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Is COPD an Autoimmune Disease ? Professor Bill MacNee E.L.E.G.I. / Colt Laboratories

Is COPD an Autoimmune Disease ? Professor Bill MacNee E.L.E.G.I. / Colt Laboratories MRC Centre for Inflammation Research University of Edinburgh and the Royal Infirmary of Edinburgh Scotland, UK. Is COPD an Autoimmune Disease ?. Persistent inflammation in the absence of smoking

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Is COPD an Autoimmune Disease ? Professor Bill MacNee E.L.E.G.I. / Colt Laboratories

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  1. Is COPD an Autoimmune Disease ? Professor Bill MacNee E.L.E.G.I. / Colt Laboratories MRC Centre for Inflammation Research University of Edinburgh and the Royal Infirmary of Edinburgh Scotland, UK

  2. Is COPD an Autoimmune Disease ? • Persistent inflammation in the absence of smoking • What evidence is needed to prove an autoimmune aetiology • in a disease ? • Evidence of an autoimmune inflammatory response in • COPD ? • Implications for treatment

  3. The pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) is not well understood. • Established factsare: • Tobacco smoking is the main risk factor for the development of COPD, but only a percentage of smokers (so-called susceptible smokers) develop the disease2. • Tobacco smoking elicits an inflammatory response in the lungs of all smokers, but this is enhanced and fails to resolve after quitting smoking in those who develop COPD3-6. • This clearly indicates that the regulation of the inflammatory response is abnormal in COPD. • What isnot knownis (are) the mechanism(s) underlying this abnormal regulation • Important for the development of future • treatment strategies 1..Celli B, MacNee W et al ER.J 2004; 23:932; 2.Hogg et al N EJ M 2004; 350:2645. 3.Retamales et al 2001. AJRCCM 2004;164:469. 4. Willemse et al. ERJ 2005; 26:835. 6. Rutgers et al. Thorax 2000;55:12.

  4. Standards for the diagnosis and treatment of patients with COPD : a summary of the ATS/ERS position paper Definition Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressiveand is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.

  5. The inflammatory responses in COPD D Innate Immune Response Acquired Immune Response Hogg et al. N Engl J Med 2004;24:2645

  6. ABNORMAL REGULATION OF INFLAMMATION IN COPD Impaired resolution Enhanced Response Not discussed in this presentation Innate immunity Acquired Immunity

  7. ABNORMAL REGULATION OF INFLAMMATION IN COPD Impaired resolution Enhanced Response Innate immunity Acquired Immunity Epigenetic mechanisms Enhanced Oxidative Stress

  8. The nature of small-airway obstruction in COPD These studies suggest a response to an antigen Innate Immune Response Acquired Immune Response Hogg et al. N Engl J Med 2004;24:2645

  9. ABNORMAL REGULATION OF INFLAMMATION IN COPD Impaired resolution Enhanced Response Innate immunity Acquired Immunity Epigenetic mechanisms Self-antigen (autoimmunity) Non-self antigen (bacteria, virus, particles) Enhanced oxidative Stress

  10. Pathogenesis of COPD • Does infection of the lower respiratory • tract result in and enhanced adaptive • immune response ? • Hogg et al NEJM 2004;24:2645 • Is there an Autoimmune component • which enhances airspace inflammation • in COPD ? • Agusti, MacNee, Donaldson and Cosio Thorax 2003 , Barnes and Cosio PLoS Med 2004

  11. LATENT ADENOVIRUS INFECTIONIN THE PATHOGENISIS OF COPD In situ hybridisation for adenovirus EIA E1A Interaction with co-activators enhances binding and activity of transcription factors Adenovirus probe Control probe E1A CBP/p300 Increased transcription NF-kB AP-1 CREB COPD lung Inflammation No COPD COPD EIA PCR+ Ave density ratio 0.480.17 1.49 0.94* * p<0.002 Matuse et al ARRD 1992;146:177

