Eat Dirt: Why Cleanliness is Bad for Asthma

Transcription

1 Eat Dirt: Why Cleanliness is Bad for Asthma Joel N. Kline MD MSc Professor, Pulmonary Medicine Director: UI Adult Asthma Center Director, Clinical Research ICTS University of Iowa Iowa City, IA 1 Disclosures: Joel N. Kline Research Grants: NIH, Boston Scientific, Genentech, GSK, Teva Patents: CpG oligonucleotides for treatment of asthma Asthma is an airways disease: Inflammation (active blood cells in the lungs) Bronchial hyperreactivity ( twitchy airways) Reversible airflow obstruction (changing breathing impairment) These factors guide asthma therapy. What is Asthma? 3 1

2 Asthma Causes Narrowed Airways 4 Asthma Inflammation Airways are chronically inflamed, sometimes without symptoms. There are increased numbers of special white blood cells in the airway: especially eosinophils (allergic cells), and lymphocytes (controller cells) The lymphocytes (-type) release small proteins that can attract and activate other cells (IL-4, IL-5, IL-13) Asthma Inflammation (simple) B-cell eosinophil Produce IL-4, IL-5, IL-9, IL-13 Induce B Cells to make IgE Activate mast cells and eosinophils Produces Antibodies IgE (in allergy) IgG Produces Oxidants Enzymes Other proteins Irritate airways, increase mucus, stimulate nerves and smooth muscle 2

3 Asthma Inflammation (complicated) Asthma Inflammation (simple) B-cell eosinophil Produce IL-4, IL-5, IL-9, IL-13 Induce B Cells to make IgE Activate mast cells and eosinophils Produces Antibodies IgE (in allergy) IgG Produces Oxidants Enzymes Other proteins Irritate airways, increase mucus, stimulate nerves and smooth muscle Inadequately Treated Asthma Causes Airway Scarring: A Consequence of Inflammation Subepithelial Collagen (scarring) Holloway et al. Asthma and Rhinitis

4 Implications of Inflammation on Treatment of Asthma Asthma is an inflammatory disease Remodeling is a consequence of longstanding inflammation Most asthmatics require anti-inflammatory controller therapy Even mild asthmatics may benefit from antiinflammatory therapy. 10 Asthma in the USA 24.6 Million Persons 12.8 Million Asthma Attacks 1.8 Million ED Visits 456,000 Hospitalizations Over 3,400 Deaths (9/day) Disproportionately Affects Children and African Americans Centers for Disease Control and Prevention National Center for Health Statistics, National Health Statistics Report: Asthma Prevalence, Health Care Use, and Mortality: United States, : 11 Costs of Asthma $16 Billion Asthma in Iowa An estimated 7% (45,000 and 50,000) of Iowa children are currently diagnosed with asthma. Between 9% and 10% (62,000 and 67,000) of Iowa children are estimated to have ever had diagnosed asthma. 11.8% of adults have been diagnosed with asthma at some point in their lives. 12 4

5 Worldwide Asthma Epidemic Increased numbers and severity of asthma and allergy over past decades Why? Reporting? Genetics? Environment? Triggers of Asthma Attacks Cold Air Allergens Dust Tobacco and other Smoke Chemical Irritants or Vapors Strong Emotion Respiratory Infections 14 Asthma and Bugs 5

6 Thought Experiment: Germany after the Cold War In 1989, the Berlin Wall was torn down; soon afterwards, the Soviet Union withdrew, leading to reunification of East and West Germany, separate since Among the many differences between the two nations was air pollution: East Germany burned soft coal, leading to much higher levels of particles and pollutants such as Sulfur Dioxide, in contrast to West Germany 16 Germany post-cold war Erica von Mutius chose to compare childhood asthma between Leipzig (in former East Germany) and Munich (West Germany). Over 10,000 children were studied. East Germany had: More industry More air pollution Worse nutrition More children in daycare Fewer pediatricians More Asthma in East or West Germany? West Germany East Germany Asthma Ever 9.3% 7.2% Current Asthma 5.9% 3.9% Hay Fever 8.6% 2.7% Positive Allergy Test 18.4% 7.2% There was more asthma (especially allergic) in the dirty East Germany!!! 6

7 Less Asthma and Allergy With: Increased older siblings and earlier out-ofhome childcare experience Early-life rural/farm residence Early-life dogs (not cats!) Early-life infections Tuberculosis Measles Helminths (intestinal worms What do these protective environments have in common? Bugs and Dirt! Why are Dogs Helpful? Dirt! 21 7

8 Cats, on the other hand... Hygiene Hypothesis Scrupulous childhood hygiene promotes the development of asthma and allergy. Exposure to dirt (infections, products of microbes) protects against asthma /allergy. How can microbes reduce risk of atopy? Immune Cells Use Toll-Like Receptors to Detect Pathogen-Associated Molecular Patterns TLR2 - Proteoglycans (bacteria) TLR3 - dsrna (RNA viruses) TLR4 - Endotoxin (gram negative bacteria) TLR5 - Flagellin (bacteria) TLR6 (with TLR2) peptidoglycan, lipoprotein (bacteria), zymosan (fungi) TLR7 Viral ssrna TLR8 Viral ssrna TLR9 - CpG DNA (all prokaryotes) TLR10-?? TLR11-?? Each TLR is expressed in a different set of immune cell types; innate immune system designed for rapid response to microbes. Bacterial (but not mammalian) DNA is immune-activating. Frequency of CpG differs in bacterial and mammalian DNA. Bacterial DNA has many CpG (1:16 bp), whereas vertebrate DNA has few CpG (1:50) 8

9 The Mechanics of Immunity Two types of T-helper cell types Th1 Produce IL-2, IFN-, TNF- Induce B Cells IgG production Reduce effects of cells Produce IL-4, -5, -9, -13 Induce B Cells IgE production Stimulate mast cells and eosinophils Model of Th1/ Immunity Th1 Naïve T cell Antigen Presenting Cell (APC) When an APC shows an antigen to an undifferentiated T-cell, It may turn into a Th1 or a (allergic) cell. IFN- IL-4 IL-5 IL-13 Model of Atopic Immunity Ag Mast Cell IL-4 - Th1 Naïve T cell + IFN- APC When an APC shows an antigen to an undifferentiated T-cell near other allergic-type cells, it is more likely to turn into a (allergypromoting) cell. response & Allergy IL-4 IL-5 IL-13 9

10 Model of Hygiene Hypothesis Ag Microbial Product TLR Th1 APC Naïve T cell + IFN- When an APC shows an antigen to a T-cell near microbial products, it is more likely to turn into a Th1 (allergy-preventting) cell. IL-12 Reduced response & Allergic Disorders IL-4 IL-5 IL-13 The End Questions? 30 10