Medical Microbiology & Immunology Guri Tzivion, PhD tzivion@windsor.edu Extension 506 BCHM 306: January 2015 Windsor University School of Medicine

Class Outline Lecture 1: Immunology Introduction: Basic Concepts and Components of the Immune System, Innate Immunity Lecture 2: Adaptive Immune Responses, Antigens, Antibodies and Cell-mediated Immunity

Class Outline Lecture 3: Major Histocompatibility Complex, Transplantation and the Complement System Lecture 4: Immunological Methods and Diagnostics, Hypersensitivity and Allergy

Class Outline Lecture 5: Tolerance and Autoimmune Diseases Lecture 6: Tumor Immunity and Immunodeficiency

BCHM 306 MDIII Immunology Class 1 Immunology Introduction Basic Concepts and Components of the Immune System Innate Immunity

Two kinds of the immune system: Innate immunity Adaptive immunity

Innate Immunity or Nonspecific Immunity Is present before any exposure to pathogens and is effective from the time of birth Involves nonspecific responses to pathogens Consists of external barriers plus internal cellular and chemical defenses Nonspecific immunity is maintained by mechanisms that attack any irritant or abnormal substance that threatens the internal invironment. Nonspecific immunity confers general protection rather than protection from certain kinds of invading cells or substances. These defenses function the same way regardless of the invader or the number of times a particular type of organism invades.

Adaptive Immunity Also called specific immunity or acquired immunity Develops only after exposure to inducing agents such as microbes, toxins, or other foreign substances Involves a very specific response to the pathogen

Pathogens (such as bacteria, fungi, and viruses) INNATE IMMUNITY (all animals) • Rapid response Recognition of traits shared by a broad range of pathogens using a small set of receptors • Recognition of traits specific to particular pathogens using a large array of receptors • Slower response Barrier defenses: Skin Mucousal membranes Secretions Internal defenses: Phagocytic cells Natural killer cells Antimicrobial proteins Inflammatory response Humoral response: Antibodies defend against infection in body fluids Cell-mediated response: Cytotoxic cells defend against infection via cells ADAPTIVE IMMUNITY (vertebrates only) The Immune Response Figure 43.2 Overview of animal immunity.

Innate Immunity of Invertebrates In insects for example, an exoskeleton made of chitin forms the first barrier to pathogens Their digestive system is protected by a chitin- based barrier and secreted lysozyme that helps in breaking down bacterial cell walls The also have hemocytes circulating within their hemolymph that carry out phagocytosis

Phagocytosis Pathogen PHAGOCYTIC CELL Vacuole Lysosome containing enzymes Figure 43.3 Phagocytosis.

Innate Immunity of Vertebrates Innate defenses include barrier defenses, phagocytosis and antimicrobial proteins and peptides The vertebrate-specific defenses include: natural killer cells, interferons and inflammatory responses

Components of Innate Immunity: Physical barriers Phagocytic cells Immunological surveillance Interferons and and other cytokines Complement system Inflammation Fever

Barrier Defenses Barrier defenses include the skin and mucous membranes of the respiratory, urinary, and reproductive tracts Mucus traps microbes and promotes their removal Various body fluids including saliva, mucus, and tears provide hostile environment to microbes The low pH of skin and the digestive system prevents growth of many bacteria

First line barriers to infection Intact skin is a barrier that cannot normally be penetrated by bacteria or viruses although even very small abrasions may allow their passage Likewise, the mucous membranes that line the digestive, respiratory, and genitourinary tracts bar the entry of potentially harmful microbes

First line barriers to infection: secretions Secretions from sebaceous and sweat glands give the skin a pH ranging from 3 to 5, which is acidic enough to prevent colonization by many microbes Microbial colonization is also inhibited by the washing action of saliva, tears and mucous secretion All these secretions contain antimicrobial proteins One of these, lysozyme, digests the cell walls of bacteria, helping in their destruction

Second line barriers Microbes that penetrate the first line defenses face the second line defense, which depends mainly on phagocytosis (the ingestion of invading organisms by certain types of white blood cells). Phagocyte function is intimately associated with an effective inflammatory response and also with certain antimicrobial proteins. Phagocytic cells recognize groups of pathogens by surface receptors called Toll-Like Receptors (TLRs).

