1. Nonspecific Host Defense Mechanisms BY Prof. DR. Zainalabideen A. Abdulla, DTM&H., MRCPI, Ph.D., FRCPath. (U.K.)

2. Learning Objectives

3. Host defense mechanisms Non-Specific Defense: 1. First line of defense - Intact skin & mm 2. Second line of defense - Inflammation & phagocytosis Specific Defense: 3. Third line of defense - The immune system

6. First Line of Defense Skin and Mucous Membranes Physical/mechanical barriers e.g. Bacteria can not penetrate intact skin, or intact mm/sticky mucus produced (by goblet cells) entraps invaders Certain helminthes able to penetrate skin, e.g. Hookworm, Schistosomiasis

7. Cellular and chemical factors Intact skin Skin dryness: Inhibits pathogens Acidity (pH ̴ 5.0) Temperature (< 37Celsius) Oily Sebum (sebaceous glands)- Fatty acids toxic to pathogens Perspiration- Flushing organisms - Lysozyme degrades peptide- glycan specially of G+ Sloughing off of dead skin cont./…

8. cont./…cellular and chemical factors Mucus membranes Substances kill or inhibit bacteria: Lysozyme (saliva, tears, nasal secretions) Lactoferrin (Binds iron required by pathogens) Lactoperoxidase (toxic superoxide radicals) Rapidly dividing cells/ expelled with microbes Respiratory tract: Hair, mm, nose, cilia GIT: Digestive enzymes, acidity of the stomach (pH ̴ 1.5), alkalinity of intestines GUT: Urination, low vaginal pH

9. Microbial Antagonism Nonspecific host defense/ Factors mentioned Superinfection: When microbiota reduced Second Line Chemical and Cellular Transferrin Fever Interferon Complement system Acute phase proteins Cytokines Inflammation Phagocytosis

10. Transferrin Glycoprotein; synthesized by the Liver Store/deliver iron to host Sequestered: Deprive pathogens from iron Increased: In systemic bacterial infections Fever Normal = 36.2 – 37.5 (mean: 37) Celsius Fever = > 37.8 Substance: Pyrogens (pyrogenic) e.g. Endotoxin, IL-1 (endogenous pyrogen) cont./…

11. Fever augmentation of host defenses Stimulate WBC Reducing plasma iron levels Production of IL-1: Stimulate lymphocytes Fever development during infectious disease Gram negative sepsis Endotoxin Phagocytes ingest endotoxin IL-1 Prostaglandins Up hypothalamic thermostat Vasoconstriction; temp decreases when IL-1

12. Interferons Small anti-viral proteins Produced by virally infected cells “Interfere” with viral replication Types: Alpha, beta, gamma Stimulants: Viruses, tumors, bacteria, cells“F. Alpha: B-cells, monocytes, macrophages Beta: Fibroblasts, other virus-infected cells Gamma: T-cells, NK cells Save surrounding cells; spread inhibited Not specific, but species (animal) specific c ont

13. cont./… interferons Genetically produced by bacteria in which human genes inserted Use: Warts, H. simplex, Hepatitis B & C, and Cancer (leukemia, lymphoma, Kaposi sarcoma in AIDS) Activate NK cells Cause: Flulike ( malaise, myalgia, chills, fever )

14. The complement system “C” 30 different proteins (C1 – C9 & others) “Complementary” to immune system Complement cascade (stepwise) Consequences of “C” activation: 1. Initiation/amplification of inflammation 2. Attraction of phagocytes to site 3. Activation of leukocytes 4. Lysis of bacteria/ foreign cells (target) 5. Opsonization (increased phagocytosis)

15. Opsonization Opsonins: Antibodies, C3b Opsonins attach to surface of target cells Phagocytes have receptors to opsonins The process facilitate phagocytosis of certain particles such as encapsulated bacteria. Complement pathways : 1. Classical (C1-C9): Specific immunity 2. Alternative “ Properdin” (C3-C9): Non- specific (innate) immunity

