Innate immunity: An Over view

An Overview to Innate immunity for students of Medical Sciences

1. Innate Immunity by Getso , Muhammad Ibrahim Microbiology Dept; SRM MCH & RC

2. Synopsis Introduction Properties of innate immunity Components of innate immunity Epithelial barriers Cellular mechanisms Humoral mechanisms Role of innate immunity in stimulating adaptive immune respons e Defects in innate immunity Current issues in innate immunity

3. Introduction The term immunity, microbiologically, refers to state of relative resistance of host to infectious agents (microbes and their products ). The hosts’ defense against microbial infections is fundamentally the function of two major types of immune system; Innate Immune System and Adaptive Immune System . Innate forms the first line of defense; is p hylogenetically older ; non specific; Immediate and rapid; needs not prior exposure; not associated with memory

4. Principle mechanisms of Innate and Adaptive Immunity

5. Innate Immunity - Innate immunity is constitutive and can be considered at Species , Racial and Individual level.

6. C omponents of i nnate immunity Humoral : - Interferons - Chemokines -complements Cellular: -Granulocytes - Agranulocytes Epithelial: - physical barrier -chemical barrier -biological barrier

7. Cellular components of innate immunity NK Cells Recognize and destroy cancer and virally infected cells

8. Cellular defense mechanism of innate immunity Recognition via receptors: Pattern Recognition Receptors (PRRs) Toll-like Receptors (TLRs) Killer Activation Receptors (KARs) Killer Inhibtion Receptors (KIRs) Complement Receptors (CRs) Fc Receptors ( FcRs ) Response via Phagocytosis Inflammation

9. Pathogen Associated Molecular patterns (PAMPs) Structures common for certain groups/classes of pathogens essential for their life, replication and/or infectivity structures of bacterial cell wall (LPS, peptidoglycan, flagellin , Capular ...) nucleic acids of pathogens (dsRNA, unmethylated CpG dinucleotides...) not present on human cells Examples: Lipoprotein s Flage l lin Capsular antg

10. Toll-like Receptors

11. Toll-like Receptors Transmemebrane molecules as receptors to recognize microbial components They’re homologous to Drosophila protein, Toll . About 10-12 different TLR identified based on sequence homology to Drosophila Toll. They are named as TLR-1, TLR-2, TLR-3……. Functions depend on the molecule identified Binding to ligand initiates signaling pathways leading to activation of transcription factors that switch on cytokine genes.

12. Mechanism of Killer Activation Killer Inhibtion Receptors

13. Recognition and Response by Macrophages

14. Role of phagocytes in innate immunity Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen ( macrophages ) reactive oxygen species (ROS), nitric oxide (NO) and l y sosomal enzymes

15. Phagocytosis and killing of microbes Pathogen recognition

16. Zipping of membrane around microbe Phagocytosis and killing of microbes

17. Ingestion of microbe Phagocytosis and killing of microbes

18. Fusion of phagosome with lysosome Phagocytosis and killing of microbes

19. Phagocyte activation Phagocytosis and killing of microbes

20. Killing of microbe Phagocytosis and killing of microbes http://highered.mcgraw-hill.com/sites/0072556781/student_view0/chapter31/animation_quiz_3.html

21. Role of phagocytes in innate immunity Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen 4. I nduction of i nflammation (macrophages) - production of pro-inflammatory cytokines (TNF, IL-1, chemokines ...)

22. Inflammation induction Proinflammatory cytokines TNF ― Tumor Necrosis Factor IL-1 ― Interleukin-1 Chemokines ― Chemotactic cytokines

23. Role of phagocytes in innate immunity Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen 4. Inflammation induction 5. Attraction of cells to infection site - adhe sive mole cules (sele c tin s and integrin s ) and c hemokin es

24. Leukocytes arrive at the site of infection (extravasation) Weak binding and rolling Activation and firm binding Endothelium TNF & IL-1 Transmigration Arrival to the site of infection Selectins Integrins Various adhesive molecules Chemokines Macrophages

25. Role of phagocytes in innate immunity Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen 4. Inflammation induction 5. Attraction of cells to infection site 6. Pathogen e limin ation and / or adaptive immunity activation (d endritic cells ) - cytokines , costimulatory molecules ...

