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Dependency of immune function on environmental components: apparent mutualistic aspects of commensalistic and even parasitic relationships. William Parker, PhD Duke University Medical Center.

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william parker phd duke university medical center

Dependency of immune function on environmental components: apparent mutualistic aspects of commensalistic and even parasitic relationships

William Parker, PhD

Duke University Medical Center

slide2

This presentation accompanies the lecture by William parker given at the 2011 Ecoimmunology meeting in Scotland.

slide3

Popular Science

Worst Jobs in Science 2009

Vermin Handler

http://www.popsci.com/scitech/gallery/2009-01/worst-jobs-science-2009

slide4

Post industrial society serves as a testing ground for the alteration or even loss of various components from the “human biome” (the ecosystem of the human body).

In the medical world of post industrial society, we care about the “friendly components” (mutualistic organisms).

slide5

Three distinct categories of “friendly factors”

  • Bacteria in dirt. (predominantly mycobacteria)
  • Mutualistic bacteria (the microbiome)
  • Mutualistic helminths (known unfortunately as parasites)

Rook and Brunet, Gut. 2005 March; 54(3): 317–320. doi: 10.1136/gut.2004.053785.

slide6

Lessons from the microbiome

Gut

Bacteria

Mutual admiration, or reluctant tolerance?

The immune system

slide7

Accepted paradigm of Science until 2003:

Primary Mechanism of Gut Function

Immune exclusion of bacteria by Immunoglobulin A (SIgA) in the gut

slide8

SIgA inhibits 50% to 75% of the binding of common Streptococcus species to human gut cells.

Inhibition of Bacterial Adherence by Secretory IgA: A mechanism of Antigen Disposal, by R. C. Williams and R. J. Gibbons

Published in Science, 1972

slide9

Immune Exclusion

  • An attractive idea
  • Normal gut bacteria are the most common cause of death in the United States: Something has got to keep these things in check.
  • SIgA are made against pathogenic bacteria as well as good bacteria. The SIgA must then be antagonistic to bacteria.
slide11

without SIgA

with SIgA

(image not magnified)

slide12

The mucin story

No protein

SIgA

Mucin

Mucin + SIgA

(image not magnified)

slide16

Normal

Infection

Recovery

Apparent function

of the appendix

Diarrhea

Recovery

“Safe House”

slide17

Heather Smith

Michel Laurin

For an agonizingly detailed review of the vermiform appendix, see The Anatomical Record, 294:567–579

Rebecca Fisher

slide18

Three distinct categories of “friendly factors”

  • Bacteria in dirt. (predominantly mycobacteria)
  • Mutualistic bacteria (the microbiome)
  • Mutualistic helminths (known unfortunately as parasites)

Rook and Brunet, Gut. 2005 March; 54(3): 317–320. doi: 10.1136/gut.2004.053785.

slide19

Stimulatesdevelopment

Microbiome

Helminths

?

Supports and

Contains

Growth

Resource

commitment

Limits colonization

Immune

suppression

Stimulates

feedback

inhibition

Stimulates development

Immune system

slide20

Ubiquitous factors that, by

themselves, do not cause pathology

Immune

hypersensitivity caused by hygiene-associated biome depletion

Environmental stimulus (“triggers”, often reduced by hygiene)

+

2

1

+

3

Genetic predisposition and/or epigenetic effects

Hyper-immune associated diseases, including allergyand autoimmunity

Bilbo, Wray, Perkins, and Parker

Medical Hypotheses, 2011

doi:10.1016/j.mehy.2011.06.019

slide21

The adoption of “modern” culture causes epidemics of various conditions that are rare or absent in developing areas of the world.

These can be classified into two categories:

Biome depletion

incompatible with human biology

Diet, rest, exercise and other behavior

incompatible with human biology

coronary artery disease

hypertension

stroke

type 2 diabetes

obesity

lung cancer

automobile-related injury

appendicitis

asthma

allergies (all types)

multiple sclerosis

lupus

type 1 diabetes

inflammatory bowel disease

The increase in disease rate associated with industrialization depends on disease, and ranges from about 15-fold to more than 100-fold. Numbers from underdeveloped countries are very crude estimates, but have been confirmed by other means.

