Lecture-2 Innate immunity as the first line of defense.pptx

Cellular and humoral components involved in Innate immunity and their role in elicitation of innate immune response.

1. INNATE IMMUNITY Prof. Sreerama Krupanidhi Email: [email protected]

2. Objective To understand cellular and humoral components involved in Innate immunity and their role in elicitation of innate immune response. 8/29/2024 2 Prof. Sreerama Krupanidhi

3. Expected Outcomes The molecular features: PAMPs , LPS etc of pathogens will be known. The receptors embedded on leukocytes ( TLR , PRR ) to recognise PAMPs will be understood. Inflammation as a mediating step of innate immunity will be appreciated. Role of complement proteins in innate immunity will be known. 8/29/2024 3 Prof. Sreerama Krupanidhi

4. First line of defence Innate immunity is prorammed : To recognize broad range of molecules associated with pathogens . To destroy invaders rapidly: - Activation of the phagocytic system and arousal of an infl a mmatory response are initiated. 8/29/2024 4 Prof. Sreerama Krupanidhi

5. Two main goals of the innate immunity To induce inflammation To achieve antiviral defense 8/29/2024 5 Prof. Sreerama Krupanidhi

6. Recognition of the microbes by innate immunity To recognize structures :- C ommon to various microbial agent s , but not present in human . Phagocytes have LPS specific receptors . Phagocytes recognise and respon d to: Ds RNA, unmethylated CpG , oligonucleotides . 8/29/2024 6 Prof. Sreerama Krupanidhi

7. PAMPs vs. PRRs The molecules of microbes targeted by th e immune system are  pathogen asscociated molecular patterns ( PAMPs) . The receptors of the innate immunity for these molecules are “pattern recognition receptors ” (PRRs) . The targets of the innate immunity are critical regarding the survival and infectivity of the microbes . 8/29/2024 7 Prof. Sreerama Krupanidhi

8. DAMPs Innate immunity can also recognise those molecules released from d a maged or stressed cells of the body  damage asscociated molecular patterns (DAMPs) 8/29/2024 8 Prof. Sreerama Krupanidhi

9. Innate immune Receptors These receptors are encoded in the germline  Receptors expressed on all cells of a certain type (not clonal) Innate immunity invariably does not rea c t against the host as it is ontogenetically conditioned. I nnate immunity always respond in the same way to repeated pathogenic invasions . 8/29/2024 9 Prof. Sreerama Krupanidhi

10. Receptors to recognize pathogens are expressed on Phagocytes D endritic C ells L y m phocytes E pithelial and E ndothelial cells 8/29/2024 10 Prof. Sreerama Krupanidhi

11. Receptors on Phagocyte 8/29/2024 11 Prof. Sreerama Krupanidhi

12. Toll Like Receptors 8/29/2024 12 Prof. Sreerama Krupanidhi

13. TLR signalling in DCs & Macrophages 8/29/2024 13 Prof. Sreerama Krupanidhi

14. TLRs mediate through TFs TLR activates transcri p tion factors, which stimulate the expression of genes encoding cytokines, enzymes and other proteins . Most important transcription factors are: Nuclear factor-kappa B (NF-kappa B) and interferon response factor -3 (IRF-3) . 8/29/2024 14 Prof. Sreerama Krupanidhi

15. NF-kappa B & IRF-3 NF-kappa B promotes expression of cytokines and endothelial adhesion factor . IRF-3 stimulates type I interferons and cytokines with antiviral activity . 8/29/2024 15 Prof. Sreerama Krupanidhi

16. Soluble Defense Mechanisms T y pe I interferons : DC (IFN-alfa), fibroblasts (IFN-beta) Microbicidal molecules : Epithelial cells, PMN and macrophages secrete cystein e rich peptides (defensines). Others are cathelic i dine, lysozyme, DNAase, RNAase . 8/29/2024 16 Prof. Sreerama Krupanidhi

17. Complement Proteins Dormant Serum proteins: ~20 in number 8/29/2024 17 Prof. Sreerama Krupanidhi

18. Lytic pathway: insertion of lytic complex into cell membrane C5 b C6 C7 C8 C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 8/29/2024 18 PERFORIN MOLECULE Prof. Sreerama Krupanidhi

