Chapter 1

1. Chapter 1 Elements of the Immune system and their Roles in Defense

2. Introduction • Immunology is the study of physiological mechanisms that are used to defend the body from invasion by foreign or infectious agents • In response to diseases caused by infectious agents, the body develops cells dedicated to defense – these form the immune system • Protective immunity takes time to develop, while microorganisms can rapidly multiply and cause disease • Immunity involves two responses, the flexible but specific defenses of the adaptive immune response and the fixed defenses of the innate immune response

3. Defenses Facing Invading Pathogens

4. The Ubiquitous Enemy- Microbes • Microbes survive on animal & plant products • Release digestive enzymes • Grow on living tissues (extracellular) where they are bathed in nutrients • Other intracellular microbes infect animal/human cells, utilizing host-cell sources • Some microbes are harmless and some even helpful (e.g. E. Coli in our intestines) • Many others cause disease (human pathogens) • There is a constant battle between invading microbes and the immune system

5. Immunity-The Immune Response • People who survive a specific infection become immune to it – protective immunity • To provide protective immunity, the immune system must first engage the microorganism • There is lag time between infection and protection • The first infection is the most dangerous one • This understanding led to the concept of immunization or vaccination • Disease is prevented by prior exposure to an attenuated infectious agent

6. Historical Perspective • Origins of immunology attributed to Edward Jenner • Discovered in 1796 that cowpox “vaccinia” • protected from human smallpox • Procedure called vaccination • Prevents severe disease by exposing the immune system to the infectious agent in a form that cannot cause the disease

7. The Eradication of Smallpox by Vaccination • Vaccination was Initiated in 1796 • WHO in 1979 announces eradication of smallpox • What are the risks to the human population should the virus emerge again? • Naturally • Deliberate act of human malevolence

8. The Nature of Pathogens • Any organism with potential to cause disease is a pathogen • Opportunistic pathogens cause disease if the body’s defenses are weakened • Constant evolutionary struggle between the host and the pathogen • REPLICATION TIMES favor the PATHOGEN!!!

9. The Four Kinds of Pathogen that Cause Human Disease

10. Refer to Figure 1.3: The Diversity of Human Pathogens Blastophores (yeast-like cells) Pseudohyphae Cocci-grape like clusters Candida albicans-normal inhabitant of the human body, thrush & systemic infections Staphylococcus aureus-gram positive bacterium that colonizes human skin, pimples & boils (other strains = food poisoning) Mycobacterium tuberculosis-causes tuberculosis

11. Avian Influenza (Bird Flu) • Bird flu or Avian Influenza, is a contagious disease of animals caused by viruses that normally infect only birds • By the middle of 2005, some 50 people had died from bird flu • Virus can mutate to a more contagious form, experts continue to warn of the potential for a full-blown pandemic

12. Skin and Mucosal Surfaces -Physical Barriers Against Infection • Skin is first line of defense against infection • Tough impenetrable barrier • Skin continuous with epithelia lining • respiratory • gastrointestinal • urogenital tracts The impermeable skin gives way to specialized tissues that are more vulnerable to microbe attack; Known as mucosal surfaces or mucosae

13. Skin and Mucosal Surfaces -Physical Barriers Against Infection • Mucosal surfaces are bathed in mucus; thick fluid containing glycoproteins, proteoglycans, and enzymes - protective • Lysozyme in tears and saliva – antibacterial • Respiratory tract mucus is continuously removed to clear unwanted material • Stomach, vagina, skin acidic – protective When skin and mucosal barriers are breached - immune system responds

14. Secretions at Epithelial Surfaces Secretions from epithelial surfaces at external sites of the body are important for protection against entry of microbes

15. Physical Barriers that Separate the Body from its External Environment Strong barriers to infection provided by the skin, hair, and nails are colored blue More vulnerable mucosal membranes are colored red

16. Immune Defense-Innate Versus Adaptive Immunity • Innate immune system • Is the first line of defense against infections • It works rapidly • Gives rise to the acute inflammatory response • Has some specificity for microbes • Adaptive immune system • Takes longer to develop • Is highly specific for antigens, including those associated with microbes • Remembers that it has encountered a microbe previously, (i.e. shows memory)

17. Immune Defense-Innate Versus Adaptive Immunity • The innate and adaptive immune systems work together…. • through direct cell contact • through interactions involving chemical mediators, cytokines and chemokines • Many of the cells of the innate immune system are the same cells used by the adaptive immune system

