2 Immuno: Mt

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fate of Ag

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fate of Ag/ clearance after primary vacc Ag or exposure:
1. peak: equilibrium phase
2. catabolic decay phase: degradation by macs
3. immune elimination phase: newly made Ab combines with Ag to form complex which is removed
- if there is circulating Ab in serum at time of second exposure, then there is rapid elimination of Ag

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primary Ab response

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primary Ab response phase:
1. lag: Ag recognized by naive B cell which then proliferates, differentiates and starts to make Ab
2. log: [Ab] increases as more plasma cells appear
3. plateau: peak, steady state between Ab synthesis and degradation
4. decline: Ab degradation exceeds synthesis

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secondary (anamnestic) Ab response

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secondary (anamnestic) Ab response:
- lag phase: much shorter
- log phase: more rapid, higher (100-1000x higher)
- decline phase: not as rapid, Ab may persist for months to years or lifetime

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qualitative changes in Ab during primary and secondary responses

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qualitative changes in Ab during:
1. primary: IgM major class produced but doesn't persist
2. secondary: IgG (or IgA or IgE) major class produced and persists

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Ig class acute vs chronic

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Ig class:
1. acute: IgM indicating recent Ag exposure
2. chronic: secondary/ persistent exposure to Ag, higher IgG

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affinity maturation of Ab

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affinity maturation of Ab:
- usually a lower dose of Ag leads to a higher affinity Ab production:
IgG
- IgM affinity stays constant

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primary vs secondary

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primary vs secondary:
1. lag after immunization: 5-10 vs 1-3 days
2. peak response: smaller vs larger
3. Ab isotype: usually IgM> IgG vs IgG, IgA or IgE under certain situations (heavy chain class switching)
4. Ab affinity: lower, more variable vs higher (affinity maturation)

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opsonization

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opsonization:
- removal of complexes or Ab-bound microbe via Fc portion of Ab to the FcR of phagocytes

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neutralization

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neutralization:
Ab bound to:
1. toxins inhibits effects
2. viruses inhibits ability to infect cells

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Ab blocking attachment

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Ab blocking attachment:
- Ab bound to pathogen prevent binding to epithelial surfaces
- primarily IgA
- GI pathogen that can't bind the epithelium can be carried out by fluid and peristalsis

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mast cell degranulation

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mast cell degranulation:
- IgE binding to mast cell FcR induces degranulation
- complement proteins
- allergies, asthma, protection against parasitic worms

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Ab dependent cell cytotoxicity (ADCC)

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Ab dependent cell cytotoxicity (ADCC):
- Killer cells that have FcR (monos, eosinophils, PMNs, B cells, NK cells) bind target cells or bacteria coated with Ab
- killing Ag- specific but not MHC restricted

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Ag-Ab aggregation

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Ag-Ab aggregation:
- Ag usually soluble, Ag-Ab becomes large and insoluble
- vitro: diagnostics
- vivo: initiate hypersensitivity or disease

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sterile immunity

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sterile immunity:
1. re-exposure to Ag
2. recognition by Ab (memory B cells) and CTLs
3. removal of ALL infectious agents: sterile immunity
- vs inapparent infection: persistent infection but no dz due to control by immune response

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complement components

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complement components:
- 20 proteins syn by hepatocytes and macs, some stored by PMNs
- up to 10% serum globulin
- proenzymes of zymogens until proteolytic cleavage exposes the active site
- C1-9, Factor D, B, F, I
- NO CELLS

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complement Fx

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complement Fx:
- targets surface of pathogen
1. Ab and non- Ab mediated lysis of cells, bacteria, viruses, parasites
2. facilitate phagocytosis by opsonization
3. induce tissue inflammation: chemotaxis of PMNs, increased vacular perm, smooth m contraction
4. mast cell degranulation
5. clear immune complexes from cirulation, deposits in spleen and liver

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complement cascade

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complement cascade:
- series of activations of enzymes that can then cleave other complement proteins to form another enzyme...
repeating

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alternative (natural) complement pathway

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alternative (natural) complement pathway:
- activated w/o help of Ab or acquired immune system
- eg:
1. polysacc on pathogen surface (bacterial cell wall): immediate c activation without prior exposure
2. serum lectins

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lectin pathway

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lectin pathway:
(alternative complement pathway)
- lectins: proteins that bind CHO
- doesn't depend on Ab
- mannose-binding lectin (MBL): acute phase protein, binds to mannose residues on glycoproteins of microorganism surfaces (usually G- cell wall)

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classical (specific) complement pathway

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classical (specific) complement pathway:
- triggered by specific immune response when IgG or IgM binds Ag at surface of a pathogen ( or as complexes)
- Fc region of Ab can activate complement (C')

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complement fixation by IgM vs IgG

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complement fixation by IgM vs IgG:
1. IgM: much more efficient at activating C' system than IgG
- closely spaced C' binding sites
2. IgG: two molecules have to be close together to activate C'

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results of complement cascade activation

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results of complement cascade activation:
- at some point proteolysis of a complement= small protein + peptide
1. small protein: remains bound to the complex at surface of pathogen
2. peptide: diffuses away leading to
a. degranulation of mast cells and basophils: vascular changes
b. chemotaxis of PMNs

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C3

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C3:
1. bound to complex on pathogen surface
2. cleaved to C3b and C3a
a. C3a: small peptide diffuses away, chemotactic factor, promotes inflammation
b. C3b: remains bound to complex at surface of pathogen, also activates next step, good opsonin

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membrane attack complex (MAC)

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membrane attack complex (MAC):
- final product of complement cascade
- formed at pathogen surface
- causes cell lysis

