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The Hygiene Hypothesis - first proposed by D. Strachan 1989 To explain an epidemiological study showing a striking inverse correlation between family size & incidence of allergy …. … clothes weren\'t the only things your older sibs passed down

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The Hygiene Hypothesis - first proposed by D. Strachan 1989

To explain an epidemiological study showing a striking inverse

correlation between family size & incidence of allergy ….

… clothes weren\'t the only things your older sibs passed down

and it quickly followed from other epidemiologists that individuals

from small families that spent a lot of time in daycare also fared

better during later life in having a lower incidence of allergy


However not all epidemiologists agreed with the hygiene hypothesis:

Allergy (2008) 63:274-83.Infections presenting for clinical care in early

life and later risk of hay fever in two UK birth cohorts.

"CONCLUSIONS: Of 30 infectious illnesses investigated, none had strong or

consistent associations with hay fever after adjustment for consultation


Though the journal editors questioned this counter claim & noted that:

"… minor infections not brought to a doctors attention were not

recorded …."

"… likelihood of a child being taken to a general practitioner may

depend on such factors as parental anxiety and inexperience…"


More evidence in favor of the hygiene hypothesis:

perhaps it\'s the type of bugs you\'re exposed to

Epidemiologic studies note a lower incidence of allergy/ asthma

in rural farm children ….

Riedler, J. et. al. ALEX Study Team. 2001. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet. 358:1129

von Mutius, E., K.Radon. 2008. Living on a farm: impact on asthma induction and clinical course. Immunol. Allergy Clin. North Am. 28:631

Prevalence of allergy, patterns of allergic sensitization and allergy risk factors in rural and urban children. Allergy. 62:1044 (2007)


Molecular microbiologists identify the innocuous cowpie microbe

Acinetobacter lwoffii as a possible allergo-protective agent

Korthals et al. Application of PCR-SSCP for molecular epidemiological studies on the exposure of farm children to bacteria in environmental dust. J. Microbiol. Methods. 73:49 (2008)

and test it in an animal allergy model system …..


Maternal TLR signaling is required for prenatal asthma protection

by the nonpathogenic microbe Acinetobacter lwoffii F78

Conrad et. al. - J. Expt. Med. 206 (13): 2869 (2009)

Pregnant mice given repeated intranasal inoculations of A. lwoffii

Offspring are sensitized to Ova (i.p.) and then given ova inhalant to

mimic asthmatic response

Lung leukocytes:





BAL – branchio-aviolar lavage = lung wash


Maternal inoculation reduces offspring allergy via maternal TLRs

Conrad et. al. - J. Expt. Med. 206 (13): 2869 (2009)

red is







Protection can also be through self TLRs ….


In allergy and autoimmunity prone animal models induction of host TLR

protects from onset of allergy or autoimmunity

Innate immunity and intestinal microbiota in the development of Type 1 diabetes (T1D).Nature 2008; 455(7216):1109-13.

"Here we show that specific pathogen-free NOD mice lacking MyD88 protein do not develop T1D. The effect is dependent on commensal microbes because germ-free MyD88-negative NOD mice develop robust diabetes"


…. and further …..

Systemic Toll-Like Receptor Stimulation Suppresses Experimental Allergic Asthma and Autoimmune Diabetes in NOD Mice. (2010) Aumeunier A, Grela F, Ramadan A, Pham Van L, Bardel E, et al. PLoS ONE 5(7)

“These observations demonstrate that systemic administration of TLR ligands [individually or in the context of probiotic bacteria] can suppress both allergic and autoimmune responses.”


genetic & cellular mechanisms for microflora suppression of disease

Microbial Exposure During Early Life Has Persistent Effects on

Natural Killer T Cell Function. Science. March 22, 2012 Olszak et al. R.S. Blumberg

They investigated the susceptibility of GF and SPF mice to oxazolone-induced ulcerative colitis (UC), a model of intestinal inflammation that possesses features of ‘natural’ UC in that it’s dependent on IL-13 production by CD1d-restricted iNKT cells

