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Mechanisms of Allergic Immunity
crah1@le.ac.uk Normal larynx Laryngeal oedema Cellular culprits of allergy: Mast cells Most informative early analysis conducted in patients with asthma
Early studies (pre-1980) implicated mast cells and histamine as part of an archetypal immediate type I hypersensitivity
Provoked by allergenic and non allergenic substances
Explained atopic and non-atopic asthma
Explained why mast cell stabilising drugs worked Cellular culprits of allergy: Mast cells?? Corticosteroid treatment worked, but had no effect on histamine release
Anti-histamine treatment had little effect on asthma
Could not explain ‘organ specificity’ of asthma
Could not explain the hyperresponsive airway in asymptomatic asthmatics
Fibreoptic bronchoscopy - immunohistology, biopsy and analysis of bronchoalveolar lavage (BAL) cells (1980’s - present)
The early evidence:
Eosinophil & mononuclear cells infiltrate the bronchi of asthmatics
Activated T cells elevated in the peripheral blood of severe acute asthmatics
Activated T cells in peripheral blood correlated with airway narrowing
Bronchial CD4 lymphocyte numbers correlated with eosinophil numbers
Elevated IL-5 expressing T cells in asthmatic bronchial mucosa and BAL
T cells that release IL-5 co-localise with eosinophils
Eosinophils cause airway hyperresponsiveness, inflammation desquamative bronchitis, mucous hypersecretion and smooth muscle contraction
IL-5 promotes differentiation and regulates the survival of eosinophils
Steroid treatment associated with a decrease in IL-5 producing cells Cellular culprits of allergy: T cells Cellular culprits of allergy: T cells Wider analysis of cytokines in atopy showed that BAL T cells that expressed elevated levels of IL-5, also expressed IL-4 - a profile typical of Th2 cells in mice IL-3 Growth of progenitor haemopoeitic cells
GM-CSF Myelopoiesis.
IL-4 B cell activation and growth
IgE isotype switch.
Induction of MHC class II.
Macrophage inhibition
IL-5 Eosinophil growth
IL-6 B cell growth
Acute phase protein release
IL-10 Inhibits macrophage activation
Inhibits Th1 cells
TGF- Inhibits macrophage activation Lebman & Coffman 1988 J Exp Med 168, 853-862 ‘Textbook’ scheme of allergic immunity is centred around polarised Th cells Where do Th2 cells come from?
Why are they so dominant in allergic individuals?What are they really for? Journal of Immunology 136, 2348-2357 1986 The discovery of Th1 and Th2 subsets IL-4 IFN-g T cell clones that make IFN-g, but not IL-4 T cell clones that make IL-4, but not IFN-g Enhances
IgE & IgG1 Do not provide help to IgE and IgG1 secreting B cells Provide help to IgE and IgG1 secreting B cells In vitro - Th1 and Th2 subsets Relevance in vivo - Infection Leishmania - specific T cells Reiner & Locksley Annu. Rev. Immunol. 13, 151-177, 1995
Pro-Th1 treatments or anti-Th2 treatments protect against infection Relevance in vivo - Infection Macrophage infected with Leishmania
kills pathogen when activated
Macrophage activation is dependent upon Th1 cells Leishmania resistance - mechanism Tuberculoid leprosy
Low infectivity
Localised infection
Normal serum Ig
Normal T cell response
Poor growth of mycobacteria in macrophages
Lepromatous leprosy
High infectivity
Disseminated infection
Hypergammaglobulinaemia
Unresponsive
Florid growth of mycobacteria in macrophages Relevance of Th subsets in humans
Lepromatous and tuberculoid leprosy Infection with Mycobacterium leprae shows two main clinical forms associated with Th1 and Th2 responses Tuberculoid leprosy Lepromatous Leprosy ‘Textbook’ scheme of allergic immunity is centred around polarised Th cells Immunological fashions
1960’s & 1970’s Immunoglobulin E
1970’s & 1980’s Mast cells & Eosinophils
1980’s & 1990’s Environment – ante-natal & adult, allergens, Th2 cells
1990’s & 2000’s Microbial experience, Epithelium, Tregs
Although undoubtedly a useful model, the textbook ‘skew to Th2’ model is too simplistic to explain allergy
Allergy is a disease of impaired immune regulation
Where is the regulatory lesion? Barrier: Skin, gut, lung, eye, nose etc Non self protein from
allergen or pathogen Allergic immune responses are much like any other immune
response and involves the same regulators Inflammation inc.
