Lecture1-InnateVsAcquired

8/3/2019 Lecture1-InnateVsAcquired

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Innate vs. Acquired Immunity- conceptual and practical

difference

The vertebrate invention of acquired immunity

How does innate immunity work? (Chapters 1 and 8)

Cells

Recognition receptors

Mediators

Lecture 1 Introduction to the Principles of Immunity


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The Triumph of Death - Pieter Brueghel the Elder ca. 1562


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Why the immune

system?

What is its function?

How widely is it present in nature?

Why does it affect so many aspects of life?

How can we alter it for improved quality of life?


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How does the Immune System (IS) affect

your life?

Infectious Diseases:Almost any deficiency in immunity--you die

Autoimmune diseases:Graves'/hyperthyroidism, Type I diabetes, pernicious anemia, rheumatoid arthritis,thyroiditis, and vitiligoThe incidence of 24 autoimmune diseases is 1/31 Americans. Women are at 2.7x greaterrisk Clin Immunol Immunopathol1997 Sep;84(3):223-43

Cancer:Evidence in the past year indicates that the immune system does indeed function in tumorsurveillance

Hypersensitivity Diseases:Allergy-Incidence rise from 6%-20% in the past two decadesAsthma-Incidence rise from 3%-8% of the total population in the past two decades

-The hygiene hypothesis-Heart Disease-The blood vascular system is an integral part of the immune system. Itinstructs leukocytes to migrate from the blood to a site of infection. New evidence supportsthat idea that coronary heart disease results from chronic arterial inflammation


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Big bugs have little bugs

Upon their backs to bite em

Little bugs have littler bugs

And so on ad infinitum-Ogden Nash, I think

Colonization of large organisms by smaller organisms orviruses is the inverse food chain

Large complex organisms present a source of energy and ahabitat for smaller organisms and viruses via colonization

Colonization and defense against colonization is a fundamentalprinciple in biology

The immune system is principally and most importantly evolvedto sculpt colonization to benefit the host

Immune

Evolution


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Dance of the Eons

Virtually every organism faces pressure from viral or microbial colonizationand so has evolved strategies to control colonization

Likewise, every parasitic organism or piece of selfish DNA has evolved astrategy to mitigate the effects of immunity

This eternal waltz of parasites and their hosts surely began with the origin oflife

Corollaries

Just as predator species improve the fitness of their prey, colonial agentsselect for fitness in their hosts

Just as a host cannot be too permissive for a parasitic agent, theparasitic agent cannot be too effective in killing a host

The more effective the immune system, the more complicated andevolved the parasite

Perhaps we should view the host-parasite interaction as a constantlyescalating war or an uneasy (metastable) truce


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One view of

animal phylogeny


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Biological Invention

of Acquired Immunity


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Innate vs. Adaptive ImmunityFigure 1.5

Memory


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Innate Immunity

All animals have an innate immune system

Innate immunity is manifest in many cells of the body. The basis is the

recognition ofmolecular patterns, that occur in microbes but not

animals (e. g., unmethylated DNA sequences, dsRNA, cell wall

components, etc)

This is the bedrock of immunity in all organisms--even bacteria have

defense mechanisms against bacterial viruses


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Innate Immunity, cont

An apparent limitation is that parasitic agents have a

generation time orders of magnitude less than that of theirhosts

A second limitation is that there is only limited

amplification of the response

A third limitation is that there is no memory


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Adaptive Immunity

Recognizes any biochemical determinant

Provides a mechanism for immune recognition

that can evolve as rapidly as the parasite (clonalselection)

There is rapid amplification of a response

There is memory


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Components Principle Functions

Barriers

Epithelial layers Prevent entry

Defensins and Cryptidins Microbial killing

Circulating and Tissue Effector Cells

Neutrophils Early phagocytosis and killing of microbes

Mast Cells Release of inflammatory granules

Macrophages Efficient phagocytosis and killing of microbes: cytokines

Eosinophils Nasty toxic cells designed to kill helminths (worms)

NK cells Lysis of infected cells, activation of macrophages

Circulating ProteinsComplement (C) Killing of microbes, opsonization of microbes, actvn leukocytes

Mannose-binding protein Opsonization of microbes and activation of C

C-reactive protein Opsonization of microbes and activation of C

Lysozyme Bacterial cell wall lysis

Cytokines

TNF, IL-1, 6, 18 Inflammation

IFN a, b Resistence to viral infection

IFN g Macrophage activation

IL-12 IFNg production by NK cells

IL-15 Proliferation of NK cells, memory T cells

IL-10, TGF b Control of Inflammation Adapted from: Abbas (Saunders)

Components of Innate

Immunity


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Defensins (epithelium)

Figure 8.6


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Figure 1.4


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Figure 8.9


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Figure 8.1


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Salmonella infection with and without adaptive immunity

Mice deficient

for innate

immunity

(macrophage)

WT

T lymphocyte

deficient


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What is the basis for innate immunity, and how does

is relate to vertebrates? Drosophila melanogastermutants were found that were susceptible to fungaland bacterial infections.