GF – germ free – no gut bacteria

SPF – specific pathogen free – normal (healthy) gut microflora only

Science DOI: 10.1126/science.1219328 – next 4 slides


microflora suppresses

the # of gut iNKT cells

increased iNKT #’s

assoc. with pathology

Inflammation in gut

of GF mice given

Oxazolone (Ox) UC

Mortality & hi cytokine

levels in GF-Ox mice


UC is prevented by blocking CD1d or by neonatal exposure to bacteria

blocking CD1d

reduces disease

… and reduces

cytokine prod.

inoculation of

GF pregnant mice

just before delivery

(GF/n) rescues pups

from UC pathology

Inoculation of pups 5 weeks after birth (GF/a) doesn’t protect them

19G11- anti-CD1d MAb

IgG2b – isotype control


iNKT also cause lung inflammation in the Ova model of asthma in mice

more iNKT in

lung of GF mice

iNKT asthma

is CD1d


neonate bacteria


protects from

asthma development

… but after birth exposure (GF/a) to bacteria is not protective


Neonatal exposure to bacteria causes epigenetic inactivation of the gene

for CXCL16 which recruits iNKT cells to gut and lung

CXCL 16 levels

are hi in GF &

GF/a mice

anti-CXCL16 MAb

reduces iNKT


They propose that


of Cxcl 16 leads to

gene inactivation


Eubiosis (healthy – see slide notes)

Mucins, sIgA & AMPs keep bacteria

from populating intestinal epithelial

cell (IEL) surface.

MAMPs promote development of

tolerogenic MFs & DCs which

produce lots of TGF-b which in turn

induce Treg development

IL-10 & TGF-b prevent or dampen

inflammation through their effects

on various innate leukocyte types


Dysbiosis – disruption of the

normal microflora ecosystem

Damage to, or stress of

intestinal epithelial cells by

pathogens combined with MAMPs

lead to a pro-inflammatory response

of MFs & DCs and potential for

further damage to tissues

e.g. colitis

(see slide notes)

Nature489, 231–241 (2012) doi:10.1038/nature11551


Grouping bacteria based on immunomodulatory effects

  • Transiente.g. Lactobacillus spp. - confer health benefits when present in sufficient #’s
  • ProbiontsBifidobacterium spp.
  • - not necessarily part of ‘normal’ microflora
  • beneficial immunostimulatory effects - may influence normal microflora populations
  • Commensal e.g. Bacteroides spp. - direct influence on immune cell homeostasis
  • Symbionts Clostridia spp.
  • Fecalbacterium spp. - part of the ‘normal’ microflora
  • Commensal e.g. Klebsiella spp.- permanent facultative pathogens
  • Pathobionts C. difficile
  • Helicobacter spp.- they don’t cause disease when amongst healthy
  • microflora
  • - cause disease when host microflora or immunity
  • is perturbed
  • Transiente.g. Salmonella spp. - transiently disrupt normal microflora & cause disease
  • PathogensVibrio cholerae

adapted from: Cell Host & Microbe, 12 (4):445-457 (2012)


Defining the specifics of what constitutes a healthy microbiota is

difficult. In the meantime rather crude means of restoring

healthy microflora are being used in some diseases …..

J. Clin. Gasterenterol. 37(1):42-47 (2003)


The mechanisms by which specific bacteria species restrain pathobionts

are beginning to emerge …..

Nature453, 620-625 (2008)

A microbial symbiosis factor prevents intestinal inflammatory disease

The human symbiont Bacteroides fragilis produces a protective

sugar called PSA

In the absence of PSA another commensal, Helicobacter hepaticus, will

induce colitis in mice ….

… regardless whether (PSA-) Bacteroides fragilis is present

… injected PSA alone also ameliorates the inflammatory colitis


But is it all based on immune system modulation by bacteria?

