Host defenses
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Host Defenses. Anne Nicholson-Weller. Innate (Natural, Non-Specific) Immunity VS Adaptive Immunity. Why is the distinction between Innate Immunity and Adaptive Immunity relevant for Clinical Medicine?. Vaccines Inflammation Autoimmunity. Innate vs Adaptive Immunity. Innate Adaptive.

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Host Defenses

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Host defenses

Host Defenses

Anne Nicholson-Weller


Host defenses

Innate (Natural, Non-Specific) Immunity

VS

Adaptive Immunity


Host defenses

Why is the distinction between

Innate Immunity and Adaptive Immunity

relevant for Clinical Medicine?

Vaccines

Inflammation

Autoimmunity


Host defenses

Innate vs Adaptive Immunity

InnateAdaptive

Origin:

Genes:

Recognize:

Function:

Invertebrates Sharks

Germ line, Periphery,

no mutations mutations

Patterns Details

Immediate 7-10 days


Host defenses

Time Frame and Relative Capacity of

Innate vs. Adaptive Immunity

A

D

A

P

T

I

V

E

Log

kill

Acute

phase

reactants

C’

NK

PMN

Barrier

0 4 810

HoursDaysYears


Host defenses

Innate Immunity

Fluid phase proteins that recognize

Pathogen Associated Molecular Patterns

Examples:

 Defensins--small intestine

 Defensins--skin and respiratory epithelium

Natural antibody

Complement


Host defenses

Natural Antibody

Made by B1 type B cells

B1 cells line cavities

Have restricted VH recombination

Usually are CD5+

When transformed = CML


Host defenses

Functions of Complement

C1,

Alternative &

Lectin pathways

C3a, C5a,

iC5b,6,7

C5b,6,7,8,9

C4b, C3b,

iC3b

Tag

Signal

Recognize

foreignness


Host defenses

Complement Effectors

C1q--opsonic

MBL--opsonic

C4b--opsonic

C3b--opsonic, removal of IC

iC3b--opsonic

C3d--activation of B cells

C3a--mast cell release

C5a--chemotaxis, superoxide

iC5b67--chemotaxis

C5b,6,7,8,9--cytokine and lysis of Neisseria


Host defenses

Spectrum of Disease Caused

by Neisseria meningitides

Low burden of organisms,

moderate disease, but often recurrent

±Ab

C’ deficient

+ Ab

C’ intact

No disease

Colonization

No Ab

C’ intact

Fulminant disease:

Intact complement lyses

organisms and releases LPS


Host defenses

Innate Immunity

Cellular effectors:

Neutrophils--

Monocytes--

Macrophages--

Reticulo-endothelium of liver and spleen--

NK cells--lysis

phagocytosis +

NADPH oxidase


Host defenses

Receptors of Innate Immunity--

Recognize PAMPs:

Pathogen Associated Molecular Patterns

Scavenger Receptors

Integrin (Mac-1)

Toll-like Receptors


Host defenses

Toll-like Receptors

Predominately on monocytes and macrophages

Ten different receptors that

associate as homo- or heterodimers


Host defenses

Toll-like Receptors

Receptor Dimer

1/1, 2/6

4/4

5/5

Pathogen-derived Ligand

zymosan, gm+ cell wall

LPS

flagellin


Host defenses

Adaptive Immunity

Receptors: B cell receptor

T cell receptor

These receptors mutate during the life time

of an individual and are positively selected

in response to the particular antigens

encountered.

B and T cell receptors recognize details,

not general patterns.


Host defenses

Ag MHC Recognized

SourceComplex by T cell Effect

CD8+lysis

CD4+

Th1 act.MØ

Th2help B cell

Endogenous--Class 1

eg. Virus encoded proteins

Exogenous----Class 2

Intravesicular

eg.intracellular bacteria

Endocytic

eg.extracellular bacteria


Host defenses

Overview of Adaptive Immunity

Endogenous proteins (made by the cell’s

own ribosomes) such as viral proteins,

associate with Class 1 MHC and are

expressed on the cell surface.

If a CD8 T cell recognizes the Ag in the

MHC class 1--Ag complex, the cell will be

lysed.