26. Role of phagocytes in innate immunity Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen 4. Inflammation induction 5. Attraction of cells to infection site 6. Pathogen e limin ation and / or adaptive immun i ty activation 7. Tissue repair and remodeling (macrophages) - enz ymes and c yt okin es ( growth factors , metaloproteina ses ...)

27. Mechanism of phagocytosis

28. Role of NK cells in innate immunity Killing of cells infected by intracel l ula r pat h ogen s ( eg . viruses ) and tumor cells Activation of macrophages (by IFN- γ )

29. Humoral components of Innate Immunity

30. Properdin

31. Components of complement system

32. Defects in innate immune system Cystic fibrosis- gene defect in ion-gated chloride channel, leading to accumulation of abnormally thick secretion in air ways. Congenital achlorhydria - inability of gastric mucosal cell to produce HCl , Chronic Granulomatous Disease- congenital defect in NADP phargosome oxidase (NADP phox ) production, leading to poor generation of ROSs and RNS by phagocytes. Congenital deficiency of C8 Compliment - Defective MAC formation Hereditary angioedema ( C1 esterase deficiency)-excessive C1s activity Factor I deficiency- uncontrolled complement activation, leading to complement protein depletion.

33. Evaluation of innate immunity Single, specific and direct lab test is not available in practice Inferences can be drawn from level of certain components that can be evaluated in the labs. Examples: Evaluation of phagocyte defects by - Neutrophil Oxidative Burst using Nitro Blue- Tetrazolium (NBT) test - Dihydrorhodamin (DHR) flow cytometry - Neutrophil enzyme assay (G6PD, Myeloperoxidase …..) Specific complement components assay ( Eg CH 50 , C1q, C2)

34. Role of innate immunity in stimulation of adaptive immune response T or B- cells need two signals for activation First signal : antigen recognition while Second signal : derrived by innate immunity Lymphocyte proliferation and differentiation

35. Current Issues in Innate Immunity Application of innate immune system in: Pathogenesis of disesease Role of TLR 7 and 9 in pathogenesis of AIDs ( Arthritis Foundation research 2007, USA.) Association between Acute Coronary Syndrome and elevated level of MBL ( Kardiologiia Jounal 2014, 54(1):27-33) Association btw TLR 2 gene variants and Early Onset Bipolar disorder . (Jose Olivera et al; J Affective Dis (May 2014) vol 165, pg 135-141)

36. Disease Diagnosis: Use of TNF- α and IL-1 β as markers and prognostic factors in sepsis and septic shock . (Jacob RF and Tabor DR, 1990.) Use of lipocarlin-2 to differentiate between acute bacterial and acute viral infection. ( Xu et, 1995.) Use of Neutophil Gelatinase Associated Lipocarlin (NGAL) to descriminate between Acute Bact Meningitis and Acute Viral Meningitis in patient with clinical Meningitis symptoms . ( Guiddir T et al, May 2014)

37. Disease Therapy: Use of INF- α in HCV infection treatment Use of IL-13-PE (IL-13 immunotoxin ) for treatment of Pancreatic Adenocarcinoma (Toshio F et al; Int J Cancer (2011):28; 12211-1231 ) Use of aerosolized IL-2 for treatment of pulmonary metastatic liver cancer (2014, ongoing research in US National Inst of Health Development; Clinicaltrial.gov )

38. References Abbas AK, Litchman AH (2004). Basic Immunology 2 nd Ed. Saunders (Elsevier Inc.) USA Baron S. (1996). Medical Microbiology, 4 th Ed. The University of Texas Medical Branch at Galveston ( Online textbook) Ch.86-92 Christine DS (2010). Clinical immunology and serology : a laboratory perspective, 3 rd Ed. FA Davis Company, Philadelphia, USA. John BZ (2009). Essential Clinical Immunology , 2 nd Ed. Cambridge University Press, UK. Johnson AG, Ziegler R J, Lukasewycz O A, Hawley L B; (2002). BRS Microbiology and Immunology , 4th Edition. Lippincott Williams & Wilkins. USA Owen JA, Punt J, Stranford SA (2013). KUBY Immunology 7 th Ed. W. H. Freeman and Company, NY. USA Paul WE (2003). Fundamental Immunology 5th ed . Lippincott Williams & Wilkins Publishers, USA. Ch 17. Warren Levinson (2010). Review of Medical Microbiology & Immunology 5 th Ed. McGraw-Hill Companies, Inc. USA.

39. Thanks for your attention !