MIP-1a, MCP-1 MIP-1b Tracheal Dendritic Cells Langerhan’s cells In-vitro differentiated monocyte-derived Dendritic Cell [Ca2+]i Time (s) [Ca2+]i Time (s) Immature DC migrate into inflamed tissue in response to MIP-1a, MCP-1 MIP1-b which bind to, and trigger CCR1, CCR2 and CCR5 respectively. Migration of immature DC to sites of inflammation
Sallusto et al., Eur. J. Immunol. 1998 28 2760-2769 Immature DC do not respond to the lymph node derived CCR7 ligand MIP-3b Time (s) [Ca2+]i Mature DC stop migrating into inflamed tissue and make no response to MIP-1a, MCP-1 MIP1-b Migration of mature DC to 2º lymphoid tissue
Sallusto et al., Eur. J. Immunol. 1998 28 2760-2769 Mempel, T.R et al Nature 427: 154-159, 2004. Not pulsed with Ag DC – T cell interactions in the lymph node Imaging at various timepoints 2. Distribution of Ag-loaded DCs and T cells is ordered 4-5hr after T cells are injected 1. DCs strategically cluster around HEV 18hr after entering the LN Early entry of DC to the lymph node Mempel, T.R et al Nature 427: 154-159, 2004. 3. DC become highly migratory & change shape (20hr) 4. T cells cover large territories in LN 6. Short, serial T cell-DC contacts of ~ 5 minutes (2-4hrs after injection of T cells) 7. Stable T cell-DC conjugates of 30-180 minutes (8-12hr after injection of T cells) 8. Simultaneous stable and dynamic interactions between DC and T cells 5. 44hr after injection of T cells, DCs decrease motility and become anchored to reticular fibres, T cells rapidly migrate again T cells start to proliferate and produce cytokines 44hr after transfer More information than is provided by the antigen is exchanged between the DC and T cell DC have a profound influence on the properties of the T cell that develops Signals 1, 2 Signal 1 antigen &
antigen receptor Signal 2
B7 - CD28
Costimulation and 3 Signals 1 & 2 activate T cells to proliferation and effector function
But what ‘tunes’ the response to Th1 or Th2? Polarised DC subsets The properties of the allergen, or allergen carrier influences the DC to drive the development of appropriate Th cells Signal 3
Th polarising signal Integration of signals from pathogen/allergenand the extracellular milieu polarise the DC toproduce qualitatively different signals 3 Signal 1 Signal 2 Microbial Patterns Janeway & Medzhitov 2002 Ann Rev Immunol 20 197-216 Pathogen-associated molecular patterns (PAMPS)
Conserved microbial molecules shared by many pathogens
Include:
Bacterial lipopolysaccharides
Peptidoglycan
Zymosan
Flagellin
Unmethylated CpG DNA
Pattern Recognition Receptors (PRR)
Include:
Toll like receptors
Receptors for apoptotic cells
Receptors for opsonins
Receptors for coagulation and complement proteins Pathogen-associated molecular patterns (PAMPS)
Conserved microbial molecules shared by many pathogens
Include:
Bacterial lipopolysaccharides
Peptidoglycan
Zymosan
Flagellin
Unmethylated CpG DNA CD80/CD86 Type 1 and 2 DC Polarising PAMPS Th1 polarisingfactor IL-12 Th2 polarisingfactor CCL2 (MCP-1) Type 1 PAMPS and their PRR Peptidoglycan (Gram + bacteria)
Lipoproteins
Lipoarabinomannan (Mycobacteria)
LPS (Leptospira)
LPS (Porphyromonas)
Glycophosphatylinositol - (T. Cruzi)
Zymosan (Yeast) LPS
Lipotechoic acid -
(Gram + bacteria)
RSV F protein dsDNA Unmethylated
CpG DNA Low level IL-12p70
Some ligandsinduce IL-10or IL-12p35 HighIL-12p70IFN-a HighIL-12p70 HighIL-12p70IFN-a Type 2 PAMPS and their PRR ? ? Endogenous molecular patterns Endogenous molecular patterns
Include:
Heat shock proteins
(HSP60 HSP70 GP96)
Extracellular matrix proteins
(hyaluronan, fibronectin, fibrinogen)
Immune complexes
Surfactant protein A
Necrotic cell components
Pattern Recognition Receptors (PRR)
Include:
Toll like receptors
Receptors for apoptotic cells
Receptors for opsonins
