The biology of frequent copd exacerbator
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The phenotype of the frequent COPD exacerbator, definition, risk factors, cellular and humoral factors, genetics, apprach,
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The biology of frequent copd exacerbator
- 1. FREQUENT COPD EXACERBATOR Jamal Turki, M.D
- 37. Conclusions • Emerging understanding of the biological basis of increased susceptibility to exacerbations in COPD • Rethink and re-orient our approach to exacerbation prevention in COPD • Enhance aspects of innate immunity • Acute and chronic infection in COPD likely share mechanisms, therefore chronic infection could also be reduced
- 38. Conclusions • Frequent Exacerbator phenotype is characterized by defective Innate Immunity • Defective Humoral Immunity 2ry to reduced IgA production as well as accelerated proteolysis • Defective Cellular Immunity as shown by defective AM function in relation to phagocytosis, Immune regulation and cytokine production as well as reduced efferocytosis of Eosinophils • Reduced Macrophage function is related to defective TLR response and expressin, MBL response and incresed susceptibility to oxidative stress • Treatment directed at those defects are being developed and understood
- 39. THANK YOU
Editor's Notes
- Mucosal defence mechanisms are critical in preventing colonization of the respiratory tract by pathogens and penetration of antigens through the epithelial barrie. Polymeric IgA. Exclusion is prevention from attachment, IC neutr. Esp of viruses, Immune complex that helps in elimination of m.os, Immune regulatory by helping orchestrate the fx. Of cells like N. and L. and monocytes…
- Polymeric Ig receptor PIgR is important for transepithelial IgA transport. relationships between bronchial epithelial remodeling, polymeric immunoglobulin receptor (pIgR) expression, secretory IgA (SIgA), airway inflammation, and mural remodeling in COPD.
- To the right is intensity of staining for RNA for IgA in vever smoers---COPD stage 3-4. And down right never smokers vs COPD
- Prevalence of IgAB NTHI
- IgA response freq and intensity after acquisition of moraxella. Less IgA in exacerbation vs colonization
- M1 is pro inflammatory. M2 is anti infl. In COPD 5-10 fold increase in macrophages. In COPD M1 predominates
- AM alveolar macrophages. Acquisition of a new type of NTHA is associated with AECOPD
- Interactions of nontypeable Haemophilus influenzae (NTHI) with human alveolar macrophages are implicated in the persistence of NTHI in chronic obstructive pulmonary disease (COPD). AM frm ex smoers with COPd, without COPD and non smokers were incubated with 3 types of NTHI Results: AM from COPD pts had lower phagocytosis activity compared to blood Monocytes
- Outer membrane protein (OMP) P6 and lipooligosaccharide (LOS) of NTHI are potent immunomodulators. We theorized that alveolar macrophages in COPD possess fundamental immune defects that permit NTHI to evade host responses. To test this hypothesis, we obtained human alveolar and blood macrophages from exsmokers with COPD, exsmokers without COPD, and nonsmokers. Methods: Alveolar and blood macrophages from each donor were incubated with purified LOS and OMP P6 and with OMP P2 and the total outer membrane preparation (0.1–1 μg/ml). Measurements: Supernatants (24 h) were assayed for IL-1β, TNF-α, IL-10, IL-12, and IL-8 by multianalyte multiplexed flow cytometry. C/W defective immune responsiveness
- Nuclear factor of kappa light chain gene enhancer in B cells inhibitor alpha
- Toll like recptors are transmembrane receptors for F.B that mediate immune response. They are induced by bacterial stimulation which is suppressed in exacerbation prone COPD. Nuclear Translocation is stimulated by activation of TLRs. This is cyokine induction
- MBL is apattern recognition molecule that binds to sugars and helps in m.o recognition, genotypes that are associated with deficiency of MBL is associated with AECOPD
- Defective efferocytosis and phagocytosis in response to oxidative stress ox MBL is oxidized MBL, so oxidized MBL has reduced activity compared to the native pd MBL
- Nrf is a zipper protein that regulates the expression of anti oxidant proteins and reduces the oxidative damage by inflammation or damage. Nrf2 (nuclear erythroid–related factor 2) . Sulforafane improves the oxidative damage and so improves phagocytosis of NTHI and pseudomona
- AM alv macrophages. MDM is monocyte derived macrophages