immunity and infection Flashcards
infectious diseases
1) 1/3 disease burden is due to infectious diseases
2) viruses, fungal, bacterial, parasites
immunity to infection
1) immune system protects from pathogen and cancer
2) most pathogens do not overcome this
- surface barriers
- immune system
3) few potential pathogens cause diseasep
physical and physiological barrier
1) saliva and skin
- lysozyme breaks down proteoglycan in cell wall
disease caused by pathogens
1) can damage directly
- exotoxin damage surfaces of host cell
2) indirectly
- via immune response
- pro-inflammatory cytokines cause local symptoms
- epitopes can bind to heart tissue (complement mediated)
3) virus replication can destroy host cell
immune responses are specific for different compartments
1) almost all pathogens have a extracellular stage, some have intracellular
early immune response to infection
1) preexisting molecules like complement
- inflammation
cooperation between innate and adaptive
1) adaptive is activated after innate immune system
2) innate controls most infections, but need both branches to eliminate pathogens that cause disease
stages in typical infections
1) pathogen reaches physical barrier
2) innate immunity contains the infection through inflammation
3) Ag captured in secondary lymphoid tissue stimulate adaptive immune response (Ag can also be carried by DC)
4) activated TH1 and CD8+ cells migrate to site of infection
complement
1) C3 is first immediate immune defenders
2) C3 is hydrolyzed spontaneously at low rate => iC3
- alternative pathway
alternative pathway
1) iC3 can recruit serum factor B, a substrate for protease factor D
2) alternative pathway is initiated and surface bounded C3b is produced
3) C3b fixation leads to alternative C3 convertase
4) binding of another C3b subunit leads to formation of alternative C5 convertase
5) C5a attracts phagocytes and inflammatory response
—
1) it is inhibited by complement control proteins (DAF, MCP, CR1)
2) pathogens lack these control proteins, and they also attract factor P which stabilized alternative C3 convertase
other components of early response (4-96 hrs)
1) phagocytes
2) NK cells
3) interferon
phagocytes
1) both macrophages and neutrophils are
2) recognize pathogens through DC14, TLR4 and scavenger receptors
3) receptors that simulate phagocytosis
- CR1, CR3 and CR4
4) have chemicals and enzymes that destroy pathogens in phagolysosomes
macrophages
resident in most tissues and abundant in mucosal tissues
- long lived
2) antigen presentation
3) inflammatory mediators
PMN
1) abundant in blood and rapidly recruited to any site with active complement
- short lived
2) reactive chemical species
3) antimicrobial peptides
4) antibacterial enzymes
5) NETs
phagocytes and innate immunity
1) receptors are PAMPs
- LPS, teichoic acids, or G+ bacteria
2) PAMPs recognized by PRR
- TLR4 recognizes LPS
PRR on macrophage
1) CD14
- binds LPS from gram negative bacteria
2) mannose receptor
- lectin binds to some bacteria and viruses
3) scavenger receptors
- heterogenous family of receptors
4) TLR4
role of macrophages
1) PRR or complement stimulate macrophage
2) macrophages transcribe cytokine genes
- TNF alpha, IL06, IL1beta, IL-12, IL-8
3) APC
TNFalpha
1) contain infections
2) local inflammation
IL-8
1) attract neutrophils
2) local inflammation
iL-12
NK cell activation
fever and acute phase protein production
1) IL-1beta, TNFalpha, IL-6
TNFalpha
1 )activates local vascular endothelium
- increase vascular permeability
- supply of complement
- more fluid drains to lymph nodes
2) primes phagocytes, activating oxidative burst
3) induces maturation of DCs
- via direct contact with PAMPs
- or being secreted by macrophage
pyrogens produced by macrophages
1) IL-1beta, IL-6, TNF alpha make fever
- increase metabolism of muscle and fat cells
- over 10% increase in metabolic rate per degree celcius
2) fever inhibits pathogen replication
3) stimulates adaptive immunity
acute phase response
1) IL-1 beta, IL-6, and TNFalpha stimulate this in the liver
- massive increase in MBL and CRP in liver
- MBL and CRP are PRR
- both can activate complement
2) CRP binds to phosphocholine group of LPS
- can bind C1q (classical complement pathway)
3) MBL activates lectin pathway
CRP and MBL
1) activate Complement and behave as opsonins
2) CRP is a marker for inflammation in clinics
septic shock