18. Principle Characteristics of Innate and Adaptive Immunity Immunological Memory

19. Cells of the Immune System • Lymphoid cells – 20-40% of white blood cells • There are 1011 lymphocytes in the human body • Mononuclear phagocytes – monocytes that circulate in the blood and macrophages found in tissues • Granulocytic cells, classified as neutrophils, eosinophils and basophils based on morphology and cytoplasmic staining characteristics • Dendritic cells, whose main function is the presentation of antigen to T cells

20. Hematopoiesis • The generation of the cellular elements of blood, including: • Red blood cells (RBC) • White blood cells (WBC) or leukocytes • Platelets • These cells originate from pluripotent hematopoietic stem cells (HSC) whose progeny differentiate and divide under the influence of various hematopoietic growth factors • HSC give rise to other cells in a process called self-renewal, becoming more mature stem cells that commit to different lineages

21. Types of Hematopoietic Cells • The pluripotent stem cell divides and differentiates into more specialized progenitor cells that give rise to the • lymphoid lineage • myeloid lineage • erythroid lineage

22. Types of Hematopoietic Cells • The pluripotent stem cell divides and differentiates into more specialized progenitor cells that give rise to the • lymphoid lineage • myeloid lineage • erythroid lineage

23. Types of Hematopoietic Cells • The pluripotent stem cell divides and differentiates into more specialized progenitor cells that give rise to the • lymphoid lineage • myeloid lineage • erythroid lineage

24. Abundance of Leukocytes in Blood • Most abundant leukocytes are the neutrophils, followed by lymphocytes

25. Leukocyte Versus Lymphocyte • Leukocytes- a general term for a white blood cell Lymphocytes, granulocytes and monocytes are all leukocytes • Lymphocytes- a class of white blood cells that consist of small and large lymphocytes, two classes • Small lymphocyte- • B lymphocytes (B cells) and • T lymphocytes (T cells) • Large granular lymphocytes are • natural killer (NK) cells, lymphocytes of innate immunity

26. Figure 1-9 part 1 of 6

27. Lymphoid Cells • Lymphocytes are divided into three classes, B cells, T cells and natural killer cells (NK cells) • Naïve lymphocytes or small lymphocytes are resting cells that have not interacted with antigen • Lymphoblasts are lymphocytes that have interacted with antigen and proliferate • Lymphoblasts eventually differentiate into effector cells or into memory cells • Effector cells eliminate antigen – plasma B cells that secrete antibody, cytokine-producing T helper cells (TH) and T cytotoxic cells (TC)

29. Figure 1-9 part 2 of 6

30. Natural Killer Cells • NK cells (large granular lymphocytes) are found throughout the tissues of the body but mainly in the circulation • Constitute 5-10% of lymphocytes in human blood • Contain cytotoxic substances which are important for protection against viruses and some tumors • Secrete cytokines which prevent viral replication and helps to activate T cell mediated immunity

31. Neutrophils • Effectors of innate immunity – specialized in the capture, engulfment and killing of microbes • Work in the anaerobic conditions found in damaged tissue • Are short-lived and die at site of infection • Are phagocytic cells with that contain toxic substances in intracellular granuales • Employ oxygen-dependent and oxygen-independent pathways to destroy pathogens

32. Figure 1-9 part 5 of 6

33. Mononuclear Phagocytes • Granulocyte-monocyte progenitors in the bone marrow differentiate into pro-monocytes, which enter the blood, where these differentiate into monocytes • Monocytes circulate on the blood for about 8 hours, then migrate into tissues and become tissue specific macrophages or dendritic cells

34. Mononuclear Phagocytes • Differentiation of monocyte into macrophage requires changes • Cells enlarge 5-10 times; increased intracellular organelles, increased phagocytic ability; production of hydrolytic enzymes; secretion of soluble factors • There are tissue specific “fixed” macrophages and “free” macrophages

35. Figure 1-9 part 4 of 6

36. Dendritic Cells • Dendritic cells are so called because of their many surface membrane folds, similar in appearance to dendrites of the nervous system • These folds allow maximum interaction with other cells of the immune system • There are three main kinds of dendritic cells which are found in skin and in T cell and B cell areas of lymphoid tissue: • Langerhans cells (LH) • Interdigitating cells (IDC) • Follicular dendritic cells (FDC)

