1. Hygiene III The Hygiene Hypothesis ENVR 890 Mark D. Sobsey Spring 2007

2. “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: – Urban/rural differences – Farming/non-farming differences – Birth order / small families / day care – Early exposure to parasites, allergens, viruses, etc.

3. 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.

4. 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.

5. 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

6. 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.

7. Components of Human Immune System

8. The Immune System

9. Immunity and the Immune Response System

11. Four Types of Hypersensitivities

12. 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

13. 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 antigen- presenting structures on the surface of the presenting cell. Recognizes antigens presented by B-cells, macrophages, or any other cell type

14. 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.

15. 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

16. Immune Response and TH1 and TH2 Cells

18. GeneticsEnvironment Genetics and Environment are important for the development of allergies hygiene hypothesis The “hygiene hypothesis” of allergy induction Susceptibility genes Susceptibility genes for asthma (certain alleles make individuals more susceptible to allergies)