1) bacterial infection of blood causes septic shock via endotoxins such as LPS
- lading to massive secretion of TNFalpha
- dilation of blood vessels and leakage of fluid into tissues
- failure of vital organs (kidneys, heart, lungs) due to low blood supply
2) over 100k deaths per year in US
PMN
1) short lived and focused on killing
2) most abundant WBC
3) circulate in blood and go to infected area due to release of CXCL8, N-fMet, C5a
- interactions between cell adhesion molecules (selectins, LFA-1, ICAM1)
4) die in few hours and make pus
PMN phagocytose and kill bacteria
1) PMN have CR, FcR and receptors for bacterial sugars
2) PMN have many granules with antimicrobial toxins
(PMN are more aggressive than macrophages)
3) DNA nets
INF
1) type II - INFgamma
2) type I - IFNalpha and IFN beta
- activate NK cells
3) limit viral infection in early phase
- have direct and indirect effects
type I INF
1) activate endonuclease that degrade RNA
2) phosphorylation and inactivation of initiation factor eIF-2 (inhibit protein synthesis)
3) inhibit viral replication, activate NK, enhance Ag presentation
type II IFN
1) activate macrophages
2) activate enzymes that degrade essential AA
- host cell can survive temporarily without but bacteria cannot replicate
NK cells
1) cytotoxic lymphocytes but do not express CD8+
2) do not express TCR or make Ig
2) circulating lymphocytes in blood that go to infection site because of pro-inflammatory cytokines
NK cells activation
1) activated before an infection, similar killing method to CD8+
- perforin, FasL, granzymes, and also secrete IFN gamma
2) activate by IFN alpha and beta, IL-12
3) early response to viral infection
NK and viral infection
1) recruited by cytokines
- IFN alpha/beta by infected cells
- TNF alpha and IL-12 by macrophages at site of infection
NK cell receptors
1) heterogenous set of activating and inhibitory receptors are expressed by different subpopulations of NK cells
- recognize MHC-like molecules that reveal abnormal target cell
- MIC-A and B which are expressed by stressed cells
2) some recognize MHC molecules that inhibit the NK
- some viruses inhibit expression of MHC1
NK recognize missing self
1) no MIC ligand
- healthy cells
- inhibitory receptors dominate
2) MIC ligand for NKG2D
- expressed and will cause death
- activating receptors dominate
innate and adaptive immunity
1) innate controls many infections
2) innate sets stage for adaptive immunity
3)adaptive may be required for complete elimination of certain pathogens
adaptive immune response
1) after 4 days
2) early response, DC stimulated by PAMPS carry antigens on MHC to lymph node
3) T cells (CD8+ and TH) recognize MHC peptide are activated
4) Ag specific B cells acquire Ag via surface IgM and present peptides via MHCII
5 )B cells presenting these are activated by cognate TH cells in lymph nodes
primary immune response
1 )DC mature and migrate to lymph nodes under influence of chemokines
2) DC in lymph nodes secrete chemokines that attract naive T cells
- CD4+ cells become TH2 or TH1
- activated T helper and CD8+ cells migrate to site of infection
- TH2 cells stimulate specific B cells in lymph nodes
secondary immune response
1) protective immunity
- B and T cells activated
- inhibit 2ndary infection shortly after primary infection
2) memory cells can be activated rapidly years after first exposure to antigen
secondary vs primary antibody responses
1) unimmunized
- low affinity of Ab
- somatic hypermutation
- IgM>IgG
2) immunized
- high affinity
- high hypermutation
- IgG, IgA, IgE
immunological memory
1) ability of immune system to respond more rapidly an effectively to a pathogen that has been encountered previously
- reflects the preexistence of clonally expanded population of Ag-specific lymphocytes
2) memory due to a small but persistent population of memory cells that is independent of the continued persistence of the original antigen
- most memory cells in resting state
memory cells production
1) memory T cells can survive in the absence of MHC peptide stimulation
immune response to infection
1) adaptive responses begin after 4 days
2) protective immunity provided temporarily
3) memory cells are activated faster in subsequence infections
vaccines
1) memory B and T cells can allow you to respond to the pathogen
2) most provide lifelong protection
- live, attenuated, inactivated, recombinant, peptide, anti-idiotype, naked DNA, RNA