19. Cytokines: Communicating molecules 19 Proinflammatory Anti-inflammatory Act to make disease worse Reduce inflammation and promote healing IL-1, TNF a , IL-6 IL-10, IL-4, TGF 8/29/2024 Prof. Sreerama Krupanidhi

20. Neutrophil Infiltration at the site of Inflammation 8/29/2024 20 Prof. Sreerama Krupanidhi

21. Steps in Phagocytosis Attachment bacterial carbohydrates (lectins) receptor for opsonins fibronectin receptors Fc receptors Internalization (phagocytic vacuole) Digestion (phagosome) 8/29/2024 21 Prof. Sreerama Krupanidhi

22. Antibacterial compounds of the phagolysosome I Oxygen-dependent compounds Hydrogen peroxide: NADPH oxidase and NADH Superoxide Hydrox y l radicals (OH) Activated halides (Cl _ , I _ , Br _ ) M yeloperoxidase Nitrous oxide 8/29/2024 22 Prof. Sreerama Krupanidhi

23. Antibacterial compounds of the phagolysosome II Oxygen-independent compounds Acids Lysosome (degrades bacterial peptidoglycan) Lactoferrin (chelates iron) Defensin and other cationic proteins (damage membranes) Proteases, elastase, cathepsin G 8/29/2024 23 Prof. Sreerama Krupanidhi

24. Phagocytosis & killing of bacteria 8/29/2024 24 Prof. Sreerama Krupanidhi

25. 8/29/2024 25 Cells involved in innate and adaptive immunity Prof. Sreerama Krupanidhi

26. Macrophages in antibacterial response I mportant antibacterial activity by phagocytic cells Killing by oxygen-dependent and oxygen-independent mechanisms . Production of IL-1, IL-6, and IL-12; TNF- a and TNF- b , and interferon- a . Activation of acute-phase and inflammatory responses . Presentation of antigen to CD4 T cell . 8/29/2024 26 Prof. Sreerama Krupanidhi

27. Inflammation reactions Expansion of capil l aries to increase blood flow (seen as a rash) . Increase the permeability of the microvasculature structure to allow the escape of fluid, plasma proteins, and leukocytes from the circulation ( edema ). Exit of leukocytes from the capillaries and their accumulation at the site of injury . 8/29/2024 27 Prof. Sreerama Krupanidhi

28. Acute-Phase Reactants a 1 -antitrypsin a 1 -glycoprotein Amyloid A & P Antithrombin III C-reactive protein C1 esterase inhibitor C3 complement Ceruloplasmin Fibrinogen Haptoglobulin Orosomucoid Plasminogen Transferrin L i popolysaccharid e -binding proteins 8/29/2024 28 Prof. Sreerama Krupanidhi

29. SUMMARY Innate immunity (I.I.) is the first line of defence. I.I. comprises of cellular components, receptors and mediators of inflammation. Pathogens are having their own molecular patterns called PAMPs. Macrophages are endowed with TLRs , PRR for antibacterial response. Complement proteins lyse bacterial cells. Inflammation with acute-phase reactants kills/ drives pathogens out. 8/29/2024 29 Prof. Sreerama Krupanidhi

30. Nobel reward for the Scientists deciphered Innate immunity in the year 2011 Dr. Jules A. Hoffmann and Dr. Bruce A. Beutler  shared the Nobel Prize in Physiology or Medicine for their discoveries about the role of Toll-like receptors in innate immunity. 8/29/2024 30 Dr. Jules A. Hoffmann Dr. Bruce A. Beutler Prof. Sreerama Krupanidhi

31. Study Questions Why is Innate Immunity called as First line of defense? How do phagocytes recognize pathogens? Elaborate the acronyms: PAMPs, PARs, TLRs, NFkB and DC. Elaborate the steps in Phagocytosis . Enlist acute-phase reactants in Innate Immunity. What would be the consequence if the Innate immunity fails; and adaptive immunity prevails? 8/29/2024 31 Prof. Sreerama Krupanidhi

32. Acknowledgements 8/29/2024 32 We acknowledge the online resources and public domains for the Preparation of the content to develop teaching material. Prof. Sreerama Krupanidhi

33. Thank you 8/29/2024 33 Prof. Sreerama Krupanidhi