Host Defenses

Anne Nicholson-Weller

Innate (Natural, Non-Specific) Immunity

VS

Adaptive Immunity

Why is the distinction betweenInnate Immunity and Adaptive Immunity relevant for Clinical Medicine?

Vaccines Inflammation Autoimmunity

Innate vs Adaptive Immunity

Innate Adaptive

Origin:

Genes:

Recognize:

Function:

Invertebrates Sharks

Germ line, Periphery,no mutations mutations

Patterns Details

Immediate 7-10 days

Time Frame and Relative Capacity of Innate vs. Adaptive Immunity

Logkill

Barrier

C’NK PMN

Hours Days Years0 4 8 10

Acutephasereactants

ADAPTIVE

Fluid phase proteins that recognizePathogen Associated Molecular Patterns

Examples: Defensins--small intestine Defensins--skin and respiratory epitheliumNatural antibodyComplement

Innate Immunity

Natural Antibody

Made by B1 type B cellsB1 cells line cavitiesHave restricted VH recombinationUsually are CD5+When transformed = CML

Functions of Complement

Recognizeforeignness

C1,Alternative &Lectin pathways

Tag

C4b, C3b,iC3b

Signal

C3a, C5a,iC5b,6,7C5b,6,7,8,9

Complement EffectorsC1q--opsonicMBL--opsonicC4b--opsonicC3b--opsonic, removal of ICiC3b--opsonicC3d--activation of B cellsC3a--mast cell releaseC5a--chemotaxis, superoxideiC5b67--chemotaxisC5b,6,7,8,9--cytokine and lysis of Neisseria

Spectrum of Disease Caused by Neisseria meningitides

Colonization

±AbC’ deficient

Low burden of organisms,moderate disease, but often recurrent

Fulminant disease:Intact complement lyses

organisms and releases LPS

No AbC’ intact

+ AbC’ intact

No disease

Cellular effectors:Neutrophils--Monocytes--Macrophages--Reticulo-endothelium of liver and spleen--

NK cells--lysis

Innate Immunity

phagocytosis + NADPH oxidase

Receptors of Innate Immunity--

Recognize PAMPs: Pathogen Associated Molecular Patterns

Scavenger Receptors

Integrin (Mac-1)

Toll-like Receptors

Toll-like Receptors

Predominately on monocytes and macrophages

Ten different receptors that associate as homo- or heterodimers

Toll-like Receptors

Receptor Dimer

1/1, 2/6

4/4

5/5

Pathogen-derived Ligand

zymosan, gm+ cell wall

LPS

flagellin

Adaptive Immunity

Receptors: B cell receptorT cell receptor

These receptors mutate during the life time of an individual and are positively selectedin response to the particular antigensencountered.

B and T cell receptors recognize details, not general patterns.

Ag MHC Recognized Source Complex by T cell Effect

Endogenous--Class 1eg. Virus encoded proteins

Exogenous----Class 2Intravesicular

eg.intracellular bacteria

Endocyticeg.extracellular bacteria

CD8+ lysis

CD4+

Th1 act.MØTh2 help B cell

Overview of Adaptive Immunity

Endogenous proteins (made by the cell’sown ribosomes) such as viral proteins, associate with Class 1 MHC and areexpressed on the cell surface.

If a CD8 T cell recognizes the Ag in theMHC class 1--Ag complex, the cell will belysed.

Adaptive Immune Responses

Cytosolic/Class 1 pathway:

Viral proteins

MHC-1

MHC-1MHC-1

Proteosome

ER

Transportvesicle

Effectors of Adaptive Immunity

For Influenza infectedepithelial cell:

LysisLysis

Perforin + Granzymes

CD8+

MHC-1MHC-1Fas LFas

Apoptosis

Endogenous Antigens--overlap of Innateand Adaptive Immunity

Uninfected cell,expressingself antigens

EarlyInfection, MHC

NK

lysis lysis

CD8+

Later infection,viral Ag-MHC-1

IFN

ComplementMast cellsPMNNK cells

Activation of APC(upregulation of costimulatorymolecules)

Innate and Adaptive Immunityare linked by cytokines--an adaptive immune response can only be initiated ifinnate immunity has recognized anantigen as “foreign”.