  12. Bacterial colonisation of the airways is associated with Neutrophilic inflammation in ex smoking COPD patients Sethi et al AJRCCM 2006;173:991

  13. Is COPD an Autoimmune Disease ? • Persistent inflammation in the absence of smoking • What evidence is needed to prove an autoimmune aetiology • in a disease ? • Evidence of an autoimmune inflammatory response in • COPD ? • Implications for treatment

  14. Evidence of autoimmunity in clinical diseaseWitebsky’s Postulates Direct proof Transfer of disease by Autoantibody Experimental Maternal To animals Indirect proof Transfer of disease by cells to SCID mice Induction of disease in animals by autoantigen Identification with lesions of: AB / T-cells Transfer of disease by lymphocytes in experimental models Genetic models Auto-antibodies or self-reactive T cells Circumstantial evidence from clinical clues

  15. Increased susceptibility to pulmonary emphysema among HIV-seropositive smokers Age 34 yrs, 16 pack yrs, HIV +ve Age 30yrs, 9 pack yrs,HIV +ve Diaz et al. Ann Intern Med 2000;132:369

  16. The rate of annual decline in FEV1 and DLCO during the 5-year follow-up period in COPD patients with or without Hepatitis C virus – response to INF Kanazawa, H. et al. Chest 2003;123:596-599

  17. Inflammatory cell profile in the lungs of nonsmokers (NS), smokers without anatomic emphysema (SNE), and smokers with emphysema (SE) Cosio, M. G. et al. Chest 2002;121:160-165S

  18. Correlation between emphysema (expressed as the density of alveolar walls [Vv1 ALV]) and the numbers of neutrophils (PMN), T lymphocytes, and alveolar macrophages per mm3 in the alveolar walls of 6 nonsmokers and 15 smokers Cosio, M. G. et al. Chest 2002;121:160-165S

  19. Phenotypic characterisation of T-lymphocytes in COPD: Abnormal CD4+CD25+ regulatory T-lymphocytes in response to tobacco smoke • Regulatory T-lymphocytes have important anti-inflammatory • and immunmodulatory effects CD4+CD25+ cells are identified as (bright) regulatory T-lymphocytes CD4+CD25+ are increased in BAL In smokers but not in COPD Barcelo et al ERJ 2008

  20. Phenotypic characterisation of T-lymphocytes in COPD: Abnormal CD4+CD25+ regulatory T-lymphocytes in response to tobacco smoke • Suggestive of : • a final maturation–activation state of CD8+ T-lymphocytes in COPD • a blunted regulatory T-cell response to tobacco smoking in COPD • supports a potential involvement of acaquired immune system in COPD Barcelo et al ERJ 2008

  21. T-regulatory cell expression of activation and memory markers In BAL in COPD Smyth, L. J. C. et al. Chest 2007;132:156-163

  22. An animal model of autoimmune emphysema Levels of antibodies in serum in rats immunised with human umbilical vein EC (HUVEC) or human pulmonary artery smooth muscle cells (HPASMC) HUVEC Control Rat lungs develop emphysema following IP injection of HUVECs (d), but not HPASCs (e) HPASC Taraseviciene-Stewart et al. AJRCCM 2005;171:734

  23. * 2500 2000 1500 Pixels /mm2 1000 500 0 Control CD4 An animal model of autoimmune emphysema Adoptive transfer of CD4+ lymphocytes from HUVEC–immunised rats develop airspace enlargement Control CD4 Taraseviciene-Stewart et al. AJRCCM 2005;171:734

  24. Oligoclonal CD4+ T cells in the lungs of patients with severe emphysema • Blasting of lung T cells from subjects with emphysema and normalsubjects after 2 weeks in culture with interleukin (IL) 2. • Light microscopy of lung tissue (B) Forward- versus side-scatter density plots are shown for representative emphysema (left panel) and control (right panel) lung tissue culture. Blasting lymphocytes are found within the upper gate with the resting lymphocytes in the lower gate. (C) A density plot of CD4 versus CD8 expression on CD3+ T cells from a representative subject with emphysema after in vitro culture in the presence of IL-2 is shown. Sullivan et al AJRCCM 2005;172:590