16. Acute phase protein Increased: Infections, inflammation, tissue injury Function: - Enhance resistance to infections - Promote tissue repair Examples: C-reactive protein (inflammation marker), serum amyloid A protein, protease inhibitors, coagulation proteins

17. Cytokines For cells’ communication (chemical messages) Cells “sense” cytokines by surface receptors Roles/examples: - Chemo-attractants (e.g. phagocytes) - Role in host defense

18. Inflammation (inflammatory response) Vasodilatation Increased vascular permeability; plasma escape Leukocytes escape Purpose: - Localize infection - Prevent spread of invaders - Neutralize toxins - Aid in repair of tissue damage Cardinal (main) 4 signs: redness, heat, pain, swelling (edema); + Pus, Function loss cont./…

21. cont./… inflammation Physiological events Vasodilatation (histamine & PG)- endothelial cells stretches/separate > Blood Redness, Heat, Plasma escape Edema Influx of phagocytes (chemotactic agents) Pain/tenderness (nerve damage: Injury, PG, Toxins, pressure by edema) cont./…

22. cont./… inflammation Inflammatory exudate: Fluid + cellular debris Purulent exudate: Thick greenish yellow exudate + live/dead leukocytes (PUS) e.g. Staphylococci, Streptococci Pseudomonas aeruginosa Green pus (due to bluish pigment of m.o.: Pyocyanin) Lymphatic system: - Draining circulating fluid - Transport fat from GI - Filter: T, B, macrophages - Antibodies/others sub.

23. Phagocytosis Engulf (phagocytosis) Professional phagocytes ( M & N) Phagocytic granulocytes (N & E; 1 st >> 2 nd ) Monocytes Macrophages - Wandering macrophages - Fixed macrophages: Histiocytes in C.T., Liver: Kupffer cells, Brain: microglia Phagocytosis steps: Chemotaxis, Attachment, Ingestion, Digestion

26. Chemotaxis Chemotaxis (to site): Chemotactic Agent (Chemokines) Produced during complement activation Move along concentration gradient Attract: N, Mo, E

27. Attachment Attachment to objects (microbes) by receptors Role of opsonization (Ab & C) Ingestion Surround objects by pseudopodia & FUSE (Phagosome “membrane bound vesicle”)

29. Digestion Phagosome + Lysosome Phagolysosome Lysosomes: Membrane-bound vesicles with digestive enzymes: - Lysozyme, Beta-lysin, Lipase, Protease, Peptidase, DNAses, RNases Degrade CHO, lipids, proteins, and nucleic acids Neutrophils: - NADPH oxidase reduces Oxygen Superoxide Anions, Hydroxyl Radicles, Hydrogen Peroxide, and Singlet Oxygen/ cont

31. cont./… digestion Myeloperoxidase (from lysosomes) in the presence of hydrogen peroxide & chloride ion Hypochlorous acid (potent microbicidal agents) Example: Phagocytosis of Giardia lamblia by neutrophils

32. Pathogens escape destruction Capsule: Anti-Phagocytic Leukocidin by m.o.: Kills phagocytes Wax protects: Mycobacterium tuberculosis Survival inside phagocytes: Transported e.g. Salmonella spp., Brucella abortus, Toxoplasma gondii, Leishmania spp.

34. Disorders affecting phagocytic and inflammatory processes Leukopenia Low WBC numbers; Neutropenia (low N No.) Bone marrow injury : Radiation, drugs, nutritional deficiencies, congenital stem cell defects

35. Disorders of Leukocyte Mobility/Chemotaxis Defect in actin production (for mobility) Corticosteroids Chediak-Higashi syndrome: N chemotaxis affected, PMN abnormal lysosomes ( not fuse to phagosomes ) resulting in decreased bactericidal activity + albinism, CNS abnormalities, recurrent bacterial infections

36. Disorders of intracellular killing Deficiency of myeloperoxidase (MP) Inability to generate: Superoxide anion, hydrogen peroxide (HP), Hypochlorite Chronic Granulomatous Disease (CGD): - Fatal genetic disorder - Repeated bacterial infections - PMNs can ingest bacteria, but can not kill - Forms: Unable to produce HP or lack MP Additional Factors: See Table