Immune System & Pathogen Avoidance

what are some of the first line defences

• skin

• enzymes

• lysozymes

what are the 3 pathways for complement

• classical pathway

• lectin pathway

• alternative pathway

what are proenzymes

enzymes that must be cleaved to be activated, 2 fragments

• structural - helps form other complexes

• A-fragment - inflammatory mediators

explain the classical pathway

consists of the C1 complex (C1q, C1r, C1s)

• binds to microbe, converts C4 → C4b, C2 → 2a

• C4b & 2a form C3 convertase

• converts C3 → C3a + C3b

• C3 convertase + C3b = C5 convertase

• converts C5 → C5a + C5b

explain the lectin pathway

MBP complex (MASP1/2)

• binds to microbe, converts C4 → C4b, C2 → 2a

• C4b & 2a form C3 convertase

• converts C3 → C3a + C3b

• C3 convertase + C3b = C5 convertase

• converts C5 → C5a + C5b

how are the classical & lectin pathway different in activation

classical = triggered by binding to Fc region of antibody

lectin = triggered by binding to mannose sugars

explain the alternative pathway

• C3 spontaneously undergoes hydrolysis

• binds factor B, cleaved by Factor D → Bb + Ba

• C3b + Bb = C3 convertase

• converts C3 → C3b + C3a

• C3b + C3b + Bb = C5 convertase

explain how the membrane attack complex works

C5 convertase recruits C5-C9

• proteins are recruited in a “circular” fashion hence forming pores in the membrane of the microbe

explain how opsonization works

C3b on microbes can bind to C3b receptors on phagocytes

• induced endocytosis → phagocytosis

explain chemoattractants

C3a & C5a recruit & activate leukocytes

• both can bind to receptors on leukocytes

• leukocytes can destroy microbes

what are some ways that microbes can avoid complement

• possessing a capsid, physically blocks complement

• Fc binding proteins, binds to antibody Fc hence preventing complement action

how are pathogens detected by the immune system

pattern recognition receptors (e.g. toll-like receptors)

• recognize different PAMPs

• all drives NF-kB transcription factor

what is NF-kB

a transcription factor responsible for synthesis of pro-inflammatory mediators

• TNF-α

• IL-6

• Pro-IL-1β

describe the process of interleukins synthesis

parts of pathogen are recognised by PRRs, downstream phosphorylation of NF-kB

• translocate into nucleus

• promotes gene expression for pro-interleukins

• pro-form = inactive

describe the process of inflammasome activation

PAMPs invade cell → recognised by nod-like receptors

• causes oligomerization of nod-like receptors, ASC & pro caspase 1

• this forms inflammasome (this activates pro caspase)

• inflammasome cleaves & activates pro-interleukins

how can bacteria interfere with the inflammasome activation

• intercept signaling events

• degrade NF-kB subunits

what is some information on NK cells

contain granules with cytolytic molecules

• perforin & granzyme B

can also produce inflammatory mediators

• interferon-y

what is antibody dependent cellular cytotoxicity

when an antibody binds to a pathogen, the Fc receptor on NK cells can bind to the antibody

this triggers the degranulation of perforin & granzyme B

how do NK cells function normally

contain an inhibitory & activating receptor

• inhibitory receptor bind MHC I receptors

• this suppresses the activity of the NK cell

how do NK cells function against non-self pathogens

pathogens DON’T expression MHC I, thus activating receptor is triggered

• degranulation occurs, pathogen dies

• pathogens downregulated MHC I expression by interfering with the biochemical pathway

how can pathogens evade NK cells

• express MHC I like molecules

• block cell expression of activating ligands

what are the contents of granules in eosinophils, basophils, mast cells

vasodilators - prostaglandins, leukotrienes

degrading enzymes - proteases, lipases, etc.

how do basophils & eosinophils function

circulate in the body, when moved to tissues via cytokines, they bind to pathogens via IgE receptors

• release histamine, vasodilators.

what are some cells of the adaptive immune system

B cells - antibody production

CD4+ T cell - maturation of adaptive response

CD8+ T cell - recognition & removal of viral host cells

explain the design of the T cell receptor

2 chains α & β, each chain has 2 domains

• proximal = constant

• distal = variable (binding)

explain the design of the B cell receptor

pair of heterodimers (heavy + light chains)

• constant Fc region

• variable Fv region

• associates with other protein for signaling clonal exp.

describe selective antigen recognition by Helper T cells (CD4+)

CD4+ binds to APC via MHC II (stabilized by CD28 ligand)

• triggers CD3 phosphorylation

• causes expression of IFN-y which is released

describe selective antigen recognition by cytotoxic T cells (CD8+)

T cell binds to antigen-MHC I complex on abnormal cells

• stabilized by CD28 ligand

• delivers granzymes & perforin to cell

explain how antigen-MHC I complexes are formed

cytosolic protein is broken down by proteasome

• peptides are transported to ER by TAP transporter

• empty MHC I is loaded with peptide

• complex is transported to surface via vesicle

explain how antigen-MHC II complexes are formed

endocytosis of extracellular protein, processed through endosome

• MHC II with pre-loaded invariant chain is dispatched

• endosome and vesicle with MHC II combine

• invariant chain is displaced by peptide

• vesicle is transported to surface

how can pathogens interfere with MHC I/II pathways

• preventing processing (proteasome)

• preventing transport of vesicle

describe co-stimulation in T cells

CD28 ligand is expression on naive T cells

• contains an immune tyrosine activating motif (ITAM)

• triggers phosphorylation of signaling kinases

• induces signaling for cell survival

how do you stop T cell proliferation

CTLA-4, has higher affinity for CD80/CD86

• contains an ITIM motif (inhibitory) competitor for CD28

• upregulated after activations

• dephosphorylates signaling tyrosine kinases

what are PD-1 & TIM3 checkpoints

receptors that act as phosphatases (dephosphorylates) activated kinases

• limits effector function

how might chronic infection result in sustained expression of checkpoint molecules

if an infection cannot be cleaned up, the constant activation of T cells also drives the constant activation of inhibitory signals'

• thus T cells cannot be restimulated

• infection persists

what is the role of cytokines in CD4+ T cell function

different cytokines stimulate different T cell responses

what are T follicular helper cells

specialised CD4+ T cells which help B cells produce antibodies

• provide costimulation (CD4 & CD40L)

what is the general process of B cell activation via Tfh cells

B cell endocytosis of antigen & receptor

• antigen is loaded on MHC II, transported to surface

• Tfh cell binds via MHC II, CD4 & CD40L

• releases cytokines allowing expansion

explain B cell activation in the lymph node

lymph node is split into a B cell & T cell area

• B cell expresses CCR7 chemokine attracting Tfh cells

• Tfh cell expresses CXCR5 chemokine attracting B cell

what is affinity maturation

introduce mutations within Ig gene regions

• if mutations increase affinity cell get selective survival

• i.e. if B cell cannot bind antigens no survival signals

• if B cell binds induces survival signals & proliferation

what is isotype switching

after VDJ recombination for the Fv region, AID & cytokine induced factors can alter the Fc region of an antibody

• based on presence of interferon/interleukin

what are some qualities of different antibodies

how can pathogens evade antibody responses

• blocking Ab binding (capsule)

• reverse Ab binding (receptors for Fc region)

• antigen variation (genetic mutations)