Innate Immunity

what are some key components of the innate immune system

• epithelial barriers

• phagocytes

  • neutrophils, monocytes, macrophages, dendritic cells

• type II immunity

  • mast cells, eosinophils, basophils

• lymphoid cells

  • ILC1-3 & NK cells

• innate T cells

  • NKT cells, MAIT cells, γδ T cells

• complement

what are some components of the adaptive immune system

• T cells

• B cells

  • antibodies

how do the innate & adaptive system respond

innate - response is rapid, can be detected within quickly

adaptive - response is slower, detected after several days

why is the innate immune system so good a detection

innate immune cells detect the expression of many different types of pattern recognition receptors (PRR)

• these recognize structures of microbes not expressed in mammals

what are pattern associated molecular patterns (PAMPS)

structures that are present on microbes but not present in mammals

• these are recognised by immune cells

why is the adaptive immune system so selective

each lymphocyte displays an antigen receptor with a unique single specificity

what is important to note about PRR (regarding germline)

they are germline encoded & broadly specific

• cannot distinguish PAMPS from different species

• EXAMPLE: can recognize LPS cant distinguish e. coli vs salmonella

what is somatic recombination

the process by which DNA segments are rearranged (V, D, J cut & rejoined) to create new combination

• gives rise to receptor diversity

summary of innate & adaptive immunity

how are epithelial cells involved in an immune response

they secrete chemokines & cytokines at the basal surface that recruit immune cells

describe mucociliary transport

refers to the movement of mucus (produced by goblet cells)

• usually to remove microbes from the body (e.g. lungs)

what is meant by complement

a series of serum proteins (C1-C9) that collectively form a biochemical pathway, has 3 immunological outcomes:

• inflammation

• opsonisation

• microbial lysis

what are the 3 ways of activating complement

1. the alternative pathway - an ancient non-specific chemical reaction

2. the classical pathway - activated by complexes of antibody with antigen

3. The lectin pathway - triggered by recognition of unique microbial carbohydrates

what is important to note about all 3 pathways

all pathways create a C3 convertase, after which the pathways converge

describe the mechanism of the alternative pathway

C3 spontaneously hydrolyses to from C3a & C3b

• C3b then forms a C3 convertase

• triggers rest of pathway

this is non-specific with no specific recognition event

what is the mannose binding lectin

a soluble pattern recognition receptor found in serum that binds to mannose found in the surface of microbes

describe the mechanisms of the lectin pathway

proteases associated with MBL then cleave C4

• rest of pathway is identical to classical pathway

describe the mechanism of the classical pathway

1. C1q recognises IgG or IgM bound to antigen

2. C1q also contains proteases that cleave C4

3. C2 is cleaved generating the C3 convertase

4. C3b converts the C3 convertase into a C5 convertase

describe late stages of complement activation (all pathways)

1. C5 gets cleaved into C5a & C5b

   • C5a is a potent pro-inflammatory factor

2. C5b is stuck on the cell/microbe surface and initiates the assembly of the MAC (C5b, C6, C7, C8, C9)

3. MAC generates pores in membrane leading to cell lysis by osmotic shock

how do complements drive inflammation & leucocyte recruitment

the proteolysis of C3 & C5a release the soluble fragments C3a & C5a

• leucocytes have receptors for C3a & C5a

C3a & C5a are chemo-attractants (attract leucocytes to the site of infection)

how do complements drive opsonization & phagocytosis

all complement pathways deposit C3b on the pathogen surface

• phagocytes have receptors for C3b

A microbe covered in C3b is then recognized by the complement receptor which activates the phagocyte leading to phagocytosis

what is some general information on macrophages

• antigen presenting cell

• can differentiate into several different forms

  • inflammatory macrophages

  • anti-inflammatory macrophages

what is the function of monocytes

an emergency source of macrophages

• upon infection, monocytes leave the circulation & differentiate into macrophages

• arrive slower than neutrophils

what is some information about neutrophils

• rapidly migrate out of circulation to site of infection

• can’t present antigen, limited cytokine secretion

• effective killers of organisms growing extracellular

what are the 3 mechanisms by which neutrophils can kill

1. phagocytosis

2. degranulation: release granules that contain anti-bacterial proteins

3. neutrophils extracellular traps (NETs), release a DNA web that traps & destroys bacteria

describe the process of phagocytosis

1. PRR specialised in uptake bind to microbes

2. involution of the phagocyte membrane leads to microbial uptake into the phagosome

