Update on Immunology 12/31/12. Disclosures. Outline. Outline. Outline. Pathophysiology of Allergic Disease. Allergy background Novel T cell subsets

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1 Update on Immunology Mitchell H. Grayson, MD Associate Professor Medical College of Wisconsin Dec 2012 Disclosures Employer Medical College of Wisconsin Research support National Institutes of Health $100,000 or more MCW Dept. of Pediatrics / Children s Research Institute Under $5000 Merck $50,000 $100,000 Organizational interests (other than AAAAI) ACAAI Deputy Editor of Annals of Allergy, Asthma, and Immunology Member, Lit. Review, Annual Mtg., Abst. Rev., and Symposia Committees Pathophysiology of Allergic Disease Production of specific IgE IL-4 IL-6 B cell Th2 Damage to epithelium; cellular recruitment ~4 weeks 15 mins. 4-6 hours + Release: MBP/ECP/EDN Leukotrienes Presentation of allergen APC Specific allergen Mast Cell Allergen crosslinking IgE Mediators released: Histamine Tryptase Leukotrienes PGD 2 IL-4 & other cytokines Eosinophil Cells recruited Th2 Can substitute basophil for mast cell; however, no tryptase or PGD 2 release. Basophil 1

2 CD4 T cell instruction Th17 CD4+ T cells Associated with the immune response to extracellular pathogens IL-17 is a family of 5 members (A-E) Is a chemotactic agent for neutrophils May drive some mucous cell metaplasia Have been found in human asthma Cosmi L, et al. Allergy. 2011;66:989. Th17 cells can be Th2, too! Cosmi L, et al. Allergy. 2011;66:989. Nuocytes: Innate Lymphoid Cells type 2 (ILC2) Typical lymphocyte morphology Lack cell surface markers of major hematopoietic lineages, but do express CD25 (IL2Ra) CD90 (Thy1) CD117 (c-kit) CD127 (IL7Ra) CD278 (ICOS) ST2 (IL33R) so IL-33 responsive IL-17BR so are IL-25 responsive Apparent major source of IL-13 Also can make IL-5, 6, and 9 Scanlon ST, McKenzie ANJ. Curr Opin Immunol. 2012;24:707. Nuocytes Represent a novel immune cell (innate) that has the ability to modulate nearly all components of the atopic immune response. Scanlon ST, McKenzie ANJ. Curr Opin Immunol. 2012;24:707. 2

3 Viruses and atopy: Respiratory syncytial virus 80-90% of children have had RSV at least once within the first 2 years of life 0.5-2% of infants require hospitalization Especially between 2-6 months of age Adapted from: Psarras, S, et al. Pediatr Respir Rev. 2004; 5 Suppl. A: S179. Sigurs N. Ped Resp Rev. 2002;3: Sigurs N. AJRCCM. 2000; 161: years 7.5 years Viruses and asthma: Respiratory syncytial virus Timing is everything.. Adapted from: Sigurs N. Ped Resp Rev. 2002;3: Sigurs N. AJRCCM. 2000; 161: Infections in the first year of life tend to be associated with an increased risk of asthma and atopic disease RSV Parainfluenza virus 1 and 3 (PIV-1,3) Possibly Rhinovirus (hrv) Infections from 2 years of age onward tend to be associated more with exacerbations of asthma hrv PIV-1,3 Influenza RSV Coronovirus, others Ann Allergy Asthma Immunol. 2009;103: Lessons from a mouse model Evidence of IgE against hrv hrv39 is a lab strain of hrv that is not present in the wild J Exp Med. 2007;204:2759. J Immunol. 2010; 185(9): Ann Allergy Asthma Immunol. 2010; 105:437. Allergen specific IgE Serum from 8 subjects obtained 5 subjects had history of working with hrv39 3 subjects had no known history of working with the virus hrv39 ELISA used to determine presence of anti-hrv39 IgE Jonathan Tam, et al. In preparation. 3

