Pulmonary Immunology. Chad Steele, Ph.D ; THT 437A

Transcription

1 Pulmonary Immunology Chad Steele, Ph.D ; THT 437A

2 Outline Significance of lung diseases Uniqueness of the lung: MCC, alveolar macrophages Asthma COPD/emphysema Intermingled Steele Lab data 5 min Nature Immunology video

3 Breathing can kill you Major function of the respiratory system is to procure O2 and to eliminate CO2 from the body at rates required by tissue metabolism The average person at rest takes breaths per minute You are going to take over 1,500 breaths during this lecture 21,000/day, 7e6/year With every breath: toxins (noxious gases), pollutants (diesel exhaust), particulates (dust), allergens (spores), bacteria, viruses, fungi Air quality study performed in Rome, Italy (New Microbiol 25:51, 2002; PMID: ) Occupied university auditorium (Surface Air System sampling) Bacteria: 925-1,225 CFU/m 3 Fungi: 1,256-1,769 CFU/m 3 Austin/San Antonio study (PNAS 104:299; 2006) Air sampled for 24 h period 1X/week for 17 weeks (May 2003) 1,800 different bacterial species detected

4 Breathing can kill you Major function of the respiratory system is to procure O2 and to eliminate CO2 from the body at rates required by tissue metabolism The average person at rest takes breaths per minute You are going to take over 1,500 breaths during this lecture With every breath: toxins (noxious gases), pollutants (diesel exhaust), particulates (dust), allergens (spores), bacteria, viruses, fungi Air quality study performed in Rome, Italy (New Microbiol 25:51, 2002; PMID: ) Occupied university auditorium (Surface Air System sampling) Bacteria: 925-1,225 CFU/m 3 Fungi: 1,256-1,769 CFU/m 3 Austin/San Antonio study (PNAS 104:299; 2006) Air sampled for 24 h period 1X/week for 17 weeks (May 2003) 1,800 different bacterial species detected

5 Breathing can kill you Lancet 380: (2012) Disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death; measurement of the effects of chronic illness is time lost due to premature death and time spent disabled by disease.

6 Breathing can kill you Lancet 380: (2012) Disability-adjusted life year (DALY) is a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death; measurement of the effects of chronic illness is time lost due to premature death and time spent disabled by disease. NEJM 376:2513/2522 (2017)

7 Mortality associated with chronic lung diseases and pneumonia U.S.A. (2015)

8 World Health Organization

9 Respiratory anatomy

10 Respiratory anatomy Al: Alveoli AlDu: Alveolar duct Bi: Bronchiole Bu: Bronchus PuAr: Pulm artery PuVe: Pulm vein

11 The respiratory epithelium: the lung immune response start button Upper (nasal; tracheal)

12 The respiratory epithelium: the lung immune response start button Lower (alveolar)

13 The respiratory epithelium: the lung immune response start button

14 Resident defense in the alveoli Alveolar macrophages dust cells or garbage collectors of the lung highly phagocytic mediocre abilities to kill microbes sentinel cells of the lung excellent abilities to sound alarm must be able to ignore non-pathogenic stimuli

15 Alveolar macrophage responses

16 Alarm heard - neutrophils

17 Neutrophil responses

18 Mucociliary clearance (MCC) Definition: Organized movement of airway surface liquid (ASL) from distal to proximal airways. The mucociliary transport system is comprised of three layers: ciliated epithelium, the aqueous layer and mucus. Temperature and humidity dependent: the higher the both, the more efficient MCC. Millions of cilia lining the airway (around 200 individual cilia per cell) beat in the aqueous layer at up to 15 times per second. The clearance speed relies on the cilia beat frequency and quality of the mucus. Both are dependent on the body s ability to replenish moisture to all three layers

19 Mucociliary clearance (MCC) z3i 1:00 3:30 2F %2Fjournal.pone #s6

20 Cystic fibrosis a disease resulting in impaired MCC CFTR (cystic fibrosis transmembrane conductance regulator): is a regulated epithelial Cl- channel; influences other ion channels by pumping Cl- ions into the cell, CFTR can regulate absorption of ions in excess of water, thereby creating hypotonic water outside the cell (lung) Disease characterized by persistent bacterial infections colonization occurs early and is nearly impossible to eradicate Immunology A: high salt renders antimicrobial defenses inactive (defensins) B: low ASL = impaired MCC = persistent infection = persistent immune activation = persistent inflammation = lung destruction