Receptors for coagulation and complement proteins Receptors for apoptotic cells Receptors for opsonins
Receptors for coagulation and complement proteins Indirect activation of DC by ‘modulatory tissue factors’ Direct activation by PAMP-PRR interactions Necrotic/apoptotic cell death - neo expressionof PRR ligands Heat shock proteins Extracellular matrix components
Necrotic cell lipids
Cytokines
Chemokines
Eicosanoids
Coagulation components
Complement components Allergen Activates the expression of costimulatory molecules on DC Could be argued that the development of Th2 cells is the default pathway DC polarisation by modulatory tissue factors DC polarising factorsIFN-g IFN-a IFN-b Th0 to Th1 polarising cytokines
IL-12p70 IL-27 TNF-b IL-18 DC polarising factorsCCL7 (MCP-3), CCL13 (MCP-4), PGE2, Histamine Th0 to Th2 polarising cytokinesCCL2 (MCP-1), ?IL-4
Lack of high level IL-12p70
IL-27 TNF-b IL-18 NK Mast Fibroblast PGE2
CCR2L Histamine IFN-g IFN-a IL-18 Viruses
Fungi
Parasites
Bacteria Viruses Viruses
Fungi
Parasites Viruses Sources of modulatory tissue factors The hygiene hypothesis (Strachan, 1989)
Based upon the epidemiology of hay fever
“Declining family size, improved household amenities, and higher standards of personal cleanliness have reduced the opportunities for cross-infection in young families. This may have resulted in more widespread clinical expression of atopic disease"
..can be interpreted in terms of a failure to microbially modulate default Th2 responses in childhood young families Explains how Th2 arise, but… …does not explains why some individuals are allergic and others are not and why the incidence of allergy is increasing.
Reduced numbers of IL-12 producing cells?
Reduced ability to produce or respond to IL-12?
Reduced stimulation of IL-12 by microbial substances? Neonatal & infant immune systems Serial infections Delayed maturation of Th1 capacity Few serial infections – hygiene, small family size etc Do infections only reduce Th2 dominance by inducing Th1 responses? Aerosolised ovalbumin (OVA) OVA – allergic mice with asthma-like symptoms
Eosinophils in airway, dominance of OVA-specific Th2 cells, OVA-specific IgE Wheeze Vaccinate with mycobacteria No asthma-like symptoms Wheeze Have the Th1 cells induced by the mycobacteria downregulated the activity of the Th2 responsible for the symptoms? Wheeze No asthma-like symptoms Do infections only reduce Th2 dominance by inducing Th1 responses? CD4+ cells specific for OVA that produce high levels of the immunosuppressive cytokines TGFb and IL-10 Mycobacteria induced REGULATORY T cells Th cell polarisation DC mediated – decision influenced by infection
Extracellular milieu - mediated 0 1 10 Factor increase over control 0 1 10 Factor increase over control Journal of Immunology 1994 152 4755-4782 Priming conditions IFNg U/ml IL-4 pg/ml
Control Ab 5892 256
Anti-IFNg Ab 1534 624
IL-4 + control Ab 1740 839
IL-4 + anti-IFNg Ab 348 1245 Resting Mast cell Degranulated mast cell Mediators released include: Leukotriene C4 & D4, Prostaglandin D2 Platelet Activating Factor, Chymase, Tryptase, Heparin, Histamine IL-4, IL-5, IL-6, IL-8, TNF-a IL-4, IL-5 IL-4 is not only a product of Th2 cells IL-4 from the innate immune system Journal of Experimental Medicine, 1992 176 1381-1386 Sequential 2mm sections from a mucosal biopsy of a patient with asthma What properties and characteristics make a substance an allergen?
How do these properties disregulate the processes described? L. destructor G. domesticus D. pteronyssinus D. pteronyssinus A. siro T. putrescentiae Allergens of Dermatophagoides pteronyssinus Proteinase allergens are common and widespread:
Fungi, insects, plants, parasites, drugs
(but…most allergens are not proteases) Der p 1 Cysteine protease
Der p 2 ?
Der p 3 Trypsin (serine protease)
Der p 4 Amylase
Der p 5 ?
