(FE) Week 9 Innate and Adaptive Immunity Flashcards
What is the timeline of infection and immunity?
First 12 hours: Epithelial barriers + innate immunity
> 12 hours - 5 days: Lymphocytes -> Antibodies, Effector T cells
What is innate immunity?
- Responses that start acting immediately upon encounter
- Without history of previous encounter
- Generic response against invading pathogens
- Recognises broad classes of microbes
- No long-lasting immunity
How do physical and chemical barriers help in immunity?
- In the absence of wounds, pathogens normally cross epithelial barriers by binding to molecules on internal epithelial surfaces
~ Avoids dislodgement by air or fluid across the epithelial surface
What are some examples of the exterior defense barriers?
- Lysozyme in secretions
- Cilia in nasopharynx
- Skin
- Mucus in trachea
- Rapid pH change in stomach
- Flushing of urinary tract
- Normal flora
How do antimicrobial peptides work in innate immunity?
- Defensins
~ Secreted by epithelial cells, macrophages, neutrophils and dendritic cells
~ Direct bactericidal properties (insertion into membranes leading to cell lysis) - Lysozymes
~ High concentrations in macrophages, neutrophils and dendritic cells
~ Hydrolyses polysaccharide component of bacterial and yeast cell walls
How do commensal bacteria aid in innate immunity?
- Prevents pathogen colonization and attachment by producing bacteriocins
~ Antimicrobial peptides which inhibit growth of similar bacteria
How does innate immune receptor binding work?
- Pathogens have Pathogen Associated Molecular Patterns (PAMPs) which are recognized by Pattern Recognition Receptors (PRRs) on innate cells
~ PAMPs are invariant molecular patterns shared by broad classes of related pathogens
~ PRRs recognize patterns of repeating structural motifs on pathogens
~ PRRs can be secreted, located on the cell surface or intracellular on the innate immune cells - Eg of PRR: Toll-like receptor (TLR)
~ On cell surface: To identify bacteria components
~ Intracellular: Sense viral RNA and bacterial DNA, and tumor-derived nucleic acids
What are the effects of innate immune receptor binding?
1) Phagocytosis
2) Complement activation
3) Production of inflammatory cytokines and chemokines
4) Killing of infected cells by NK cells
5) Induce immune cell recruitment to infected sites
6) Induce T cell activation by APC
What is phagocytosis?
- Engulfing and digestion of a microbe by neutrophils, monocytes, macrophages and dendritic cells
- Induced by ligation of cell-surface receptors that recognize pathogens
What are the mechanisms of phagocytosis?
1) By membrane receptors (direct)
- Mannose receptor: Directly binds to polysaccharides on microbes
- Scavenger receptor: Directly recognizes charged molecules on targets
2) Opsonin directors (indirect)
- Fc receptors: Only binds to Ab-opsonized targets
- Complement receptors: Only recognizes complement-reacted targets (including Ab)
IFN in innate vs adaptive immunity?
Type 1 IFN: IFN-alpha (innate)
- Anti-viral cytokines
- Can be produced by almost all nucleated cells in response to viral infx
- Interferes with viral replication in neighbouring cells (paracrine activity)
Type 2 IFN: IFN-gamma (adaptive)
- Activates macrophages
- Aids in differentiation of Th1 cells
- Mostly produced by activated T cells and NK cells
What is the complement system?
- A family of defense proteins that act in a cascade to produce different effector responses/functions
~ Opsonisation (to enhance phagocytosis)
~ Inflammation
~ Complement-mediated cytotoxicity + cytolysis through membrane-attack complex (MAC) - Defends against extracellular bacteria and fungi
What is an example of how the cascade in complement system works?
- Activated C3 -> C3a and C3b
~ C3b binds to microbe to initiate opsonisation - C3b spits C5 -> C5a and C5b
~ C5b binds to C6 to form MAC - C3a + C5a cause mast cells to release histamine
~ Inflammation
~ C5a attracts phagocytes
What are the stages of inflammatory response?