Host defenses

MHC-1

MHC-1

Adaptive Immune Responses

Cytosolic/Class 1 pathway:

Transport

vesicle

ER

Proteosome

Viral proteins


Host defenses

Effectors of Adaptive Immunity

For Influenza infected

epithelial cell:

CD8+

Perforin + Granzymes

Fas L

Fas

MHC-1

Lysis

Apoptosis


Host defenses

Endogenous Antigens--overlap of Innate

and Adaptive Immunity

IFN

CD8+

NK

lysis

lysis

Early

Infection,

MHC

Uninfected cell,

expressing

self antigens

Later infection,

viral Ag-MHC-1


Host defenses

Innate and Adaptive Immunity

are linked by cytokines--

an adaptive immune

response can only be initiated if

innate immunity has recognized an

antigen as “foreign”.

Activation of APC

(upregulation of

costimulatory

molecules)

Complement

Mast cells

PMN

NK cells

Selection/

Activation of T cell


Host defenses

DC

PPR-signaling

IL-12

Naive

CD4

IL-4, IL-5

IFN

IL-4

Th1

Th2


Host defenses

Extracellular pathogens

Intracellular pathogens

Neisseria Cryptococcus

S. pneumoniaeSalmonella

H. influenza

E. coliListeria

S. pyogenes

S. aureusmTB


Host defenses

Adaptive Immune Responses to

Antigens Synthesized by Bacteria

Intravesicular Ag

Acidification of

phagosome

Addition of MHC

class 2

Presentation of Ag

in MHC class 2

complex To CD4

T cells (Th1)

Activation of infected M

Extracellular Ag

Endocytosis by APC--

Presentation of Ag

in MHC class 2

complex to CD4

T cells (Th2)

Activation of B cells

= Ig production


Host defenses

Adaptive Immune Responses

Intravesicular/Endocytic/Class 2 pathway:

M Ag

MHC-2

TB Ag MHC-2

tb

MHC

-2

MHC

-2


Host defenses

Effectors of Adaptive Immunity

For TB infected

macrophage:

CD4, Th-1

IL12

IFN

TB Ag MHC-2

Activated MØ

NADPH oxidase

iNO


Host defenses

The Killing of Intracellular Pathogens

Strategy of the pathogen:

Induce the host to ingest it,

and then with the use of specific

virulence factors, prevent

lysosomes from fusing with its

phagosome.


Host defenses

The Story of Nramp

1970’s--genes for susceptibility to

salmonella, tb, and leishmania

map to same genetic locus in mice

1990’s--gene cloned, found in RE cells

of mice and men

Natural resistance associated macrophage

protein (Nramp).


Host defenses

The Story of Nramp

H+ H+

H+

Fe++

Mn++

lysozyme

H+

lysozyme

Phagolysosome

Lysosome

Phagosome


Host defenses

Consequences of Nramp deficiency:

1. Pathogen-derived superoxide dismutase

can not function without Mn++.

2. Phagosome-lysosome fusion is impaired

3. Acidification of phagolysosome impaired

4. Excess Fe++ around mycobacteria

encourages their growth/survival.


Host defenses

DC

PPR-signaling

IL-12

Naive

CD4

IL-4, IL-5

IFN

IL-4

Th1

Th2


Host defenses

Th2 Pathway

Th2

Ag-specific B cell

lymphoblast

plasma cell


Host defenses

The interaction between APCs and CD4

T cells is strengthened by adhesion molecules.

CD4

CD28

CD40L -- X-linked hyper IgM

CD40

B7

APC

Activated by innate immunity


Host defenses

Why is the distinction between

Innate Immunity and Adaptive Immunity

relevant for Clinical Medicine?

Vaccines are not effective unless they

activate innate immunity first.

Inflammation secondary to trauma

and sepsis syndromes is due to

innate immunity.

Autoimmunity?


Host defenses

When should you suspect a

defect in host defenses?

Age of onset of infections

PMN--immediate

IgG-- delayed to 4-6 mos

Common variable Ig deficiency

Site of infections

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

Skin--PMN


Host defenses

When should you suspect a

defect in host defenses?

Type of organism

Encapsulated organisms-- Ig, C’, PMN

S. aureus. P.cepacia, S. marcescens,

Asprigillus spp.--PMN (CGD)

Neisseria spp.--complement

deficiencies (properdin, C5, C6

C7, C8, C9)


Host defenses

When should you suspect a

defect in host defenses?

  • Sometimes there is a pattern that makes no

  • sense in terms of host defense mechanisms:

  • New syndrome

  • Psychiatric illness


Host defenses

Resources/References

Diagnostic and Therapeutic Resources:

www.mgh.harvard.edu/depts/id/hmindex.html

The Jeffrey Modell Foundation: National Resource

Center for Primary Immune Deficiency

www.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


Host defenses

Clinical Observation

Experimental Studies

Immunologic Knowledge


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