37. Dendritic Cells (cont.) • Most dendritic cells • possess high levels of surface MHC class II molecules • process and present peptide antigens to T cells • Their role is to recognize microbial antigens through innate receptors and process and present them to T cells of the adaptive immune system • Follicular dendritic cells hold intact antigens in specialized areas of lymphoid tissues

38. Mast Cells • Mast cells are found in the skin, connective tissue and mucosal epithelial tissue of the respiratory and digestive tracts • The origin of mast cells is uncertain but precursors differentiate in the bone marrow and mature in tissues • When activated mast cells degranulate releasing pharmacological mediators which cause • vasodilation • increase vascular permeability and • attract leukocytes to the site of degranulation

39. Figure 1-9 part 3 of 6

40. Eosinophils • These are granular leukocytes which stain with eosin (red) • They are present at low levels in the circulation (2-5% of blood leukocytes • Eosinophils have some phagocytic activity but are primarily responsible for extracellular killing of large parasites such as worms • They usually bind to an antibody-coated parasite and release the contents of their granules (degranulate) onto the parasite surface

41. Basophils • Basophils are granulocytes which stain with basic dyes (blue) and are present in very low numbers in the circulation (<0.2% of the granular leukocytes) • Basophils and mast cells are very similar in morphology • Both contain and release large characteristic electron-dense granules in their cytoplasm during allergic reactions • Like all the granulocytes, basophils are produced from stem cells in the bone marrow

43. Figure 1-9 part 6 of 6

44. Erythrocytes • Erythrocytes bind to immune complexes composed of antigen and antibody and carry these complexes to the liver where these are cleared are Kupffer cells • Erythrocytes have an important immunological role in clearing immune complexes from the circulation in persistent infections and in some autoimmune diseases • Kupffer cells = phagocytic cells of the liver that line the hepatic sinusoids

45. Pluripotent Hematopoietic Stem Cells • HSCs are multipotent or pluripotent – able to differentiate in various ways • There are fewer than one HSC per 5 x104 cells in the bone marrow • A normal mouse has 3 x108 bone marrow cells • A lethal dose of radiation (x-rays, 950 rads) will kill mice within 10 days unless they receive a bone marrow transplant from a genetically identical mouse • Infusion of 104-105 donor bone marrow cells will restore the hematopoietic system • HSCs growth is supported by stromal cells, which form the hematopoietic-inducing microenvironment (HIM), consisting of cellular matrix and factors

46. The pluripotent stem cell divides and differentiates into more specialized progenitor cells that give rise to the lymphoid lineage, the myeloid lineage and the erythroid lineage Figure 1-11

47. Site Of Hematopoiesis in Humans Changes During Development • The site for hematopoiesis changes with age • In early embryo, blood cells are first produced in the yolk sac and later in the fetal liver • From months 3-7 of fetal life the spleen is the major site of hematopoiesis • As bones develop (4-5 months) hematopoiesis shifts to the bone marrow • In adults hematopoiesis occurs mainly in the bone marrow Hematopoiesis is active throughout life because blood cells are both vital and short-lived

48. Innate Immune Response • Innate refers to the fact that mechanisms are determined by the genes a person inherits from their parents • There are many families of receptor proteins expressed by immune cells that recognize pathogens • These receptors recognize chemically diverse ligands – peptides, proteins, glycoproteins, proteoglycans, peptidoglycans, carbohydrates, glycolipids, phospholipids and nucleic acids – produced by pathogens

49. Key Elements of Innate Immunity • Cells and molecules of the innate immunity identify common classes of pathogen and destroy them • Four key elements of innate immunity • Molecules that noncovalently bind to surface macromolecules of pathogens • Molecules that covalently bond to pathogen surfaces, forming ligands for phagocyte receptors • Phagocytic cells that engulf and kill pathogens • Cytotoxic cells that kill virus-infected cells

50. Innate Immune Response • Recognition that the pathogen is present • Involves soluble proteins and cell surface receptors that bind • either to the pathogen and its products (ligands) • human cells and serum proteins that become altered in the presence of the pathogen • Recruitment of destructive effector mechanisms that kill and eliminate the pathogen • Effector cells that engulf bacteria, kill virus-infected cells or attack protozoan parasites • Complement • serum proteins that help the effector cells by marking pathogens with molecular flags • complement also attack pathogens in their own right