Immunology 2: Innate immunity Flashcards
Differentiation pathway of immune cell subsets
Myeloid progenitor cells
- majority of the innate immune cells
Lymphoid progenitor cell
- adaptive immune cells
- natural killer cells
Types of innate cells overview
Epithelial (enterocyte) cells
Macrophages
Polymorphonuclear cells
Dendritic cells
Natural killer cells
Epithelial cells
Epithelia that line the external and internal surfaces form the anatomic barrier-> physical block and chemical barrier
Epithelial surface: skin, urogenital tract, gastrointestinal tract and the respiratory trac
Example: skin
- physical barrier
- acidic nature due to sweat and sebum providing a lipid rich environment -> ideal pH for antimicrobial peptides
Example: Gut epithelila cells (Enterocytes)
- Cover the Villi of the gut and make a physical barrier by sticking together tightly and a chemical barrier by secreting mucus (dense mucus full of AM and lose mucus to anchor microbe)
- Enterocytes can differentiate into paneth cells and goblet cells
Subsets:
enterocytes -> absorbative cells
Goblet cells -> produce mucus and Trefoil factor proteins (antimicrobial)
Paneth cells -> secrete antimicrobial peptides (defensins)
Proliferative zone -> stem cells
Intermediate cells -> Secrete mucus and AM
PRR activation
- PRR leads enterocytes to secrete inflammatory cytokines + chemokines
- Paneth cells release AM at enhanced rates
- PRR dilemma of sensing commensal microbiota so TLRs only on basolateral not lumen side of membrane -> only recognise pathogens if cross membrane
Monocytes and macrophages
Monocytes: white blood cells
macrophages: Monocytes that have migrated into tissues and matured depending on the specific balance between IL-10 (supress) and IL-12 (excite)
-> Classicly acitvated macrophage (>IL-12)
-> Regulatory macrophage (>IL-10)
-> Wound healing macrophage (IL10= lL12)
-> Hybrid macrophage (interacting stimulus)
There is also a residant population involved in homestasis and remodelling
Following activation
- Macrophages secrete pro-inflammatry cytokines (Interleukines e.g. IL-6 activating lymphocytes and increasing antibody production, chemokines attracting other cells and Interferon a and b causing an anti viral cascade)
- phagocytosis (digest and survive)
- Antigen presenting
- later control
Polymorphonuclear cells
Neutrophils
o Predominant type
o Go to inflamed tissues due to chemokine signals
o Cannot regenerate granules
o Different granules contain different antimicrobials e.g. Lysozyme, Lactoferrin, a-defensins
kill pathogen:
1) release of granule contents (e.g. defensins which interact with microbial membranes to form multimolecular pores killing pathogen-> hydrophobic and phillic region)
2) phagocytosis.
3) Formation of nets (neutrophil extra cellular traps) released by:
- The cells die, the nuclear envelope falls apart, and chromatin decondenses, the plasma membrane ruptures, releasing NETs.
- The cell expels their DNA out at the pathogens, leading to a net
> nets = many dead nutrophils leading to problems like cell damage and sepsis or blood clots
Eosinophils
- Important for allergies -> covered in immunoglobulin E (IgE) which are sensitive to antibodies released in allergic reactions
- produce histamine leading to vaso dilation (increased blood flow) and increased permeability
Basophils
- Important for allergies -> covered in immunoglobulin E (IgE) which are sensitive to antibodies released in allergic reactions
- Produce histamine leading to vaso dilation (increased blood flow) and increased permeability
- High producers of IL4 which drive T cells into TH2 type
Macrophage-neutrophil interactions in inflammation and wound repair
Macrophages produce cytokines and chemokines
This attracts more monocytes into the tissue which become macrophages (phagocytosis, antigen presenting and signalling)
Polymorphonuclear cells are attracted and rapidly engage pathogens -> cause chaos
Macrophage in the tissue recognises the neutrophil activity and starts to phagocytose the neutrophils (regulatory macrophage)
Macrophages release anti-inflammatry cytokines -> IL-10
This leads to the clearance of neutrophils
Phagocytosis
- Removes microbes + dead / damaged cells in response to activation of surface receptors
- Ca2+ dependent formation of phagosome
Phagocytic cells
- dendritic cells
- macrophages
- Neutrophils
Process
- The phagocyte membrane surrounding the microbe and internalising it into a phagosome.