- Release of chemical signals (eg histamine) upon tissue injury
- Dilation of capillaries to increase blood flow
- Increased leakiness/ escape of plasma proteins (eg Ab, complement) from bloodstream
- Phagocytes consume bacteria and cell debris
- Leucocyte transmigration through the endothelium and accumulates at the injury site
- Tissue heals
What proteins are elevated in plasma in acute phase response of inflammation?
- CRP (synthesized by liver in response to IL-6, TNF and IFN)
- Procalcitonin
- ESR
How do NK cells aid in innate immunity?
- Defense against intracellular viruses, bacteria and parasites
- Exerts function in early phase of infection to contain it
~ Compared to T cells, which clear the infection when viral titer has decreased - Activated by IFN, TNF and IL-12 cytokines
How do dendritic cells aid in bridging innate and adaptive immunity?
- Small numbers of DC activate large numbers of T cells
- Recognition of PAMPs by TLR/PRRs on immature DC is followed by ingestion of antigens in tissues -> becomes mature
~ Mature DC migrate to lymph nodes - DC presents fragments of the antigen to T cells to stimulate the adaptive immune response
What is adaptive immunity?
- Immunity that occurs after recognition of an antigen by specific receptors on T/B lymphocytes
- Takes over when innate response is insufficient to control an infection
~ Adaptive response is stronger and more focused but takes a few days to be initiated - Provides host with long-term protection from reinfection through memory cells
~ Quicker and more efficient response - 2 types of responses
~ Humoral (B cells and Ab)
~ Cell-mediated (T cells)
Where are antigen receptors found on T and B cells?
- Cell surface on T/B cells
- Secreted by B cells
~ Known as antibodies
How do T cells recognize antigens?
- TCR binds to peptides from foreign particle that is expressed on MHC (formed by complement in innate immunity)
- APC (bearing MHC) go to lymph nodes and spleen to find naive T cells
Note: Must always have MHC; no direct binding b/w T cell and bacteria antigen
What are the functions of APCs?
1) Dendritic cells
- Transport antigens to lymphoid organs to present to naive T cells
- Results in T cell activation, clonal expansion and differentiation into effector T cells
2) Macrophages
- Presents antigens to T cells in tissues but does not migrate to LN
- Results in T cell activation and macrophage activation to kill microbes
3) B lymphocytes
- BCR recognizes and uptakes antigen to present to T cells using MHC
- Results in T cell and B cell activation, and antibody production
4) Provides “second signals” for T cell activation
- First comes from costimulatory molecules and cytokines
- Ensures that T cells respond best to microbial agents
What happens in TCR-MHC interaction?
- TCR recognizes part of MHC (found on APC) as “self”
~ So that it is only activated by the correct MHC - TCR are also specific for peptide antigen of foreign body
What are the signals needed for T cell activation?
- Both signals are provided by activated APCs
- Signal 1: (ensures that T cells are Ag- specific)
~ MHC + Peptide - Signal 2: (prevents excessive immune responses to self-antigens)
~ Costimulatory molecules and cytokines
What is antigen processing?
- Conversion of native antigen into peptides capable of binding to MHC molecules
- Source of pathogen determines class of MHC:
~ MHC I (intracellular antigens) expressed by CD8+ T cells
~ MHC II (extracellular antigens) expressed by CD4+ T cells
What is the exogenous pathway for APCs?
- Extracellular pathogen is engulfed by phagocytosis and degraded in the phagosome (eg in macrophage or APC)
- Antigen is presented on MHC II to CD4+ T cells
- CD4+ T cell activates macrophages to kill phagocytosed microbes (eg in macrophage at start)
What is the endogenous pathway for APCs?
- Intracellular virus is degraded into viral proteins, which are processed in the ER
- Antigen is expressed on MHC I to CD8+ T cells
- CD8+ T cell signals infected cell to kill itself
What is the difference in effector function in CD4+ and CD8+ T cells?
