Host Defenses Anne Nicholson-Weller. Innate (Natural, Non-Specific) Immunity VS Adaptive Immunity.
-
Upload
june-booker -
Category
Documents
-
view
222 -
download
1
Transcript of 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
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.
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