extracellular immunity

classification of parasites

protozoa

• unicellular - amoebae, flagellates, ciliates, apicomplexa(sporozans)

• can be intracellular or extraceullar but cause extracellular diseases

helminths

• multicellular - nematodes(round worms), trematodes(flukes), cestodes(tapeworms)

ectoparasites

• ticks, fleas, lice and mites

immune responses to parasites infections

most extracellular and too big for phagocytosis

thick coat, not penetrated by complement or T cell perforins

need to target weak spots e.g parasites digestive tract 

mainly Th2 driven immune responses 

type 2 response at mucosal surfaces

worms cause damage to epithelial cells

release of alarmins from epithelial cells(e.g IL-33,IL-25)

together with parasite molecules, alarmins act on DCs in tissue and instruct them to promote Th2 response

meanwhile DCs take up and process helminth antigens for presentration on MHC class II

DCs migrate from tissue to lymph node and present antigen to CD4+ T cells

induction of Th2 response

antigen recognition leads to clonal expansion of T cells and idfferentiation towards Th2 lineage

signals recieved by DCs in infected tissue allow the to promote Th2 receptors

induction of Th2 response also requires IL-4

DCs don’t produce IL-4

innate lymphoid cells support Th2 response

innate lymphoid cells(ILC) don’t express a TCR or BCR and don’t depend on recognition of specific antigen for activation

ILC can respond to alarmins by producing IL-13, IL-4 

• ILCs can respond within hrs

• exact cytokines needed for Th2 differentiation 

ILC-derived IL-4 supports differentiation of Th2 cells

ILC-derived IL-13 can promote migrationof DCs(dendritic cells) to lymph nodes 

Th2 effector cytokines

IL- 10 = regulatory role, prevents excessive inflammation

B cell production of IgE

Th2-derived IL-4 mediates class switching to IgE or IgG1

• IgE = mast cell degranulation, eosinophil antibody dependent cellular cytotoxicity (ADCC)

• IgG1 = immune cell degradtion, enhanced phagocytosis, ADCC trapping of tissue migrating larvae by macrophages 

effect of Th2 cytokines on intestinal epithelium g

goblet cell hyperplasia/ increased mucus production(worm expulsion)

• lubrication in gut, reduces parasites ability to attach, traps parasite

increased production of resistin-like molecule - beta(RELM-beta)

• specialised epithelial molecule that distrupts parasites nutrient uptake which affect its abilities 

RELM beta inhibits ability of worms to feed on host tissues during infection → reduced fecundity 

epithelial escalator and weep and sweep

Th2 cytokines and mast cell proteases increase fluid leakage across epithelium → weep

IL-13 drives increased intestinal muscle hypercontractility → sweep

IL-13 stimulates increased turnover → epithelial escalator

Th2 cytokines and mast cell proteases increase fluid leakage across epithelium. IL-13 drives increased intestinal muscle hypercontractility = weep and sweep 

physiological host changes induced by anti-worm immunity

strong effects of anti-worm immune response on host gut physiology

does not kill worms

makes GI tract inhospitale for parasite

increases number of goblet cells = increased mucin secretion, increased intestinal mobility, increased water influx into intestinal lumen 

helminth infections

promote antibodies and eosinophil and mast cell activities

choice towards Th2 response is driven by IL-4

Th2 cell cause alternative activation of macrophages and activate eosinophils and mast cells 

Th2 cells promote a strong antibody response based on neutralising IgG and IgE

Th2 response is most effective to combat extracellular pathogens 

alternative activation of macrophages

M2 macrophages = maintanence and repair

• minimises damage where possible

• traps and expels parasite

• less about killing more about making a hostile environment and protecting the host

role of mast cells

early in response

• sentinel function(produce cytokines to produce Th2 response)

• produce alarmin, IL-33

• initiation/amplification of Th2 response

later

• expand and become activated in response to IL-9

• express receptor for Fc region of IgE

• mast cells degranulate when IgE bound to Fc receptors on mast cells surfacwe interacts when antigen

• degranulation = release of antimicrobial or cytotoxic molecules from granules in cells(secretory vesicles)

• release histamine, proteases, cytokunes

• serine proteases directly toxic to helminths

• mast cells protease opens tight junctions allowing fluid egress

role of eosinophils

IL-5 drives accumulation of eosinophils in blood(eosinophilia)

express high affinity receptor for Fc region of IgE (FcεRI)

IgE binds to surface of heminths. he FcεRI on eosinophils binds to the Fc

region of IgE. This causes the eosinophil to degranulate = destruction of helminth cuticle (ADCC).

eosinophils are bridge between adaptive and innate immunity via ADCC

eosinophil/mast cells oles in parasite immunity

how antibodies control extracellular infections 

helminth evasion tactics

size - too large to be phagocytosed

thick extracellular coat

adsorbing host proteins - masking antigens 

molecular mimicry - expressing antigens similar to host, trying to get recognised as self

anatomical seclusion

surface antigen shedding

interference with antigen presentation 

immunosuppression

migration

production of enzymes (anti Ig/C5a)

Th2 cells promote neutralising antibodies

choice of Th2 response is driven by IL-4

Th2 cells suppress activation of macrophages 

Th2 cells promote strong antibody response based on neutralising IgGs

Th2 response is most effective to combat extracellular pathogens 

antibody mediated protection against extracellular bacteria

neutralises toxins

kill bacteria

opsonise bacteria

intracellular killing macrophages

essential protection for neonates