Der p 6 Chymotrypsin (serine protease)
Der p 7 ?
Der p 8 Glutathione transferase
Der p 9 Collagenase (serine protease)
Der p 10 Tropomyosin
Der p 14 Apolipophorin like protein Protease allergens can breach epithelial barriers Wan et al., Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions J Clin Invest, 1999, 104, 123-133 Leads to immune sensitisation without the ‘deliberate’ invasion and infection mechanisms of a pathogen Proteases as activators of cells Protease Activated Receptors PAR Activators Inactivators
PAR1 Thrombin, Trypsin Granzyme A Cathepsin G, Elastase, Plasmin
Proteinase 3
PAR2 Trypsin, Tryptase, Factor Xa, Proconvertin Cathepsin G,, Plasmin, Proteinase 3
PAR3 Thrombin Cathepsin G, Elastatase
PAR4 Thrombin, Trypsin, Cathepsin G ? Inactivators Journal of Immunology 2001 167 1014-1021 PAR are also involved in:
Induction of of epithelial cell & fibroblast proliferation
Induction of cytokines & chemokine expression
Induction of pharmacological mediator release
Induction of metalloproteases
Regulation of smooth muscle tone Resting Mast cell Degranulated mast cell Mediators released include: Leukotriene C4 & D4, Prostaglandin D2 Platelet Activating Factor, Chymase, Tryptase, Heparin, Histamine IL-4, IL-5, IL-6, IL-8, TNF-a IL-4, Do protease allergens induce IL-4 release by Mast cells Journal of Leukocyte Biology 2003, 73 165-171 Constitutive & Induced CytokineExpression by KU812 Basophils b-actin Der p1 Induces Cytokine Type-2 Cytokine mRNA
Expression in KU812 516bp 516bp PMA/Ionomycin
Inhibitors - - + + + + - - b-actin IL-13 Protease Inhibitors Do Not Prevent Cytokine mRNA
Expression by KU812 516bp b-actin IL-13 - - - + PMA/Ionomycin Tetanus toxoid - - - + - + -ve 516bp Time (hr) 1 1 4 4 4 Non-Proteolytic Antigens Do Not Induce Cytokine
mRNA Expression by KU812 Der p1 induces IL-4 and IL-13 protein expression in Freshly isolated Basophils 516bp 516bp 516bp 516bp 516bp b-actin IL-4 IL-5 IL-13 IFN-g - Inhibitors + Inhibitors -ve +ve 0 ES 100ng/ml ES 200ng/ml ES 1000ng/ml ES 0 ES 100ng/ml ES 200ng/ml ES 1000ng/ml ES Necator Americanus Proteases Induce Type-2 Cytokine
Expression by KU812 Der p1 and hookworm excretory/secretory products induce IL-4 and IL-13 protein expression in KU812 Basophils The switch to IgE Lebman & Coffman 1988 J Exp Med 168, 853-862 Switch regions The Sm consists of 150 repeats of [(GAGCT)n(GGGGGT)] where n is between 3 and 7.
Switching is mechanistically similar to V(D)J recombination. Switch regions - repetitive regions of DNA that physically recombine
Upstream of C regions Switch recombination to IgE A three signal process:
Antigen – controls entire process
Soluble help via IL-4 or IL-13 from T helper cells
Cognate help via CD40 L from T helper cells Y Y Y T cell help to B cells B Antigen Th IL-4 and IL-13 CD40 Ligand CD40 Switch recombination to IgE A three signal process:
Antigen
Soluble help via IL-4 or IL-13 from T helper cells
Cognate help via CD40 L from T helper cells Stat-6 P Stat-6 P Soluble help via IL-4 or IL-13 from T helper cells IL-4Ra IL-4Ra gC IL-13Ra1/2 IL-13 IL-4 IL-13 IL-4 IL-4R IL-13R JAK1 JAK3 TYK1 JAK1 TYK2 P P Stat-6 P Stat-6 P P P Stat-6 P P Stat-6 P P Stat-6 P P P Dimerised Stat-6
translocates to nucleus Switch recombination to IgE A three signal process:
Antigen
Soluble help via IL-4 or IL-13 from T helper cells
Cognate help via CD40 L from T helper cells Ligation promotes aggregation in lipid rafts Cognate help via CD40 L from T helper cells CD40 2 3 5 6 TNF receptor associated factors IkB NF kB IkB NF kB Uninhibited NFkB translocates to the nucleus Stat6 Ie Ce1 Ce2 Ce3 Ce4 Se Ie NFkB C/EBP PU.1 BSAP AP-1 BSAP – B cell specific activator protein. C/EBP CCAAT/enhancer binding protein.
