Download Hygiene III The Hugiene Hypothesis

Hygiene III
The Hygiene Hypothesis
ENVR 890
Mark D. Sobsey
Spring 2007
“Hygiene Hypothesis”
• Reduction/lack of in infections and microbial
exposures early in life may be associated with
increased risk of allergy, asthma and
autoimmune diseases
• Based on observations and speculation on:
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Urban/rural differences
Farming/non-farming differences
Birth order / small families / day care
Early exposure to parasites, allergens, viruses, etc.
The Hygiene Hypothesis
• Allergies and asthma and persistent skin conditions
diseases have recently become epidemic in some parts
of the developed world
• Studies in the late 1980s and 1990s in the UK and
reunified Germany suggested that higher sanitation
increased risks of these health conditions
• The Hygiene Hypothesis: children exposed to other
children or animals early in life are exposed to more
microbes, and their immune systems develop more
tolerance for the agents causing asthma, allergies and
skin disorders.
• The human immune system evolved two types of
biological defenses. When one defensive system lacks
practice fighting bacteria and viruses, perhaps due to a
sanitary lifestyle, the other system becomes too powerful
and overreacts to harmless substances like pollen.
Hygiene Hypothesis – Proposed Mode
of Action/Mechanism
• Allergic diseases are caused by inappropriate immunological responses
to innocuous antigens driven by a TH2 type of immune response.
• Many bacteria and viruses elicit a TH1 type of immune response which
has the ability to down-regulate mediators of TH2 responses.
• Observations of immune function led to the development of the first
proposed mechanism of action of the hygiene hypothesis:
– insufficient stimulation of the TH1 arm of the immune system lead to
an overactive TH2 arm which in turn led to allergic disease
• This explanation has been challenged as inconsistent with other
evidence that the incidence of inflammatory bowel disease (IBD, multiple
sclerosis (MS), and type I diabetes, which are autoimmune diseases
linked with an overactive TH1 immune response, is increasing in the
same populations with increased allergic disease.
Hygiene Hypothesis – Alternative
Explanation of Mode of Action
• If the developing
immune system does
not receive stimuli from
infectious agents, it fails
to properly develop cells
with a regulatory
function.
• Persons lacking immune
regulatory cells are
more likely to develop
autoimmune diseases
due to insufficiently
repressed TH1 reactions
and allergic diseases
due to insufficiently
repressed TH2 immune
reactions
The Old Friends Hypothesis – A Further Refinement
• T regulator cells become fully effective only if stimulated by exposure
to certain microbes, including pathogens of low virulence, with which
human have coexisted thru evolutionary history, except until recent
times of high sanitation.
– Hygienic practices and medical care have diminished or eliminated
such traditional fauna from our exposures.
• E.g., development of T regulator cells may depend on exposure
to microbes such as lactobacilli, mycobacteria, and certain
helminths.
• The T regulatory cells learn to respond to harmless or
beneficial invaders by damping down the aggressive reaction
of the helper T cells and other immune system components to
the antigens presented by the harmless symbiotes.
• As a result, a properly developed immune system is unlikely to
aggressively attack harmless allergens or self cells.
• Both extremes of microbial environments, highly unsanitary and highly
sanitized are detrimental to optimal immune system development.
Components of Human Immune System
The Immune System
Immunity and the Immune Response System
Immunity and the Immune Response System
Four Types of Hypersensitivities
Cell-Mediated Immunity and T Cells
• T cell receptors are cell surface receptors that
bind nonself substances on the surface of other
cells
• Major histocompatibility complex (MHC)
proteins protrude from the surfaces of most
cells in mammals
– They help to distinguish self from nonself
– They coordinate interactions among lymphocytes
and macrophages
• Cytokines are soluble signal proteins released
by T cells
– They bind and alter the behavior of their target cells
Cell Mediated Immune System: T lymphocytes
• T-cells mature in the thymus (thus the name T-cell)
• Act on antigens appearing on the surface of individual
cells.
• Over a million different kinds of T-cells
– Each produces a different receptor in the cell membrane
– Each receptor is composed of 1 molecule each of two
different proteins
– Each receptor binds a specific antigen but has only one
binding site
– Receptor only recognizes antigens which are "presented"
to it within another membrane protein of the MHC type
(major histocompatibility complex)
• Recognizes specific antigens bound to the antigenpresenting structures on the surface of the presenting cell.
• Recognizes antigens presented by B-cells, macrophages,
or any other cell type
T Cells and their Functions
• Have a specific receptor for a fragment of antigen
• Cytotoxic T-cells:
– Contain a surface protein called CD8
– Destroy pathogen infected cells, cancer cells, and
foreign cells (transplanted organs)
• Helper T-cells:
– Contain a surface protein called CD4
– Regulate both cellular and humoral immune systems
– This regulation reduces autoimmunity.
T-helper cells can develop into
two types (type1 or 2)
• The immune system and its cells make
important choices
• The cells of the immune system talk to
each other through messenger
proteins called cytokines
• T-cells both make and respond to
many cytokines
• Stimulation with different cytokines
leads to the development of two types
of T-cells specialized for different
immune responses
• Th1 and Th2 strongly down-regulate
each other
• This polarization has important
consequences for the sunsequent
response and can spell life or death
Immune Response and TH1 and TH2 Cells
Genetics and Environment are important for the development of allergies
Susceptibility genes for asthma (certain alleles make
individuals more susceptible to allergies)
The “hygiene
hypothesis” of
allergy induction