Immunity in Drosophila (Innate)

Tollmutant lacks defense against fungal infections

18 Wheelerlacks defense against bacteria

This led to the discovery of a family of receptorsknown as the Toll-related receptors (TLR) present invertebrates


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Innate Immunity Pattern Recognition

Molecular Pattern

of Microbe

Source Pattern Recognition

Receptor

Principle Innate

Immune ResponsedsRNA Replicating viruses ds-RNA activated

kinase & TLR3

IFNa,b

LPS Gram-negative

bacteria

LBP/CD14/TLR4 Macrophage

activation

N-formylmethionylpeptides

Bacterial proteins NFM receptors Neutrophil andmacrophage act.

Mannose-rich

glycans

Microbial

glycoproteins

MF mannose recptr

Plasma mannose

lectin

Phagocytosis

Opsonization, C

activation

Phosphorylcholineand related

Microbialmembranes

Plasma c-reactiveprotein

Opsonization, Cactivation

CpG

(PuPuCpGPyPy)

Bacteria ? TLR9/DNAPK Macrophage

activation

Other: teichoic acid,


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Genes to Cells6(9),733-742Kiyoshi Takeda and ShizuoAkira (2001)

Activation of the

transcription factor:NFkB


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Toll family of receptors


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Toll-like receptors [TLR1-10]

Recognition alone or in

combinations of:

LPS (gram-negative cell

wall component)

Lipopeptides and

peptidoglycan (gram

positive cell wallcomponents

Yeast particles

TIRDomain

Activation of NFkB transcriptionfactor and thus induction ofcytokines and other genes that

are anti-microbial


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Unified Immunity Concept

Innate Immunity molecular pattern recognition

inflammation (alarm and danger)

mobilization of many immunecomponents including presentation of

foreign agents to the lymphoid system

Adaptive Immunity

clonal recognition of foreign agents by Tand B cells followed by selectiveexpansion (production of antibodies,cytokines, and chemokines)

+

mechanisms exclusive to adaptiveimmunity


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Progression of Immunity

At least two cell types reside within or beneath the epitheliumand induce inflammation in response to trauma or microbial

products: Macrophages and Mast Cells

Figure 8.5


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Alveolar macrophages (lung)Histiocytes (connective tissue)

Kupffer cells (liver)

Mesangial cells (kidney)

Microglial cells (brain)

Tissue macrophage

Figure 1.6ij


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Receptors on

Macrophages:

LPS receptor-CD14

Toll-like receptors

Fc receptors

Mannose receptor

Complementreceptors

IFNg receptor

Chemokine

receptors

Figure 1.13


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Function in disease, not entirely

understood

Contains high affinity receptors

for IgE, and preformed granules

that contain inflammatory

mediators including: histamine;

heparin; TNFa; chondroitin

sulfate; neutral proteases; and

other.

Mast cells can also secrete:

cytokines to induce

inflammation; chemokines to

induce infiltration by monocytes,

and neutrophils, leukotriences to

induce muscle contraction andincrease vascular permeability

Mast cells are capable of

inducing an inflammatory

cascade

Figure 1.6gh


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Mast cells are also found in the tissues

Mast cells canrelease histamineswhich induceinflammation

Redness, swelling

(erythema, edema)

Neutrophils and

monocytes are

recruited

Figure 1.14

TNF


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High affinity FceRI

receptor. Effective

against worm

infections. Granules

contain mediators-

smooth muscle

contraction and worm

toxicity

Express some of the

same receptors foundon macrophages

Figure 1.6ef


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LPS receptor:

CD14

toll-like receptor-4CR3,4:

Complement (C)receptors (C3b)

Scavenger receptor:

sialic acid-bearingprotein

Mannose receptor:

Binds mannose onbacteria, activates C

Glycan receptor:

Polysaccharides

IN ADDITION: TLRs

Figure 8.8


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Figure 1.6ab

Lymphocytes are

entirely involved with

acquired immunity.

The come in two types:T lymphocytes (T cells)

that differentiate in the

thymus and B

lymphocytes or B cells

that differentiate in the

bone marrow.

B cells can further

differentiate after

antigen-activation to

plasma cells thatproduce antibodies


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Figure 1.6cd

Nature Killer Cells

play several

interesting roles in the

immune system. One

is to monitor cells for

identification. If a cell

doesnt reveal its

identity papers, it is

killed. Youll see this

later in the course.

Dendritic cells are the

most important

antigen presenting

cells (APCs) in the

immune system


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Figure 8.10

**

**The most important inflammatory cytokine (at least in this course)


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Figure 8.14

Complement facilitates phagocytosis


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Complement facilitates phagocytosis

Figure 1.15

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