Med Hypotheses (2011), doi:10.1016/j.mehy.2011.06.019

slide22

Results of biome depletion

  • Confirmed
  • asthma
  • allergies (all types)
  • some common types of eczema
  • food allergies
  • hay fever or rhinitus
  • multiple sclerosis
  • lupus
  • type 1 diabetes
  • inflammatory bowel disease
  • Very probable
  • appendicitis
  • Graves’ disease
  • some non-allergic types of eczema
  • Non-tropical Sprue (Celiac disease or gluten enteropathy)
  • Very suspicious
  • heart disease (in part)
  • chronic fatigue syndrome
  • autism

Med Hypotheses (2011), doi:10.1016/j.mehy.2011.06.019

slide23

Why did it take so long to figure this out?

Modern medicine is so compartmentalized it did not see common factors among different diseases (Rook et al, Springer SeminImmun (2004) 25:237-255)

Common factors

Emerging, non-infectious diseases of post-industrial society

Hyper-reactivity of the immune system involving potent responses to harmless self or foreign antigens

Frequent involvement of “triggers”

A role of genetics and/or epigenetics

slide24

Why did it take so long to figure this out?

    • 2. Modern medicine is so focused on the here and now that
    • (a) The time lag between factors causing biome depletion and the onset of effects was extremely difficult to see through.
  • It took about 5 decades for the flush toilet to move from a luxury to a necessity in the US.
  • The life span of helminths and the effects of epigenetics can delay the onset of pathology for generations.
slide25

Why did it take so long to figure this out?

    • 2. Modern medicine is so focused on the here and now that
    • (b) The obvious role of “triggers” and genetics was (and still is) overwhelmingly attractive.

995 grants and 314 million dollars total research on autism

100 million dollars on cause and prevention of autism

Zero dollars on biome depletion and autism

*2009 IACC Autism Spectrum Disorder Research Portfolio Analysis Report

slide26

Why did it take so long to figure this out?

    • 3. The initial idea involved hygiene, not biome depletion

Hygiene causes biome depletion, which underlies epidemics of hyperimmune-associated disease,

BUT

Hygiene also decreases triggers for both allergy and autoimmune disease.

slide27

Ubiquitous factors that, by

themselves, do not cause pathology

Immune

hypersensitivity caused by hygiene-associated biome depletion

Environmental stimulus (“triggers”, often reduced by hygiene)

+

2

1

+

3

Genetic predisposition and/or epigenetic effects

Hyper-immune associated diseases, including allergyand autoimmunity

Bilbo, Wray, Perkins, and Parker

Medical Hypotheses, 2011

slide28

A brief interlude into the field of biomedical research and clinical studies: Putting out the fire of human disease.

Human

disease

slide29

The triple-hit paradigm of immune-associated disorders.

Environmental stimulus

+

Genetic or epigenetic factors

Pathology

+

Modern medicine tends to deal with hyperimmune-associated disorders using therapeutics that block symptoms.

Immune hypersensitivity biome depletion

slide30

Colonization of laboratory mice with a common roundworm prevents or cures the following:

  • experimentally induced colitis
  • experimentally induced allergy
  • type 1 diabetes
slide31

Helminths (worms) and MS

A prospective study, with 24 patients: 12 accidentally colonized with helminths, and 12 uncolonized(Argentina)

After colonization, 3 relapses in the colonized group, 56 relapses in the uncolonized group

Annals of Neurology (2007) 61:97-108

slide32

Helminth (worm) therapy for IBD

29 patients with IBD enrolled, most non-responsive to pharmaceuticals

A first attempt: approach not optimized in any way

A first attempt: approach not optimized in any way

  • After 24 weeks of therapy:
  • 72.4 % completely “cured”
  • 79.3% improved
  • No adverse side effects

CurrOpinGastroenterol. 2005;21:51-58

slide33

Immune Modulation

Allergy, parasites, and the hygiene hypothesis

Science (2002) 296:490-494.

Helminthimmunoregulation: The role of parasite secreted proteins in

modulating host immunity

Molecular & Biochemical Parasitology (2009) 167: 1–11

slide34

All three components of the “depleted biome” may need to be considered in concert.

Microbiome stabilized by fecal transplant.