Selection/Activation of T cell

Th1 Th2

IFN IL-4

PPR-signalingIL-12

NaiveCD4

DC

IL-4, IL-5

Neisseria Cryptococcus S. pneumoniae SalmonellaH. influenzaE. coli Listeria

S. pyogenesS. aureus mTB

Extracellular pathogens

Intracellular pathogens

Adaptive Immune Responses to Antigens Synthesized by Bacteria

Extracellular AgEndocytosis by APC--Presentation of Ag

in MHC class 2complex to CD4 T cells (Th2)

Activation of B cells = Ig production

Intravesicular AgAcidification of

phagosomeAddition of MHC

class 2Presentation of Ag

in MHC class 2complex To CD4 T cells (Th1)

Activation of infected M

Adaptive Immune Responses

Intravesicular/Endocytic/Class 2 pathway:

TB Ag MHC-2

MHC-2

MHC-2

M AgMHC-2

tb

For TB infectedmacrophage:

TB Ag MHC-2

CD4, Th-1

Effectors of Adaptive Immunity

IFN

IL12

NADPH oxidaseiNO

Activated MØ

The Killing of Intracellular Pathogens

Strategy of the pathogen: Induce the host to ingest it,

and then with the use of specific virulence factors, preventlysosomes from fusing with itsphagosome.

The Story of Nramp

1970’s--genes for susceptibility tosalmonella, tb, and leishmaniamap to same genetic locus in mice

1990’s--gene cloned, found in RE cellsof mice and men

Natural resistance associated macrophageprotein (Nramp).

H+ H+

The Story of Nramp

PhagosomePhagosome LysosomeLysosome

PhagolysosomePhagolysosome

H+

lysozymelysozyme

Fe++

Mn++

H+

Consequences of Nramp deficiency:

1. Pathogen-derived superoxide dismutasecan not function without Mn++.

2. Phagosome-lysosome fusion is impaired

3. Acidification of phagolysosome impaired

4. Excess Fe++ around mycobacteriaencourages their growth/survival.

Th1 Th2

IFN IL-4

PPR-signalingIL-12

NaiveCD4

DC

IL-4, IL-5

Th2 Pathway

Th2

Ag-specific B cell

lymphoblast

plasma cell

The interaction between APCs and CD4T cells is strengthened by adhesion molecules.

CD4

APCActivated by innate immunity

CD28

B7CD40L -- X-linked hyper IgMCD40

Why is the distinction betweenInnate Immunity and Adaptive Immunity relevant for Clinical Medicine?

Vaccines are not effective unless theyactivate innate immunity first.

Inflammation secondary to traumaand sepsis syndromes is due to innate immunity.

Autoimmunity?

When should you suspect a defect in host defenses?

Age of onset of infectionsPMN--immediateIgG-- delayed to 4-6 mos

Common variable Ig deficiencySite of infections

Otitis, sinusitis, pneumonia--Ig, C’, PMNSkin--PMN

When should you suspect a defect in host defenses?

Type of organismEncapsulated organisms-- Ig, C’, PMNS. aureus. P.cepacia, S. marcescens,

Asprigillus spp. --PMN (CGD)Neisseria spp.--complement

deficiencies (properdin, C5, C6C7, C8, C9)

When should you suspect a defect in host defenses?

Sometimes there is a pattern that makes nosense in terms of host defense mechanisms:

• New syndrome

• Psychiatric illness

Resources/References

Diagnostic and Therapeutic Resources:www.mgh.harvard.edu/depts/id/hmindex.html

The Jeffrey Modell Foundation: National ResourceCenter for Primary Immune Deficiencywww.jmfworld.com/jmfworld.html

Immune Biology by Janeway, Travers, Walport, and Shlomchik. 2001. 5th edition Garland Publishing, NY

Wed 5 PM Immunology Seminars, Armenise Ampt., HMS

Immunologic Knowledge

Clinical Observation Experimental Studies