PU.1 – Spi1 equivalent in humans, ets transcription factor Induced by IL-4/IL-13 and CD40 ligation Activation of the Ie promoter Activation/cytokine
responsive promoter Ce1 Ce2 Ce3 Ce4 Se Ie Germline IgE transcripts Transcription Why has this mechanism evolved to transcribe just the C region?
VHDHJH is needed to make a functional IgE
Why is the epsilon switch region spliced out? DNA Ce1 Ce2 Ce3 Ce4 Se Ie RNA Ce Ie Spliced
RNA Germline transcripts What do germline transcripts do? Ce Ie Ce1 Ce2 Ce3 Ce4 Se Ie RNA Spliced
RNA Se RNA S region RNA hybridises with template DNA Single stranded DNA Ie Ce1 Se Se 5’ 3’ R loop 1. S region in the genomic DNA ‘melts’ 2. S region RNA spliced from germline RNA transcript hybridises to single-stranded DNA 3. ssDNA R loop formed – a substrate for AID - ACTIVATION- INDUCED CYTIDINE DEAMINASE Mechanism of class switch recombination NFkB Activation-induced cytidine deaminase Soluble help via Th cell IL-4 or IL-13
Induces Stat 6 Cognate help via Th cell CD40 L from T helper
Releases NFkB from IkB B cell activation by antigen leads to: AID gene is expressed under the same conditions as B cells induced to switch Ig isotype Expressed only in B cells
Involved in isotype class switching & somatic hypermutation
AID knockout mice do not class switch Ig isotype
Ectopic expression in non B cells causes class switch
Mutation in the AID gene can cause hyper IgM syndrome
Deaminates cytidine on ssDNA, i.e. substitutes U for C Activation-induced cytidine deaminase AID RPA AID RPA AID RPA AID RPA AID RPA AID RPA AID RPA AID RPA GGGCTGGGCTGAGCTGRGCTGAGCTGRGCTGAGCTRARNT
CCCGACCCGACTCGACYCGACTCGACYCGACTCGAYTYNA IgE S region Non-template strand is G-Rich
and contains RGYW (A/G G T/C A/T) motifs Preferred Se region target sequence for AID GGGCTGGGCTGAGCTGRGCTGAGCTGRGCTGAGCTRARNT AID RPA AID RPA Replication protein A (RPA) targets AID to ssDNA in R loops by binding to RGYW motifs GGGCTGGGCTGAGCTGRGCTGAGCTGRGCTGAGCTRARNT
GGGCTGGGCTGAGCTGRGCTGAGCTGRGCTGAGCTRARNT
CCCGACCCGACTCGACYCGACTCGACYCGACTCGAYTYNA Non-template ssDNA RNA/template DNA hybrid GGGCTGGGCTGAGCTGRGCTGAGCTGRGCTGAGCTRARNT
GGGCTGGGCTGAGCTGRGCTGAGCTGRGCTGAGCTRARNT
CCCGACCCGACTCGACYCGACTCGACYCGACTCGAYTYNA Activation induced cytidine deaminase NH2 N N O Cytidine O N HN O Uridine AID AID mediated deamination of cytidine to Uridine Activation induced cytidine deaminase AID may also deaminate C on the template strand
?RNAase? GGGUTGA
CCCGACT GGGUTGA
CCCGACT S region DNA now contains mismatched G – U pairs that must be repaired
e.g. by the base excision repair mechanism GGGUTGGGUTGAGUTGRGUTGAGUTGRGUTGAGUTRARNT
CCCGACCCGACTCGACYCGACTCGACYCGAUTCGAYTYNA G - U mismatch repair GGGUTGGGUTGAGUTGRGUTGAGUTGRGUTGAGUTRARNT
CCCGACCCGACTCGACYCGACTCGACYCGAUTCGAYTYNA P P P P P P P P P P P P GGGUTGGGUTGAGUTGRGUTGAGUTGRGUTGAGUTRARNT
CCCGACCCGACTCGACYCGACTCGACYCGAUTCGAYTYNA Uracil-DNA glycolase (UNG) removes uracil to leave abasic sites in S region UNG UNG UNG UNG UNG UNG UNG UNG Base is removed, but backbone remains intact GGGUTGA
CCCGACT P P P P P P P P P P P P G - U mismatch repair APE1 Abasic site is processed by the apurinic/apyrimidimic endonuclease 1 (APE1) GGGUTGA