Quite a different story (and some explanations) come from

epidemiologic studies of autoimmunity and macroparasite exposure…

These inverse correlations prompted researches to see if parasite

infections prevented certain types of autoimmunity


A number of parasites were found to abrogate autoimmunity

reviewed in: A worm\'s eye view of the immune system: consequences for evolution of human

autoimmune disease. David W. Dunne & Ann Cooke.Nature Reviews Immunology5, 420-426 (May 2005)


These studies in turn prompted autoimmune disease sufferers

self-infect with parasites to ameliorate their own diseases


Modulation of immunity through helminth infections is also via TLRs

but in a different manner than the bacteria

Nat. Rev. Immunol. 10, 278-284 (April 2010)


Helminths secrete inflammatory mediators that suppress allergy

Nat. Rev. Immunol. 10, 278-284 (April 2010)


Helminths produce inflammation modulators that also diminish

frequency of allergy and autoimmune diseases

(don\'t try to remember these)

Nat. Rev. Immunol. 10, 278-284 (April 2010)


The evolution of sex-specific immune defences

Olivier Restif1,*and William Amos2 Proceedings of the Royal Society Mar 24, 2010

Males-maintaining ability

to mate more important

than getting better.


Gender bias in autoimmunity

1. Role of sex homones on immune cells.

Table 1. Expression of steroid receptors by murine immune cells.

Estrogen receptors Androgen receptors Progesterone receptors

B cells + + −

CD4 T cells − − −

CD8 T cells + − −

Monocytes + − −

Neutrophils + − −

NK cells + − −

Macrophages − + −

Sex hormones influence immune responses directly by binding to steroid receptors in lymphocytes.

Some effects include increased antimicrobial peptide secretion, recruitment of neutrophils, regulation of NK activity.

Genetic and hormonal factors in female-biased autoimmunity

Anatoly V. Rubtsova, , , Kira Rubtsovaa, John W. Kapplera, b, c and Philippa Marrack 2010. Autoimmunity Reviews


2. Role of hormones in development of autoimmunity.

-incidence of autoimmune disease is much higher in females

-severity of RA or MS decreases during pregnancy

when progesterone is high

(Th2 response predominates and these diseases are driven by

Th1 responses.)

-SLE worsens, but it is driven by autoantibodies, which increase

under Th2 responses.

Hormone levels affect onset and severity of autoimmune

diabetes, RA, EAE and SLE.

-SLE delayed in males, unless castrated.

-Ovariectomy of female mice delays onset.


3. X chromosome complement in autoimmunity

1000 X-linked genes. Of known genes, about 70 are related to disease.

X-inactivation is incomplete. 10-15% express both alleles

Random X-inactivation in somatic cells makes females mosaic for X-linked gene expression.

X monosomy. Systemic schlerosis and thyroid diseases show high frequency of blood cells with loss of one X chromosome.

TLR7 and TLR8 are X-linked, and 2-fold over-expression increases interferon-alpha production and disease severity in lupus.


HIV gender clues emerge

Women with untreated HIV develop AIDS much faster than men.

Increased TLR7 mediated recognition leads to more IFN-alpha

IFN-alpha stimulates CD8+T cells to kill more infected CD4 cells.

Women have 4.6% more activated CD8+T cells than men.

Nat Med. 2009 Aug;15(8):830.

HIV gender clues emerge.

Willyard C.

Comment on:

Nat Med. 2009 Aug;15(8):955-9.


Interferon-alpha producing pDCs are higher in women

a) Representative flow cytometry plots showing IFN- production by

CD123+ pDCs derived from women (top) or from men (bottom)

b)The percentage of IFN-+ pDCs in men (n = 20) as compared to women (n = 23)

after stimulation with the HIV-1–derived single-stranded

RNAs GagRNA1166 and Gp160RNA2093 or the TLR9 ligand ODN2216.


TLR7 Activation by Self-RNA Initiates the Type I IFN Cascades,

Leading to Systemic Autoimmunity

Apoptotic blebs, which are enriched in RNA and DNA, are thought to be cleared by macrophages.

However, reduced clearance of apoptotic debris, or if the pDC express increased amounts of TLR7, then the amount of endocytosed RNA may suffice to trigger TLR7, inducing secretion of type I IFN.

Further, in the presence of autoantibodies of appropriate specificity, the blebs form immune complexes that are readily taken up by pDC, providing a strong stimulatory signal.


Type I IFN promotes autoimmunity in multiple ways, including inducing B cells to express increased TLR7, which may provide a positive-feedback loop exacerbating autoimmunity (Bekeredjian-Ding et al., 2005).

As a result of the synergy between the B cell receptor and TLRs, B cells specific for RNA- or DNA-associated antigens can get both stimulatory signals and be preferentially stimulated to differentiate into plasma cells.