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complement system: effective lysis of

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effective lysis by complement system:
1. G- bacti
2. enveloped viruses
3. parasites
4. fungi

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evasion of complement system

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evasion of complement system:
1. bacterial capsule: prevents MAC insertion, Strep
2. bacterial capsule prevents C3b deposition: Strep
3. bacteria: elastase inactivates complement components
4. viruses: proteins that mimic regulatory proteins interrupt cascade
5. tumor cells: endocytose MAC then seal up membrane

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antigenic components of viruses

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antigenic components of viruses:
-acquired immune directed at proteins
- capsid: protein layer around nucleic acid core
- envelope: partially proteins

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viruses extracellular immune response

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viruses extracellular:
1. absorption of virus into target cell via receptors: blocking Ab, IgA at mucosal surfaces
2. virions release from cell: Ab +/- complement, lysis of virus

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viruses intracellular immune response

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viruses intracellular immune response:
- uncoating of viral envelope and release of nucleic acid
- DNA or RNA viral genome is replicated in cell using host machinery
1. interferons inhibit replication
2. CMI mechanisms kill

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innate immunity to viruses

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innate immunity to viruses:
1. interferons: most important
2. NK cells
3. antiviral activity: defensins, intestinal enzymes, bile

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interferons and virus

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interferon and virus:
- released from infected cells w/i a few hours
- peak response: 2 days, before acquired can develop
- type depends on cell
- IFN- gamma: made by Ag-stimulated T cells

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interferons: viral fx

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interferons viral fx
1. bind receptors on nearby cells: prevent infection
2. signal cells to make antiviral protein

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NKs and virus

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NKs and virus:
- peak response: 3-4 days
- cytotoxicity stimulated by IFN- alpha
- make IFN- gamma: antiviral activity

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Ab-mediated immunity to viruses

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Ab-mediated immunity to viruses:
- Ab attaching to free virus, doesn't kill virus
- peak response: 7-10 days after first exposure

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Ab against extracellular virus

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Ab against extracellular virus:
1. blocks binding to cells: neutralizing IgG, IgM, IgA
2. binds to virus to facilitate phagocytosis: opsonizing IgM, IgG
3. binds virus, triggers complement-mediated lysis of virus: IgM, IgG
4. viral agglutination: IgM

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Ab against intracellular virus

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Ab against intracellular virus:
1. Ab-mediated complement lysing of infected cell
2. Ab-dependent cell cytotoxicity (ADCC): cytotoxic cells (lymphocytes, macs, PMNs) with FcR bind Ab coated cell

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Ab making viral infection worse

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Ab making viral infection worse:
- viruses which use intermediate molecule to bind target cell receptors
- eg Ab-coated virus binding cells through FcR, facilitating cell invasion

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cell-mediated and virus

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cell-mediated and virus:
- often more important than Ab
- MHC-1 presentation of endogenous viral Ag
1. Ag-specific CTL killing
2. ADCC: less important

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acquired immunity and viruses

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acquired immunity and viruses:
- duration variable
- may persist for many years without exposure to virus or Ag

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immune evasion by viruses

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immune evasion by viruses:
1. Ag variation: Flu A, lentiviruses (HIV, EIAV)
2. block interferons: signaling, production
3. make immune suppressor substances
4. inhibit CTLs and NKs

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timetable viral response

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timetable viral response:
- 2 days: interferons (IFN alpha, beta, TNF alpha, IL-12)
- 3-4 days: NK cells
- 7 days: CMI

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harmful viral immune response

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harmful viral immune response:
- exaggerated can cause tissue damage
- some flu, SARs, hanta, FIP

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innate immunity to bacteria

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innate immunity to bacteria:
1. recognition through TLRs and Rs
2. phagocytosis: PMNs, macs
3. cytokine release: inflammation, complement activation

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acquired immunity to bacterial toxins

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acquired immunity to bacterial toxins:
- Ab to toxin can prevent binding to target cell receptors

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bacterial toxins

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bacterial toxins:
1. exo: made and secreted
- Clostridium (botulinum, tetani)
- Bacillus anthracis
2. endo: part of G- (LPS) cell wall
- Salmonella, E. coli
- can cause septic shock

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acquired immunity to extracellular bacteria

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acquired immunity to extracellular bacteria:
1. Ab-mediated neutralization of bacteria: Th2
2. opsonizing Ab against surface Ag enhance phagocytosis
3. Ab coating bacteria, activating complement lysing the bacteria

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acquired immunity to intracellular bacteria

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acquired immunity to intracellular bacteria:
- Ag specific CD4 Th1 cells make cytokines which activate:
1. macs (NO): IFN gamma, can kill engulfed bacteria which may have survives inside macs
-activated: can now kill bacteria non-specifically
2. CD8s to become CTLs

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helminths

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helminths:
- extracellular
- thick extracellular cuticle
- loose coat: some, can discard when attached, ensuring no damage by conventional immune defenses
- mechanisms different from other pathogens

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immune elimination (self cure) of intestinal helminths

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immune elimination (self cure) of intestinal helminths:
- primed by CD4 Th2 cytokines
1. embeds into gut epithelium
2. IgE made, binds sensitized mast cells
3. mast cell degranulation: release of vasoactive factors
4. increased vascular permeability, exudation of serum, smooth m contraction
5. elimination, detachment by fluid bowel contents
- involves IL4 and IL5

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eosinophilic attack of parasite

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eosinophilic attack of parasite:
1. FcR binds Ab-coated parasites
2. degranulates: releases content directly into worm cuticle
3. cuticle damage