21 Tissue macrophages

22 Not all MΦ are created equal

23 Percent killing Peritoneal vs. Alveolar * * * Peritoneal * * Alveolar * Medium Cytochalasin D Catalase MnPy L-NAME Mannan Laminarin Dectin-1 scd40l JKK Steele (unpublished; 2001)

24 Development of alveolar macrophages (AMs) J Immunol 179: (2007) Science 332: (2011) J Exp Med 210: (2013)

25 Alveolar macrophages Located in the deepest parts of the lung where they are attached to AEC type I and II Continuously encounter inhaled substances due to their exposed position in the alveolar lumen. To avoid collateral damage to type I and type II cells in response to harmless antigens, they are kept in a quiescent state, producing little inflammatory cytokines and displaying poor phagocytic activity.

26 AMs CD200R CD200 CD200R Dok-1/Dok-2 SHIP-1

27 Lung dendritic cells (DCs) subsets

28 Lung DCs Epithelial interactions Sentinel airway DCs have a half-life of 2 days Biased towards Th2 responses: TSLP, IL-33, IL-25; often migrate to LN to mediate Ag presentation and Th2 activation Periscope function: sample airway contents while awaiting instructions from airway ECs

29 Lung DCs Epithelial interactions During chronic exposure to inflammatory signals from antigens/allergens and/or innate cells, DCs release chemokines such as CCL17 and CCL22 to recruit effector Th2 and Th17 cells to the lungs, promoting the type 2/type 17 allergic inflammatory environment. It is unknown the extent to which DCs collaborate with other innate cells such as ILCs in the activation of recruited T cell populations, or innate effector cells such as granulocytes (MC; mast cells, Bas; basophils, Eos; eosinophils) and MΦs, to maintain chronic type 2 or type 17 inflammation in the lung. Semin Immunopathol Jul;38(4):449-60

30 Lung DCs periscope 11/16/jem DC1/3.html

31 Asthma Chronic inflammatory disease of the airways (a) mucus, cells or other material within the lumen, (b) thickening of the airway wall that encroaches on the lumen, (c) shortening of smooth muscle around the lumen and (d) collapse of the airway wall into the lumen Hallmarks Characteristic inflammatory cell infiltrate within and around the airways Damage to the ciliated stratified epithelium Hyperplasia and remodeling of the airways Hyper-responsiveness to a variety of inhaled bronchoconstrictor stimuli

32 Asthma Chronic inflammatory disease of the airways (a) mucus, cells or other material within the lumen, (b) thickening of the airway wall that encroaches on the lumen, (c) shortening of smooth muscle around the lumen and (d) collapse of the airway wall into the lumen Hallmarks Characteristic inflammatory cell infiltrate within and around the airways Damage to the ciliated stratified epithelium Hyperplasia and remodeling of the airways Hyper-responsiveness to a variety of inhaled bronchoconstrictor stimuli

33 Asthma it s complicated

34 Innate lymphoid cells (ILCs)

35 ILC2 (asthma)

36 ~65% of asthma

37 IA invasive aspergillosis Infect Immun 80:410; 2012 AFAA A. fumigatus associated asthma J Immunol 189:3653; 2012 Invasive aspergillosis (good) needed for lung clearance of AF Fungal asthma (bad) contributes to the severity of fungal asthma IL-10 family member Receptor thought to be primarily expressed on structural cells, such as epithelial cells and keratinocytes Via STAT3, induces a potent antimicrobial response (antimicrobial peptides, chemokines etc.) Pro-inflammatory, thus has negative effects for some diseases (IBD, psoriasis etc.)