Toll-Like Receptors and select pathogen targets EXTRACELLULAR FLUID PHAGOCYTIC CELL VESICLE Lipopolysaccharide Helper protein TLR4 Flagellin TLR5 CpG DNA ds RNA TLR9 TLR3 Innate immune responses Figure 43.6 TLR signaling.

Innate immune response to injury Pathogen Splinter Mast cell Macro- phage Capillary Red blood cells Neutrophil Signaling molecules Movement of fluid Phagocytosis Figure 43.8 Major events in a local inflammatory response.

There are several types of phagocytic cells: Neutrophils engulf and destroy pathogens Macrophages are found throughout the body but accumulate at injury sites and secrete inflammatory cytokines Dendritic cells stimulate development of adaptive immunity Eosinophils discharge destructive enzymes

Neutrophils Constitute about 60 - 70% of all leukocytes (white blood cells) Cells damaged by invading microbes release chemical signals that attract neutrophils from the blood The neutrophils enter the infected tissue, engulf the microbes and destroy them Neutrophils tend to self-destruct as they destroy foreign organisms, and their average life span is only few days

Eosinophils About 1.5% of all leukocytes Contribute to defense against large parasitic invaders, such as the blood fluke, Schistosoma mansoni Eosinophils position themselves against the external wall of a parasite and discharge destructive enzymes from cytoplasmic granules

Monocytes & Macrophages Constitute about 5% of leukocytes Provide an effective phagoytic defense They migrate into tissues from the blood and develop into macrophages They extend long pseudopodia that can attach to polysaccharides on the microbe’s surface, engulfing the microbes by phagocytosis, and fusing the resulting vacuole with a lysosome

Monocytes vs M

DENDRITIC CELLS Originate in the bone marrow Function as antigen presenting cells (APC). Four types of dendritic cells are – Langerhan’s cells Interstitial dendritic cells Myeloid cells Lymphoid dendritic cells

Classes of innate immune cells - Monocyte/Macrophage - Dendritic cell (DC) - Polymorphonuclear granulocytes (PMN): Neutrophil, Eosinophil, Basophil - Mast cell

Cellular innate defenses in vertebrates also involve natural killer cells These cells circulate through the body and detect abnormal cells (cancer or virus-infected cells) They release chemicals leading to target cell death, inhibiting the spread of virally infected or cancerous cells

THE INFLAMMATORY RESPONSE Damage to tissue by a physical injury or by the entry of a microorganisms triggers a localized inflammatory response One of the chemical signals is histamine Histamine is released by circulating leukocytes called basophils and by mast cells in connective tissues

Cells of a tissue injured by physical damage or bacteria release chemical signals such as histamine and prostaglandin In response to the signals, nearby capillaries dilate and became more permeable. Fluid and clotting elements move from the blood to the site and clotting begins. Chemokines released by cells attract phagocytic cells from the blood Phagocytic cells absorbe pathogens and cell debris promoting tissue healing

Antimicrobial Peptides and Proteins Peptides and proteins function in the innate immune system by attacking pathogens or impeding their reproduction Interferon promotes innate defenses by interfering with virus reproduction and activating macrophages About 30 proteins make up the complement system, which causes lysis of invading cells and triggers inflammation

Inflammatory Responses The inflammatory response, such as pain and swelling, is brought about by molecules released upon injury or infection Mast cells release histamine, which triggers blood vessels to dilate and become more permeable Activated macrophages and neutrophils release cytokines, signaling molecules that enhance the immune response and induce fever

Inflammation can be either local or systemic (throughout the body) Fever is a systemic inflammatory response triggered by pyrogens released by macrophages and by toxins from pathogens Septic shock is a life-threatening condition caused by an overwhelming or unbalanced inflammatory response

Evasion of Innate Immunity by Pathogens Some pathogens avoid destruction by modifying their surface molecules to prevent recognition by the immune system or by resisting breakdown following phagocytosis

The lymphatic system

Peyer’s patches (small intestine) Lymphatic vessel Spleen Interstitial fluid Blood capillary Adenoid Tonsils Lymphatic vessels Thymus Lymphatic vessel Tissue cells Peyer’s patches (small intestine) Lymphatic vessel Spleen Figure 43.7 The human lymphatic system. Lymph nodes Appendix (cecum) Masses of defensive cells Lymph node

The various types of immune cells