3. The phagosome fuses with the lysosome – an acidic vesicle rich in degradative enzymes

4. In the phagolysosome two enzymes play an important role in killing the microbes:

   • Phagocyte oxidase - Reactive Oxygen Species (ROS)

   • Inducible Nitric Oxide synthase - Nitric Oxide

differences PRR vs TCR/BCR

what are the 4 major classes of pattern recognition receptors

• toll-like receptors (TLR)

• rig-like helicases (RLH)

• nod-like receptors (NLR)

• C type lectin receptors (CLR)

what are toll-like receptors

membrane proteins expressed either at the cell surface or in endosomes

• recognize PAMPs from pathogens

what are C-type lectin receptors

a family of membrane proteins expressed at the cell surface

• many recognize polysaccharides expressed by pathogens

what are rig-like helicases

RIG-1 & MDA-5 are located in the cytoplasm and recognize viral dsRNA

what are nod-like receptors

a family of cytoplasmic receptors that recognize a variety of microbial products

what other types of molecules can PRR recognize

endogenous ligands released upon cellular damage/stress

• Damage Associated Molecular Patterns (DAMPs)

what are the 5 parts of the inflammatory response

• heat

• redness

• swelling

• pain

• loss of function

describe the general inflammatory response

1. tissue resident macrophages are activated via pattern recognition

   • release pro-inflammatory cytokines & chemokines

2. cytokines activate the vascular endothelium, thus vasodilation & increase permeability

   • redness, heat & swelling

3. chemokines recruit leucocytes to the site of infection, release inflammatory mediators

   • pain, loss of function

what is the inflammasome

a multimeric complex compromised of:

• a NLR (nod-like receptor)

• ASC (adaptor protein)

• protease caspase 1

structure forms after the NLR binds it ligand

what are the 2 signals for the inflammasome to cleave & activate IL-1B

1. pattern recognize from a PRR that leads to transcription & translation of Pro-IL-1B

2. cleavage of Pro-IL-1B by the inflammasome

what are the different stages of leucocyte recruitment

1. cytokines: activate the vascular endothelium

2. selectins: adhesion molecules that allow leucocytes

3. chemokines: activate integrins to become high affinity

4. integrins: adhesion molecules that allow leucocytes to stably adhere

5. Leucocytes transmigrate out of the vasculature and follow a chemotactic gradient towards the site of infection

what are type I interferons & functions

cytokines with potent antiviral activity, signaling through the type I IFN receptor puts the cell into an antiviral state

• inhibits viral protein synthesis

• degrades viral RNA

• inhibits viral gene expression & virion assembly

what other immune cells can type I IFNs activate

• NK cells

• dendritic cells

what are NK cells

a type of innate lymphoid cell, they kill virally infected cells

• no antigen receptor

• activated by type I interferon

what are dendritic cells

a type of leucocyte, role is to activate naive T cells

• only antigen-presenting cell that activate naive T cells and initiates an immune response

what is the function of the T cell receptor

to recognize peptide antigens presented on MHC markers

what are the 2 types of MHC marker

MHCI - expressed by all nucleated cells

MHCII - expressed only by certain immune cells

• professional antigen presenting cells

what are the 2 types of T lymphocytes

CD4+ T cells = express CD4

CD8+ T cells = express CD8

what is CD4

a cell surface molecule that can bind, in a peptide independent manner, to MHCII

• when activated, CD4 T cells → T helper effector cells

what is CD8

a cell surface molecule that can bind to MHCI in a peptide independent manner

• when activated, CD8T cells → cytotoxic T cells

what 3 signals do naive T cells require from professional antigen presenting cells

1. antigen + MHC

2. costimulation (CD80 & CD86)

3. cytokines to differentiate T cells into effector cells

what is signal 2 (costimulation)

DC display costimulatory molecules CD80 & CD86

• these interact with T cell molecule CD28

• generates signal that synergizes with MHC+peptide signal

• leads to T cell proliferation

what is signal 3 (cytokine production)

dendritic cells secrete cytokines that drive T cell differentiation

what are the 2 states of dendritic cells

immature: antigen acquisition

• highly phagocytic

• low MHCII

• low co-stimulation

mature: antigen presentation (from activation via PRR)

• low phagocytosis

• high MHCII

• high co-stimulation

what happens when a DC is activated by PAMPs

it migrates from the periphery to draining lymph nodes

• adaptive immune responses are initiated by DC

what happens to a DC upon activation via pattern recognition

1. increase MHC expression & promotes antigen presentation

2. increase costimulation (increase CD80 & CD86)

3. promotes cytokine production