-109

Specificity and Diversity

Epitopes are the site on proteins that are immunologically active.

Each lymphocyte recognizes 1 antigen or epitope

Many proteins may have more than 1 (foods)

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Adaptive Immunity

Humoral Extracellular

Toxins

Cell-Mediated

Intracellular

Humoral vs Cell Mediated

Active - Response to immune stimulus. Has memory

Passive - Placental transfer, Specific antibody (tetanus), IVIG. No memory

Together

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CD4+

CD8+

CD19+

CD16,56

+

Multiple

Cell Types

Adaptive Immunity

TH2 - IL-4, IL-5, IL-13

TH1 - INF-, IL-12,

IL-18 TNF-

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Adaptive Immunity

Memory B cells

Plasma Cells

Memory T cells

Memory increased efectiveness B cells - Anity maturation, better antibodies T cells have more vigorous and rapid response

The secondary immune response is both more rapid and more vigorous

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Two Signal Hypothesis

Adaptive Response

1. Capture and display of microbial antigens. APCs, same ones as in innate immunity present antigen to T cells. Most importantprobably dendritic cells. B cells can recognize soluble antigen directly, or have them presented to them.

2. Clonal expansion - There are subsets of lymphocytes that can recognize each antigen. A specific antigen will only berecognized by the corresponding lymphocyte. These cells then expand clonally to react to the specific agent. 2 signalhypothesis - 1st antigen in appropriate presenting molecule (MHC I) 2nd costimulators.

3. Diferentiation - T cells. CD4+ T cells secrete IL-2 which supports T cell proliferation and maintenance. Recruit leukocytes,stimulate CD8 cells and B cells. CD8 cells diferentiate into CTLs that destroy infected cells.

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Two Signal Hypothesis

Adaptive Response

1. Capture and display of microbial antigens. APCs, same ones as in innate immunity present antigen to T cells. Most importantprobably dendritic cells. B cells can recognize soluble antigen directly, or have them presented to them.

2. Clonal expansion - There are subsets of lymphocytes that can recognize each antigen. A specific antigen will only berecognized by the corresponding lymphocyte. These cells then expand clonally to react to the specific agent. 2 signalhypothesis - 1st antigen in appropriate presenting molecule (MHC I) 2nd costimulators.

3. Diferentiation - T cells. CD4+ T cells secrete IL-2 which supports T cell proliferation and maintenance. Recruit leukocytes,stimulate CD8 cells and B cells. CD8 cells diferentiate into CTLs that destroy infected cells.

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Two Signal Hypothesis

Adaptive Response

1. Capture and display of microbial antigens. APCs, same ones as in innate immunity present antigen to T cells. Most importantprobably dendritic cells. B cells can recognize soluble antigen directly, or have them presented to them.

2. Clonal expansion - There are subsets of lymphocytes that can recognize each antigen. A specific antigen will only berecognized by the corresponding lymphocyte. These cells then expand clonally to react to the specific agent. 2 signalhypothesis - 1st antigen in appropriate presenting molecule (MHC I) 2nd costimulators.

3. Diferentiation - T cells. CD4+ T cells secrete IL-2 which supports T cell proliferation and maintenance. Recruit leukocytes,stimulate CD8 cells and B cells. CD8 cells diferentiate into CTLs that destroy infected cells.

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Two Signal Hypothesis

Adaptive Response

1. Capture and display of microbial antigens. APCs, same ones as in innate immunity present antigen to T cells. Most importantprobably dendritic cells. B cells can recognize soluble antigen directly, or have them presented to them.

2. Clonal expansion - There are subsets of lymphocytes that can recognize each antigen. A specific antigen will only berecognized by the corresponding lymphocyte. These cells then expand clonally to react to the specific agent. 2 signalhypothesis - 1st antigen in appropriate presenting molecule (MHC I) 2nd costimulators.

3. Dif

erentiation - T cells. CD4+ T cells secrete IL-2 which supports T cell proliferation and maintenance. Recruit leukocytes,stimulate CD8 cells and B cells. CD8 cells diferentiate into CTLs that destroy infected cells.

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Two Signal Hypothesis

IL-2

CTLs

T cell dependent

Class switching

Adaptive Response

3. B cells. Polysaccharides, nucleotides, glycolipds antigens are T cell independent. Protein antigens require presentation by Thelper cells. Activated B cells produce antibodies. First IgM, then other types through class switching, also T helper celldependent.4. Elimination - Neutralization, opsonization, complement activation, phagocytosis5. Apoptosis - Stimulatory cytokines fade and efector cells undergo apoptosis, through the FAS:FASL system. Mutations causeALPS (autoimmune lymphoproliferative syndrome).6. Memory cells remain.

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Two Signal Hypothesis

IL-2

CTLs

T cell dependent

Class switching

Complement activation

Adaptive Response

3. B cells. Polysaccharides, nucleotides, glycolipds antigens are T cell independent. Protein antigens require presentation by Thelper cells. Activated B cells produce antibodies. First IgM, then other types through class switching, also T helper celldependent.4. Elimination - Neutralization, opsonization, complement activation, phagocytosis5. Apoptosis - Stimulatory cytokines fade and efector cells undergo apoptosis, through the FAS:FASL system. Mutations causeALPS (autoimmune lymphoproliferative syndrome).6. Memory cells remain.

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Two Signal Hypothesis

IL-2

CTLs

T cell dependent

Class switching

Complement activation

Adaptive Response

3. B cells. Polysaccharides, nucleotides, glycolipds antigens are T cell independent. Protein antigens require presentation by Thelper cells. Activated B cells produce antibodies. First IgM, then other types through class switching, also T helper celldependent.4. Elimination - Neutralization, opsonization, complement activation, phagocytosis5. Apoptosis - Stimulatory cytokines fade and efector cells undergo apoptosis, through the FAS:FASL system. Mutations causeALPS (autoimmune lymphoproliferative syndrome).6. Memory cells remain.

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Summary

Innate, Adaptive

Specificity, diversity, memory, homeostasis, tolerance

B lymphocytes, T lymphocytes

Active, passive CD4+, CD8+

Cytokines are the glue

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Questions?