38 What is the cellular source(s) of IL-22 in the lung after A. fumigatus exposure? Reeder and Steele (Mucosal Immunology in press)

39 NHLBI: Severe Asthma Research Program Wake Forest (>1,200 asthmatics, 40% fungal +) Reeder and Steele (Mucosal Immunology in press)

40 Luminex MILLIPLEX (97) Hastie and Steele, Clin Exp Allergy (accepted)

41 Reeder and Steele (Mucosal Immunology in press) Mediators that are elevated in lung lavage fluid from fungal (+) human asthmatics

42 Reeder and Steele (Mucosal Immunology in press) Mediators that are elevated in lung lavage fluid from fungal (+) human asthmatics

43 Reeder and Steele (Mucosal Immunology in press) Common gamma cytokines and innate Fungal Asthma lymphocytes during fungal exposure

44 Reeder and Steele (Mucosal Immunology in press) Common gamma cytokines and innate Fungal Asthma lymphocytes during fungal exposure

45 Reeder and Steele (Mucosal Immunology in press) Reeder and Steele (submitted) Common gamma cytokines and innate Fungal Asthma lymphocytes during fungal exposure Invasive infection γδ T inkt ILC3

46 Reeder and Steele (Mucosal Immunology in press) Reeder and Steele (submitted) Common gamma cytokines and innate Fungal Asthma lymphocytes during fungal exposure Invasive infection IL-21 KO - ( ) IL-22 IL-15R KO - IL-22 MyD88 KO - IL-22 TLR9 KO - IL-22

47 COPD - pathophysiology Looks like asthma Chronic and progressive inflammatory disease of the airways. Triggers Noxious particles and gases Cigarette smoke Hallmarks Characteristic inflammatory infiltrate within the airways cell Airway narrowing Destruction of alveolar support that maintains patency of small airways Current prevalence: > 15 million Americans; predicted to be the 4 th leading cause of death worldwide by Annual burden: 1.5 million ER visits, 15 million office visits, 100 million lost school and work days, 15 billion in health care costs.

48 COPD - immunology

49 COPD vicious circle nontypeable Haemophilus influenzae Streptococcus pneumoniae Moraxella catarrhalis Chlamydia pneumoniae Adenovirus Pneumocystis jirovecii

50 Pneumocystis a microbiological A. Morris. Association of chronic obstructive pulmonary disease severity and Pneumocystis colonization. Am J Respir Crit Care Med. 2004; 170: trigger for COPD?? A. Morris. Distribution of Pneumocystis jirovecii in lungs from colonized COPD patients. Diagn Microbiol Infect Dis Sep;71(1):24-8. A. Morris. Pneumocystis: a novel pathogen in chronic obstructive pulmonary disease? COPD Feb;5(1):43-51.

51 MMP12 - COPD MMP12 macrophage metalloelastase MMP12 deficient mice are resistant to cigarette smoke-induced emphysema MMP12 is over-expressed in sputum and lung lavage fluid from COPD patients

52 Different types of macrophage activation M1 (Classical) Proinflammatory High ROI/RNI Better killing M2 (Alternative) Wound healing Regulation

53 M1/M2: COPD Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease. J Immunol 183(4): (2009) Macrophage activation in exacerbated COPD with and without community-acquired pneumonia. Eur Respir J 36: (2010)

54 MMP12 and Pneumocystis A. Morris et al. Airway Obstruction Is Increased in Pneumocystis-Colonized Human Immunodeficiency Virus-Infected Outpatients Journal of Clinical Microbiology, November 2009, p

55 Infect Immun 77:1790; 2009 J Immunol 186:2372; 2011

56 M2a AM production of MMP12 in response to P. murina is this why Pneumocystis is associated with COPD?

57 (A) The lung at baseline is constantly exposed to fungal spores, bacteria and viral particles through alveolar macrophages phagocytosis, IFN production by epithelial cells and the mucocilliary escalator. (B) If these defenses become overwhelmed during an active infection, a robust inflammatory process involving alveolar macrophages, DCs, γδ T cells, ILCs, neutophils and epithelial cells commences and involves a variety of antimicrobial mediators. (C) However, during persistent exposure, the inflammatory response remains, contributing to the exacerbation of chronic lung diseases like COPD and asthma through an abundance of neutrophils, Th2/Th17, ILC2 and ILC3 cells. Werner and Steele, J Immunol 193: (2014)

58 Wrap up /index.html 0:40 5:03