Innate vs. Acquired Immunity- conceptual and practical difference The vertebrate “invention” of acquired immunity

1. Lecture 1 Introduction to the Principles of Immunity • Innate vs. Acquired Immunity- conceptual and practical difference • The vertebrate “invention” of acquired immunity • How does innate immunity work? (Chapters 1 and 8) • Cells • Recognition receptors • Mediators

2. The Triumph of Death - Pieter Brueghel the Elder ca. 1562

3. Why the immune system? What is its function? How widely is it present in nature? Why does it affect so many aspects of life? How can we alter it for improved quality of life?

4. How does the Immune System (IS) affect your life? Autoimmune diseases: Graves'/hyperthyroidism, Type I diabetes, pernicious anemia, rheumatoid arthritis, thyroiditis, and vitiligo The incidence of 24 autoimmune diseases is 1/31 Americans. Women are at 2.7x greater risk Clin Immunol Immunopathol 1997 Sep;84(3):223-43 Cancer: Evidence in the past year indicates that the immune system does indeed function in tumor surveillance Hypersensitivity Diseases: Allergy-Incidence rise from 6%-20% in the past two decades Asthma-Incidence rise from 3%-8% of the total population in the past two decades -The hygiene hypothesis- Heart Disease-The blood vascular system is an integral part of the immune system. It instructs leukocytes to migrate from the blood to a site of infection. New evidence supports that idea that coronary heart disease results from chronic arterial inflammation Infectious Diseases: Almost any deficiency in immunity--you die

5. Immune Evolution Big bugs have little bugsUpon their backs to bite ‘emLittle bugs have littler bugsAnd so on ad infinitum -Ogden Nash, I think Colonization of large organisms by smaller organisms or viruses is the “inverse food chain” Large complex organisms present a source of energy and a habitat for smaller organisms and viruses via colonization Colonization and defense against colonization is a fundamental principle in biology The immune system is principally and most importantly evolved to sculpt colonization to benefit the host

6. Dance of the Eons Virtually every organism faces pressure from viral or microbial colonization and so has evolved strategies to control colonization Likewise, every parasitic organism or piece of selfish DNA has evolved a strategy to mitigate the effects of immunity This eternal waltz of parasites and their hosts surely began with the origin of life Corollaries • Just as predator species improve the fitness of their prey, colonial agents select for fitness in their hosts • Just as a host cannot be too permissive for a parasitic agent, the parasitic agent cannot be too effective in killing a host • The more effective the immune system, the more complicated and evolved the parasite • Perhaps we should view the host-parasite interaction as a constantly escalating war or an uneasy (metastable) truce

7. One view of animal phylogeny

8. Biological Inventionof Acquired Immunity

9. Innate vs. Adaptive Immunity Figure 1.5 Memory

10. Innate Immunity • All animals have an “innate” immune system • Innate immunity is manifest in many cells of the body. The basis is the recognition of molecular patterns, that occur in microbes but not animals (e. g., unmethylated DNA sequences, dsRNA, cell wall components, etc) • This is the bedrock of immunity in all organisms--even bacteria have defense mechanisms against bacterial viruses

11. Innate Immunity, con’t • An apparent limitation is that parasitic agents have a generation time orders of magnitude less than that of their hosts • A second limitation is that there is only limited amplification of the response • A third limitation is that there is no memory

12. Adaptive Immunity • Recognizes any biochemical determinant • Provides a mechanism for immune recognition that can evolve as rapidly as the parasite (clonal selection) • There is rapid amplification of a response • There is memory

13. Components Principle Functions Barriers Epithelial layers Prevent entry Defensins and Cryptidins Microbial killing Circulating and Tissue Effector Cells Neutrophils Early phagocytosis and killing of microbes Mast Cells Release of inflammatory granules Macrophages Efficient phagocytosis and killing of microbes: cytokines Eosinophils Nasty toxic cells designed to kill helminths (worms) NK cells Lysis of infected cells, activation of macrophages Circulating Proteins Complement (C’) Killing of microbes, opsonization of microbes, actvn leukocytes Mannose-binding protein Opsonization of microbes and activation of C’ C-reactive protein Opsonization of microbes and activation of C’ Lysozyme Bacterial cell wall lysis Cytokines TNF, IL-1, 6, 18 Inflammation IFN a, b Resistence to viral infection IFN g Macrophage activation IL-12 IFNg production by NK cells IL-15 Proliferation of NK cells, memory T cells IL-10, TGF b Control of Inflammation Components of Innate Immunity Adapted from: Abbas (Saunders)