- This fuses with lysosomes to form a phagolysosome.
- This provides an acidified environment as well as producing highly reactive superoxide and nitric oxide radicals, which can destroy the microbe
natural killer cell
- Monitor missing self by looking at MHC1 level of cells (Viruses want to avoid presentation so turn off MHCI)
- Kill using perforin (makes pore) + granzymes (serine proteases – induce apoptosis of target cell (infected cells))
- Releases IFNγ which activates other cells to kill pathogens (macrophages / dendritic cells) and influences developing adaptive immune cells (Favours Th1 response)
- signal to other cells in the environment to go into an anti-pathogen state (release cytokines)
Antigen presentation
Professional APCs: constitutively express MHC class I and MHC class II
-> denritic cells (stimulate niave T cells)
-> macrophages (activity increased by CD4+ interaction)
-> B cells (CD4+ interaction required for maturation and antibody propoduction)
Pathways
MHC class I
- expressed on all nucleated cells
- presents peptides to killer CD8 T cells
- samples cytoplasm-> endogenous
MHC class II
- mostly on antigen presenting cells
- presents peptides to helper / regulatory CD4+ T cells
- samples extracellular -> exogenous
Dendritic cells
IMMATURE
- take up + process antigen in tissues constantly
- PRR activation triggers differentation into mature form
MATURE
- retracts dendrites and migrate to lymph nodes + present antigen on MHCII to naïve T cells (don’t take up microbes)
- This results in proliferation of lymphoctyres
After presenting + activating lymphocytes-> apoptosis
What makes them able to acticate niave cells
- Express lots of MHC
- Produce co-stimulatory molecules and cytokines
3 signals for T cell activation:
1) T cell receptor binds MHC presenting antigen
2) Co-stimulatory molecules
3) Cytokines tell naïve T cells which CD4+ T cell / T helper sub type to become (these signals also come from the environment)
Dilema: How to activate CD8 cells
- To activate CD8 cells the antigen must be presented on MHCI via endogneous pathway
- Not all pathogens are endogenous so requires cross presentation -> DC shunt extracellular antigen from endogenous to exogenous pathway so that it is presented on the MHCI
- CD8+ Proliferation and activation also enhanced by CD4+ T cell production of IL-2
Overview
- Epithelial cells try to stop entry of pathogen through physical barrier and release of mucus (e.g. gut) and activate the early immune response
- antimirobials in tissue attemt to control pathogen
- Pathogen entry leads to compliment acitvation -> phagocytosis and induces inflamation (release of signals)
- Macrophages recognise pathogen, release cytokines (chemokines, interferon, Interleucine) leading to inflammatry response and start to phagocytose the pathogens
- Basophils and eosinophils produce histamine leading to vasodilation and increased vessel permeability
- Neutrophils, NK, monocytes, Dendritic cells are attracted to the region via chemotaxis and activated via other chemokines -> escalate innflamation
- Neutrophils release granules, phagocytose, release nets
- NK cells kill cells with reduced MHCI levels
- Dendritic cells process pathogen and take it to Lymphatic nodes to activate adaptive immune system. (+ releases interferon)
- Escalation as cells produce different cytokines
- IL-10 is released causing macrophages to mature in anti-inflamatry cells and phagocytose the neutrophiles to control the immune response
Innate mechanisms
Physical barrier
antimicrorbial mechanisms ->
Antimicrobial enzymes and antimicrobial peptides
Complement system
Inflammation
1) Pathogen interacts with hosts and encounter macrophages and dendritic cells that reside in tissue
2) PR by macrophage leads to cytokine and chemokine production
3) recruit effector molecules and cells from the blood to the tissues (e.g. PNM, monocytes, NK). -> positive feedback escalation as they release cytokines
4) induce local blood clotting to provide a barrier to prevent the spread of infection
5) modify endothelial walls of blood vessels to make them more permeable and wider for leukocytes to pass through.
Longe range effect:
- elevation of body temperature (inducing fever) due to the catabolisation of brown fat tissue
- prevents pathogens from proliferating efficiently and increases the efficiency of our immune system