CD4+ (effector and memory cells):
- (E) Releases cytokines which
~ Activates macrophages to
~ Initiates inflammation and recruits more neutrophils
~ Stimulates B lymphocytes
~ Type of cytokine ditermines function
- (M) For quicker response upon re-exposure to pathogen
CD8+:
- Recognition causes CD8 cell to kill infected cell
How do T and B cells activate each other?
1) B cells -> T cells
- Before becoming plasma cells, B cells function as APC
~ Displays antigens to activate T cells, for proliferation into CD4+ or CD8+ cells
2) T cells -> B cells
- T cells release cytokines which stimulate B cells to proliferate and become plasma cells -> produce Ab
- B cells + Ag can secrete IgM only but
- B cell + CD40L (on T cell) + cytokines can cause isotype switching
How are B cells activated?
- Naive B cells enter LN and spleen and respond to antigen encounter with T cell help (by cytokines)
- Activated B cells differentiate into plasma cells (produces Ab) or memory B cells
What are the immunoglobulin structure and functional parts?
Fab (fragment antigen binding):
- Binds to and recognises Ag and toxins
- Interferes w ability to interact w cells
Fc (fragment crystallisable):
- Part that interacts with other cells
- Activates effector functions and complement
How are plasma cells formed?
- After B cells displays antigen on MHC II to CD4+ T cell, CD40 ligand on T cell interacts with B cells and activates it, with help of cytokines
(TCR triggering upregulates costimulatory molecule of CD40L)
B cell specificity?
- Each B cell expresses a single type of immunoglobulin with unique specificity
~ When activated, it secretes Ab of that same specificity
Why does isotype switching occur?
- After activation, B cells initially only secrete IgM
- Immunoglobulins with the same variable region (specific for the same Ag) but different constant regions are isotypes
~ Upon isotype switching, Ab retain the same Ag specificity but have different effector functions - Switching diversifies the functional properties of the Ab bc different isotypes perform different functions
~ Should switch for different variable regions too so more Ag can be detected
What are the different effector functions of antibodies?
- Arises from the ability of the Fc region to interact with other components of the immune system
1) IgM
- Activates complement (recap functions of complement)
2) IgG
- Neutralise microbes and toxins
- ^ Opsonisation for phagocytosis
- Activate complement system
- Activates NK cells
- Neonatal immunity
3) IgA
- Mucosal immunity in GIT and RT
- Neutralise microbes and toxins
4) IgE
- Defense against helminths
- Inflammation
How does isotype switching occur?
- Dependent on CD40L on T cells (signal to switch isotype) + type of cytokine released (to which kind of Ab)
~ Original: IgM
~ IgM + CD40L + IFN = IgG
~ IgM + CD40L + TGF = IgA
~ IgM + CD40L + IL-4 = IgE
What are memory B cells?
- Generated during primary response (when naive cell comes into contact w microbe to become APC OR when helper T cells activate B cells)
- Typically isotype switched to IgG or IgA
- Longer-lived than naive B cells
Naive vs mature vs effector cells?
Naive cell: Not encountered Ag yet
Mature cell: After development in bone marrow and thymus
Effector cell: Been activated by Ag, tasked to eliminate microbes
How are microbes and toxins neutralised?
- Presence of Ab block binding of microbe or toxin to epithelial or tissue cells
(think of competition for enzyme substrates)
~ Mainly IgG and IgA
How does antibody-dependent opsonisation occur?
1) Microbe gets opsonised by Ab
2) Opsonised microbes bind to Fc receptors on phagocytes
3) Fc receptors activate phagocytosis
4) Killing of ingested microbe
What is Type 1 Hypersensitivity Rxn by IgE?
- Defence against helminths
- Resting mast cells have IgE Ab linked to Fc receptors
- Multivalent antigen cross-links bound IgE antibody to release granules
~ Contains histamine and other inflammatory mediators