4 Treatment with anti-ige inhibited seasonal viral asthma exacerbations 419 inner city children with persistent allergic asthma for > 1 yr yrs old Had to be symptomatic or uncontrolled in 6-12 mos prior to entry 4 wk run-in and then randomized to omalizumab (208) or placebo (211) Busse WW, et al. N Engl J Med 2011; 364:11. In a substudy (n=100), 50% (pbo) 58% (oma) of exacerbations had a respiratory virus identified (usually hrv) Virus detection greater with exacerbations (p=0.001) No difference in rate of virus detection between the two groups Function of macrophage subsets M2 macrophages as protective of lung disease Modified from: Murray PJ and Wynn TA. Nat Rev Immunol. 2011;11:723. Modified from: Shirey KA, et al. Mucosal Immunol. 2011;3:291. Model M2 macrophages associated with asthma variability Bronchoscopy biopsies examined for presence of CD68 + M2 macrophages Mannose receptor + or Stabilin subjects with asthma FEV1 94% (65-114) median (range) 9 subjects without asthma FEV1 110% (85-121) Biopsy results correlated with PEF variability Modified from: Holtzman MJ, et al. Adv Immunol. 2009;102: Melgert BN, et al. J Allergy Clin Immunol. 2010;127(3):831. 4

5 Alternatively activated macrophages Are found at sites of injury Are part of the wound healing response However, when these cells become chronically activated they have the ability to drive atopic disease Chronic injury Recurrent acute injury Seasonal allergen exposure, etc. The microbiome: what is it, and why do we care? We are supra-organisms that must co-exist with this complex ecosystem viable bacteria/g large bowel content 10 times more bacteria in the gut than the body s own eukaryotic cells genetic content of the biome is fold greater than the human genome Composition of the biome has significant impact on physiology, immunology, metabolism The Human Microbiome Project Peter J. Turnbaugh, Ruth E. Ley, Micah Hamady, Claire M. Fraser-Liggett, Rob Knight & Jeffrey I. Gordon Nature 449, CCF 2002 The gastrointestinal tract Mouth Is a critical interface between the individual and the external environment The GI mucosal immune system must Prevent and respond to infection Contain colonizing bacteria in the lumen Act as a barrier to bacteria, their products, and antigens Maintain the systemic immune system in a low reactive state Allow for nutrient and water absorption Upper alimentary tract Small intestine Large intestine Rectum Mouth Upper alimentary tract Small intestine Large intestine Rectum Mechanisms leading to intestinal dysbiosis and disease CCF 2002 Mouth Esophagus Stomach Small Intestine Colon ph 7 ph 5-6 ph 2 ph 5-7 ph cfu/ml 10 2 cfu/ ml Gemella Veillonella Granulicatella Veillonella Rothia 10 4 cfu/ml cfu/ ml Lactobacilli Enterococci H. pylori Bacteroides Clostridia Lactobacilli γ-proteobacteria Enterococci cfu/ml Bacteroides Clostridia Prophyromonas Eubacteria Ruminococci Bifidobacteria Enterobacteria Enterococci Lactobacilli Peptostreptococcus Fusobacteria Round JL, Mazmanian SK. Nat Rev Immunol. 2009; 9:313. 5

6 Diversity Dysbiosis and disease Low diversity High diversity Abundance is the same, but the evenness is quite different! Round JL, Mazmanian SK. Nat Rev Immunol. 2009; 9:313. Summary/Conclusion I The standard Th2 paradigm is no longer valid in light of the multiple mechanistic pathways that can drive atopic disease New therapies will be directed at these multiple pathways, and providers need to be aware of their differences PMN IL-17 Th17 The traditional Th2 paradigm becomes (much) more complicated! BIOME Modified from: Allen JE, Maizels RM. Nat Rev Immunol. 2011; 11:375. Summary/Conclusion II Viruses have the ability to exacerbate atopic disease (and maybe cause) This effect appears to be driven through an IgE mediated pathway The microbial communities that coexist in/on us have the ability to modulate our immune responses (amongst others) Future therapies may alter these biomes to promote health and to treat disease 6