Principles of Immunology

1. Principles of Immunology Prince Agri-Products & Phibro Animal Health Training Seminar – Atlanta, Georgia July 17-18, 2006

2. Immunity: security against a particular disease; nonsusceptibility to the invasive or pathogenic effects of foreign microorganisms or the toxic effect of antigenic substances. • Innate Immune System: consists of physical, chemical, enzymatic barriers and activity of phagocytic cells (neutrophils) which are associated w/ a signaling system • Adaptive (antibody-mediated) Immune System: consists of two components • Humoral (antibody production in response to antigen, medicated by B-lymphocytes) • Cell-mediated (production of specific killer cells in response to an antigen, mediated by T-lymphocytes)

3. Phagocytes: first to arrive at the site of infection Function to contain infections, provide time for adaptive system to develop 200 billion in adult cow, 50% in circulation, remainder in bone or attached to vessel walls Life span of 1-2 days Contain a protein component: L-Selectin, index of innate immunity Innate Immune Response -Neutrophils, first line of defense

4. Neutrophil recognition of pathogen Neutrophil Receptors on surface of neutrophil Pathogen Pathogen-associated molecular Patterns: PAMPs)

5. Phagocytosis Bacterium Recognition

6. Production of NETS by neutrophils Inactive neutrophilsActivated neutrophils withNETs Source: Brinkmann et al., 2004 + interleukin-8 (IL-8)

7. Association of neutrophil “NETs” with bacteria S. aureus(gram +) Salmonella(gram -)Shigella (gram -)

8. - tethering via L-selectin (A) -shedding L-selectin (B) - Interleukin-1- pro-inflammatory (C) -migration toward “signals” (D) -phagocytosis (F) Neutrophils: a first line of defense -pathogens Source: Burton and Erskine, 2003

9. Example of relationship between stress and immunity Cortisol - Adrenal hormone • released in response to a stressful event • needed by uterus at time of calving • aids in intiating milk secretion by the mammary gland • elevated blood Cortisol cause neutrophils to lose their ability to migrate from blood into tissue by interfering with L-selectin synthesis Source: Burton and Erskine, 2003

10. Cortisol Response Relative to Parturition Puntenney & French 2003

11. Effect of stress on neutrophils Normal Stress Proliferation and invasion of pathogens L-selectin and interleukin

12. Take home on neutrophils • First line of defense against bacteria and molds • L-selectin (tethering/rolling/ “surveillance”) (A/B) • IL-8 (signal from infection site) (D) • IL-1β (access infection site/ “diapedesis”) (C) • Free-flowing blood neutrophil (E) • Killing mechanisms (digestion and NETs) (F)

13. Pluripotent hematopoeitic stem cell (Self-renewing, white blood cell producing) Common lymphoid Progenitor (lymph tissue) Common myeloid Progenitor (bone marrow) B cells T cellsNK cells White blood Red blood Megakaryocytes cells cells Platelets Monocyte Neutrophil Eosinophil Basophil Dendritic cell -Adaptive -Innate Macrophage Janeway et al., 2005

14. Phases of an infection • 1.Entry of pathogen • 2. encounter a macrophage/dendritic cell • 3. macrophage recruits neutrophils via IL-8 • 4. macrophage (phagocytic cell) and dendritic cells (antigen-presenting cells) migrate to lymph tissue where they encounter naïve B and T lymphocyte • 5. B and T lymphocytes clonally expand and differentiate and make antibodies Innate Acquired

15. 1. Activated macrophages and dendritic cells with ingested pathogen present antigen to T-lymphocytes 2. Chemokines, secreted by macrophages, enhance tissue permeability and influx of T-lymphocytes into an infection site (IL-1B) 3. Macrophages and neutrophils produce activating molecules (e.g., IL-1β and IL-6) Activated neutrophil B and T lymphocytes Linkage of innate and adaptive immunity IL-1β + 4. Activated T-cells, in turn, activate macrophages Janeway et al., 2005

16. Review • Terms • Pathogen: disease-causing infectious agent • Antigen: any molecule that stimulates the immune response (pathogen proteins or carbohydrates) • Phagocytes: cells attracted to site of infection to destroy pathogens (not antigen-specific, part of innate system) • Neutrophils • Eosinophils • Monocytes/macrophages • Natural Killer Cells (virus-infected and cancer cells)

17. Review • Terms • Leukocytes: white blood cells • Adaptive Immunity: response to repeat infection • Synthesis of antibody to bind antigen and promote elimination • T cell killing of virus-infected cells • T cell activation of macrophages to destroy phagocytosed pathogens that are resistant to destruction

18. Review • Terms • Innate Immunity: defense system that can recognize “generic danger” and responds by walling off and engulfing foreign organisms • Barriers - skin, mucous membranes • Mechanical – cilia, blinking, sneezing, coughing, vomiting • Chemical – HCl in stomach, digestive enzymes in tears, mucus • Phagocytes – Neutrophils, eosinophils, macrophages, M cells, monocytes • Natural Killer Cells – kill virus/cancer cells

19. Review • Terms • Apoptosis: programmed cell death • Macrophages: innate immune cell, binds pathogens, produce cytokines to attract other phagocytic cells and make blood vessels leaky, may present antigen to stimulate T cell activation (adaptive) • Dendritic cells: innate immune cell, may be phagocytic and may present antigen to simulate T cell activation (adaptive immune system) • Lymphocytes: antigen-specific white blood cells responsible for adaptive immunity

20. Review • Terms • Natural Killer (NK) Cells: large lymphocytes that lack specific antigen receptors but respond to altered tissue typing in virus-infected and cancer cells • Cytokines: small proteins produced by macrophages in response to bacterial antigens; signal other white blood cells; act by binding to specific membrane receptors to signal the cell to alter its behavior (gene expression) • Lymphokine (lymphocytes), monokine (monocytes), chemokine (chemotactic activity), interleukin (made by one leukocyte and acting on others)

21. Review • Terms • Antibody: antigen receptor on B cells and is also secreted to bind and remove antigen from the body • Immunoglobulins: antibodies that are antigen-binding proteins (IgG, IgM, IgD, IgA, IgE) • Interleukin-1: cytokines produced by macrophages which activate nearby vascular endothelium to promote leukocyte movement into the tissue (extravasation) • Interlukin – 8: chemokines which recruit leukocytes and attract them to site of infection • L-selectin: neutrophil-adhesion molecule that initiates binding between leukocytes and endothelium