CCCGACT P P P P P P P P P P P P OH DNA is now nicked to produce a single strand break GGGUTGGGUTGAGUTGRGUTGAGUTGRGUTGAGUTRARNT
CCCGACCCGACTCGACYCGACTCGACYCGAUTCGAYTYNA APE1 APE1 GGGCTGGGU TGAGCTGRGCTGAGCTGRGCTGAGCTRARNT
CCCGACCCGACTCGACYCGACTCGACYCGAU TCGAYTYNA
Similar mechanism on the template strand creates a staggered double strand break Processing of staggered ends GGGCTGGG
CCCGACCCGACTCGACYCGACTCGACYCGA TGAGCTGRGCTGAGCTGRGCTGAGCTRARNT
TCGAYTYNA GGGCTGGG TGAGCTGRGCTGAGCTGRGCTGAGCTRARNT
CCCGACCCGACTCGACYCGACTCGACYCGA TCGAYTYNA End fill-in reactions ACTCGACYCGACTCGACYCGAC Exonuclease activity Ca2 Ce Cg4 Cg2 Ca1 Cg1 Cg3 Cd Cm Sg3 Sg1 Sa1 Sg2 Sg4 Se Sa2 Sm Ca2 Ce Cg4 Cg2 Ca1 Cg1 Cg3 Cd Cm Sg3 Sg1 Sa1 Sg2 Sg4 Se Sa2 Sm Cm Cd Cg3 VDJ Cg1 Ca1 Cg2 Cg4 Ce Ca2 VDJ Ce Ca2 Cm Cd Cg3 Cg1 Ca1 Cg2 Cg4 Excised episomal circle of intervening DNA Activation of Im & Ie promoter by Ag, IL-4/13 and CD40L
Production of germline transcripts and splicing of Sm and Se
Deamination of ssDNA in Sm and Se by AID
Base excision and mismatch repair
Blunt-ended ds breaks and synapsis of Sm to Se by non-homologous end joining Process occurs in two S regions simultaneously 7 23 9 7 12 9 Non-homologous end joining in class switch V D J Closely resembles another B cell Ig gene mechanism Defects in NHEJ proteins impair class switch NFkB BCL-6 BCL-6 BCL-6 binds to the Stat-6 binding site and represses switching Stat6 is involved in Th2 cell differentiation, the expression of CD23 (the low affinity IgE receptor) and VCAM expression
BCL-6 may exert it’s anti/pro-allergic activities via these genes Stat6 Transcription
blocked BCL-6 -/- mice have enhanced IgE isotype switching
BCL-6 -/- Stat6 -/- mice have no IgE
An RFLP has been mapped to the first intron of the BCL-6 gene that is significantly associated with atopy - but not IgE levels Additional areas to think about Can’t get over a 2.2 mark without showing evidence of outside reading in answers Relationship between isotype switch, somatic hypermutation and proliferation of B cells in the germinal centre
What is the relationship between the deliberately mutagenic mechanisms of isotype switch and somatic hypermutation in B cells and the propensity of B cells to form tumours
Where are the holes in the ‘skew to Th2’ model of allergy?
What are allergic responses really for? What are allergic immune responses really for? Trichuris Trypanosoma Toxoplasma Enterobious Ascaris Leishmania Schistosome Hookworm Plasmodium Wuchereria Onchocerca Taenia Text book view Helminth infections induce IgE, mastocytosis and eosinophilia
A classic Th2-driven response Eosinophils killing a schistosome egg in vitro Susceptible mice However…….. Heavily parasitised individuals exist - despite Th2 responses and eosinophilia.
Scarce in vivo evidence of eosinophil and IgE control of helminth infection
Yet IL-4 may be involved - Trichuris muris model Resistant mice Else et al., 1994 J. Exp Med 179 347-351 Nippostrongylus infection Th2 cells themselves may not be needed IL-4 from any source is sufficient to induce worm expulsion IL-4 Urban et al., 1995 J. Immunol. 154, 4675-4684
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