Allergy and Asthma Epidemic in Developing Countries Devereux G.
2006. Nature Rev Immunol 6;869-874.
Slide 6
Hygiene Hypothesis early childhood infections inhibit the
tendency to develop allgergic disease
Slide 7
Helminth Infections & Allergies: Inverse Correlation %
Population*Helminth Infection** Allergic Disease*** Globally ~ 25%~
2% United States < 1%~ 13% * United States Census
(www.census.gov) ** Clin Exp Immunol, 2002. 128(3): p. 398-404 ***
Lancet, 1998. 351(9111): p. 1225-32 Helminth infections are
associated with a decreased incidence of allergic disease in
industrialized areas
Slide 8
The Hygiene Hypothesis
Slide 9
Hygiene Hypothesis - Infection history makes a difference
Slide 10
Many Helminth Species Have an Obligate Lung Stage Geohelminths
Schisto Filariasis HOOKWORM ASCARIS SCHISTOSOMA Malaria
Slide 11
INFECTION Skin penetration L3 larvae enter circulation Reach
lungs within a day PULMONARY PHASE L3 molt into L4 Larvae Spend
less than 48hrs in lung Crawl/coughed up trachea Swallowed down
esophagus ADULT PHASE L4 reach small intestine Molt into adult
stage worms Patency by day 7 RESOLUTION Normal BALB/c will expel
the worms within 11 days SCID maintain infection
Slide 12
Outline Part I: Innate responses to Nb in the lungs - Gene
array, PCR Part II: Persistent alterations in the immune
environment of the lung - Flow cytometry Part III: Molecular basis
for helminth-induced dampening of inflammation
Slide 13
Slide 14
Innate Immune Responses to Nb in the Lung Experimental
Design
Observations: Nb induces cellular/molecular changes through day
12 PI Helminth-induced suppression of reactivity to secondary
challenge (Wohlleben et al. 2004; Wilson et al. 2005; Yang et al.
2006) : Hypotheses: Helminth infection results in permanent
alterations to the lungs immunological environment
Slide 25
Nb Induces an Altered Lung Environment Experimental Design
2-413-1536
Slide 26
Granular Macrophages Contain Surfactant day 36 PI
Slide 27
Flow cytometry antibody-based detection of surface
molecules
Slide 28
Day 36 PI AMs are CD11c +, F4/80 +, Mrc1 mid & MHC II hi
day 36 PI
Slide 29
Surface Phenotype of CD11c + AAAM CD11c+ AAAM up-regulate: MHC
I & II PDL-1CD80/CD86CD40CD1d Day 0 2 4 8 13 CD11c MHC I MHC II
PDL-I PDL-2 CD80 CD86 CD40 CD1d ICAM-1
Slide 30
AAAM are Highly Phagocytic Ova- Nb+Nb- Ova+* CytoB Ova-Alexa
448 at 2 g/ml for 30 min CytoB - cytochalasin B at 800 g/ml
Ova-Alexa 448 CD11c APC CD11c APC Ova-Alexa 448 22.59.2 5.2 3.5
0.070.02
Slide 31
CD11c + AM Expression Profile AAM (arg1, fizz1, Ym1/2, trem2b)
Scavenger Receptors ( clecsf5/6/8/10, marco, mgl1/2, msr1/2 )
Chemokines ( ccl4/8/9/11/12/17/24 ) Cell Cycle Lipid Metabolism (
ppar gamma, cd68, apobec1, ch25h ) 194797 392 76 277 59524 day 2 PI
(606) day 2 PI (606) day 4 PI (1,674) day 4 PI (1,674) day 8 PI
(1,252) day 8 PI (1,252) Up-regulated >2-fold
Slide 32
Slide 33
Altered Lung Environment: Hypotheses: The Nb-altered lung
environment results in a modulation in responses to secondary
challenges - HDM allergen challenge Gene array, PCR, histology,
lung function
Altered Lung Environment: Dampened Responses to Allergen Key
Findings: Persistent changes resulted in a reduction in the overall
inflammatory response to allergen challenge in the lungs of
Nb-infected animals Distinct gene expression profiles in the lungs
of NbHDM vs HDM mice Lower fold-increase of transcription of Th1
& Th2 cytokines in NbHDM mice Resistance in the airways is
significantly depressed in the lungs of NbHDM mice
Slide 38
Hygiene Hypothesis early childhood infections inhibit the
tendency to develop allgergic disease
JHU Gene Array Core Facility Anne Jedlicka Meg Mintz Jason
Bailey Amanda Dziedzic Acknowledgments Collaborators Joe Urban
(USDA) Andrea Keane-Myers (NIH) Jamie Lee (Mayo Clinic) Funding /
Support NIH NHLBI (U01 HL66623) NIH Training Grant (T32AI007417)
Hegner, Cort Root Memorial Scholarship Martin Frobisher Fellowship
Scott Lab Josh Reece Mark Siracusa Kiwon Park Sarah Coffman Ellen
Tarr JHU Sabra Klein Mike Overstreet Fidel Zavala Mark Soloski Bill
Spannhake Wayne Mitzner Jon Fallica Doug Norris Vern Carruthers
Brian Schofield Paul Fallon Theresa Southard Cory Brayton