  25. Anti-elastin autoimmunity ( peripheral blood T and B cell responses to elastin peptides )in emphysema Seung-Hyo Lee Nature Medicine 2007

  26. IgG deposition in lung explants Anti epithelial antibodies in patients with COPD COPD Normal control COPD Normal isotype antibody Autoantibodies in COPD Feghali-Bostwick et al AJRCCM 2007;177:156

  27. Autoantibodies in COPD Compliment (C3)deposition COPD Normal subject Auto antibodies associated with clinical COPD phenotype Incubation of airway epithelial cells with COPD plasma enhances allogeneic cytotoxicity Feghali-Bostwick et al AJRCCM 2007;177:156

  28. Autoimmune diseases Therapeutic approaches Alteration of thresholds of immune activation Blockade of costimulatory factors Antagonism of inflammatory cytokines or protective cytokines Inhibition of signaling cascades by small molecules Modulation of antigen-specific cells Induction of regulatory cells (intravenous, subcutaneous, or oral delivery of antigen) Alteration of peptide ligands Formation of complexes of peptide and major-histocompatibility-complex molecules Development of T-cell receptor vaccines Induction of B-cell tolerance Immune deviation from type I to type 2 helper T cells Reconstitution of the immune system Bone marrow ablation with autologous stem cells Bone marrow ablation with donor stem cells Bone marrow ablation without stem cells Sparing of target organs Antagonism of complement Antagonism of chemokines Use of antiinflammatory agents Inhibition of matrix metalloproteases Inhibition of nitric oxide synthase Davidson et al. N Engl J Med 2001;345;5:340

  29. Evidence of autoimmunity in clinical diseaseWitebsky’s Postulates Direct proof Transfer of disease by Autoantibody Experimental Maternal To animals Indirect proof Transfer of disease by cells to SCID mice Induction of disease in animals by autoantigen Identification with lesions of: AB / T-cells Transfer of disease by lymphocytes in experimental models Genetic models Auto-antibodies or self-reactive T cells Circumstantial evidence from clinical clues

  30. Conclusions • There is good direct and indirect evidence of • autoimmunity as a pathogenic mechanism in COPD • Proof of concept therapeutic trials are necessary • to support test this hypothesis

  31. Anti-elastin autoimmunity ( peripheral blood T and B cell responses to elastin peptides )in emphysema Seung-Hyo Lee Nature Medicine 2007

  32. HAT HDAC Gene transcription Histone acetylation Inflammation EFFECT OF SMOKING AND COPD ON CYTOPLASMIC HDAC2 LEVELS IN LUNG TISSUE Compared with non-smokers, * P<0.05 ** p<0.01 Compared with healthy smokers, # P<0.05 Szulakowski et al AJRCCM 2006;171:41

  33. HDAC2 expression and activity following cigarette smoke exposure in vitro (alveolar epithelial cells) and in vivo (rat lungs) 120 80 HDAC2 activity (% control) *** 40 *** *** *** → resulting in decreased HDAC2 expression inflammation 0 Control CSC GEA 4HNE Acrolein Treatment 2.5 * 0.5 *** ** Control Smoke exposed rats 2.5 0.5 * 2.5 Cytokine:GAPDH ratio) HDAC2/modified HDAC2 ratio) * 2.5 0.5 2.5 2.5 0.5 4HNE Nitration Acrolein Modification MIP-1 alpha MIP-2 3 days smoke exposure Marwick J et al AJRCCM 2004;31:633-642 Smoke exposed alveolar epithelial cells Post-translational modification of proteins by oxidants in cigarette smoke → targets of proteolytic degradation

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