Alexander Khoruts and Janet Jansson, Journal of Clinical Gastroenterology, 44 (8), 562-566 DOI: 10.1097/MCG.0b013e3181dac035

“Friendly” bacteria from dirt activate a group of neurons that produce the brain chemical serotonin.

Chris Lowry, Neuroscience (2007), doi: 10.1016/j.neuroscience.2007.01.067

slide35

Outrageous ambition

  • Pediatricians routinely prescribe symbiotic helminths for young patients.
  • General practitioners check the health of symbiotic helminths and of the immune system as a routine part of a physical exam. *
  • Hyperimmune-associated diseases are only of historical interest.

* For examples, a simple blood test to evaluate eosinophil count, or an assessment of helminth antigens in stool

slide36

The labeling of all helminths as strictly “parasites” was apparently premature.

?

or

or

Helminths cause damage in developing countries for the following reasons, which will not impact the “reintroduction” of helminths in developed countries.

Uncontrolled infection

Some helminths are not well adapted

Malnutrition or lack of water

slide37

“Evidence from both animal and human studies implicates the immune system in a number of disorders with known or suspected developmental origins, including schizophrenia, anxiety/depression, and cognitive dysfunction.”

“We believe that cytokines are important not only for behavioral changes during acute illness, but may also underlie long-term changes in behavior as a consequence of infection early in life.”

Staci D. Bilbo, Department of Psychology and Neuroscience, Duke University

slide38

The end of our brief interlude into the field of biomedical research and clinical studies.

Human

disease

slide39

We utilize a comparison between wild-rats and lab rats to model what might be happening to the human immune system in post-industrial society.

slide40

Some limitations in comparing the immune systems of laboratory and wild rodents (in order of our concern)

  • More substantial limitations include:
  • Controlled experiments on wild rodents are very difficult to conduct.
  • Issues with stress: (reduced by breeding in lab animals, increased by trapping in wild animals)
  • Issues with exercise: (The lab animals don’t get any.)
  • Less concerning issues include:
  • 4. Differences in the genetics of the lab and the wild animals
  • 5. Difference in the diet of the lab and the wild animals
slide41

*

*Int Arch Allergy ApplImmunol 1979;59:465–8

slide43

ConA-induces

up-regulation

of CD134 and CD25 on TCR+ cells from lab rats but not wild rats.

slide44

Unpublished data in this portion of the lecture (4 slides) removed prior to publication on the web.

slide45

Biome depletion causes wide-spread changes in the immune system

Changes found

Changes possibly found

Changes not found

Your immune system

(a criminal oversimplification)

Not yet studied

Immune system diagram from Molecular Systems Biology 2:2006.0022

slide46

Acknowledgements

THE ONES WHO

RUN THE LAB

Mary Lou Everett

Zoie E. Holzknecht

Susanne Meza-Keuthen

STUDENTS

Daniel Palestrant

Aaron Wyse

Aditya Devalapali

Andrew Barbas

Andy Tan

Aaron Lesher

Anitra Thomas

COLLABORATORS

Randy Bollinger

Shu Lin

Jeff Platt

Duane Davis

Sara Miller

Paul Orndorff

SanetKotze

Rebecca Fisher

Heather Smith

Michel Laurin

Sarah Perkins

slide47

References for gut function

2003: Immunology109, 580-587.

2004: UltrastructuralPathology, 28, 23-27.

2004: Infection & Immunity, 72, 1929-1938.

2004: Clinical and Applied Immunology Reviews, 5, 321-332.

2005: Molecular Immunology, 43, 378-387.

2007: J. Theoretical Biology. 249: 826-831.

2009: Journal of Evolutionary Biology.22: 1984-1999.

2009: Experimental Biology and Medicine. 234:1174–1185

2010:Applied and Environmental Microbiology. doi:10.1128/AEM.00358-10

References for the profoundand widespread effects of biome depletion on the immune system

2006: Scand. J. Immunol. 64:125-136

2006: Immunol. and Cell Bio. 84:374-382

2011: Med Hypotheses doi:10.1016/j.mehy.2011.06.019

References allergy/autoimmune disease

2001: Am. J. Path. 159: 1957-1969

2002: Immunobiology205: 95-107

2005: Ann. Thoracic Surgery75:1037-1038

2010: Surgical Endoscopy24:1066–1074

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