14. Figure 8.6 Defensins (epithelium)

15. Figure 1.4

16. Figure 8.9

17. Figure 8.1

18. Salmonella infection with and without adaptive immunity Mice deficient for innate immunity (macrophage) WT T lymphocyte deficient

19. What is the basis for innate immunity, and how does is relate to vertebrates? Drosophila melanogaster mutants were found that were susceptible to fungal and bacterial infections. Immunity in Drosophila (Innate) Toll mutant lacks defense against fungal infections 18 Wheeler lacks defense against bacteria This led to the discovery of a family of receptors known as the Toll-related receptors (TLR) present in vertebrates

20. Innate Immunity Pattern Recognition Other: teichoic acid,

21. Genes to Cells6(9),733-742 Kiyoshi Takeda and Shizuo Akira (2001) Activation of the transcription factor: NFkB

22. Toll family of receptors

23. Toll-like receptors [TLR1-10] • Recognition alone or in combinations of: • LPS (gram-negative cell wall component) • Lipopeptides and peptidoglycan (gram positive cell wall components • Yeast particles TIR Domain Activation of NFkB transcription factor and thus induction of cytokines and other genes that are anti-microbial

24. + Unified Immunity Concept • Innate Immunity • molecular pattern recognition • inflammation (alarm and danger) • mobilization of many immune components including presentation of foreign agents to the lymphoid system • Adaptive Immunity • clonal recognition of foreign agents by T and B cells followed by selective expansion (production of antibodies, cytokines, and chemokines) • mechanisms exclusive to adaptive immunity

25. Progression of Immunity Figure 8.5 At least two cell types reside within or beneath the epithelium and induce inflammation in response to trauma or microbial products: Macrophages and Mast Cells

26. Figure 1.6ij Alveolar macrophages (lung) Histiocytes (connective tissue) Kupffer cells (liver) Mesangial cells (kidney) Microglial cells (brain) Tissue macrophage

27. Figure 1.13 Receptors on Macrophages: LPS receptor-CD14 Toll-like receptors Fc receptors Mannose receptor Complement receptors IFNg receptor Chemokine receptors

28. Figure 1.6gh Function in disease, not entirely understood Contains high affinity receptors for IgE, and preformed granules that contain inflammatory mediators including: histamine; heparin; TNFa; chondroitin sulfate; neutral proteases; and other. Mast cells can also secrete: cytokines to induce inflammation; chemokines to induce infiltration by monocytes, and neutrophils, leukotriences to induce muscle contraction and increase vascular permeability Mast cells are capable of inducing an inflammatory cascade

29. Mast cells are also found in the tissues Figure 1.14 TNF Mast cells can release histamines which induce inflammation Neutrophils and monocytes are recruited Redness, swelling (erythema, edema)

30. Figure 1.6ef Express some of the same receptors found on macrophages High affinity FceRI receptor. Effective against worm infections. Granules contain mediators-smooth muscle contraction and worm toxicity

31. Figure 8.8 LPS receptor: CD14 toll-like receptor-4 CR3,4: Complement (C’) receptors (C3b) Scavenger receptor: sialic acid-bearing protein Mannose receptor: Binds mannose on bacteria, activates C’ Glycan receptor: Polysaccharides IN ADDITION: TLRs

32. Lymphocytes are entirely involved with acquired immunity. The come in two types: T lymphocytes (T cells) that differentiate in the thymus and B lymphocytes or B cells that differentiate in the bone marrow. B cells can further differentiate after antigen-activation to plasma cells that produce antibodies Figure 1.6ab

33. Nature Killer Cells play several interesting roles in the immune system. One is to monitor cells for identification. If a cell doesn’t reveal its identity papers, it is killed. You’ll see this later in the course. Dendritic cells are the most important antigen presenting cells (APCs) in the immune system Figure 1.6cd

34. Figure 8.10 ** **The most important inflammatory cytokine (at least in this course)

35. Figure 8.14

36. Complement facilitates phagocytosis Figure 1.15