Introduction

Introduction

Smallpox Eradication

THE IMMUNE SYSTEM The Invaders The Defender

Overview of the Immune System

Overview of your immune system • First line of defense: Physical barriers that viruses, bacteria must cross • skin covers ~2 m2 • Mucous membranes that line digestive, respiratory, reproductive tracts cover ~400 m2 • Second line of defense: Innate immune system (germline-encoded receptors -- no adaptation to specific pathogens) • Macrophages (Greek for “big eater”), neutrophils, natural killer (NK) cells • Cytokines -- hormone-like proteins that mediate inflammation, Complement proteins • Third line of defense (vertebrates only): Adaptive immune system (adapts to defend against specific pathogens using variable receptors) • B cells make antibodies that vary -- can make an antibody specific for any new antigen • T cells mediate cellular responses using variable receptors (T cell receptors; TCRs)

COMPONENTS OF THE IMMUNE SYSTEM Cellular components of the immune system Lymphocytes Granulocytes Others Phagocytes B-cell Mononuclear phagocyte Basophil Platelets T-cell Neurtrophil Mast cell Large granular lymphocyte Eosinophil Antibodies Cytokines Complement Inflammatory mediators Soluble mediators of the immune system

Immune cells and other blood cells made in bone marrow -- all are descendents of self-renewing stem cells Make variable antibodies Membrane-bound variable T cell receptors Kill cells that are missing self proteins Phagocyte Phagocyte Note these are adult stem cells, NOT embryonic stem cells. p. 4 “How the Immune System Works” by Lauren Sompayrac

Innate Immunity • Initial response to microbes • Stimulates adaptive immune response • Components are directed by adaptive immune response to remove foreign material

The innate immune system responds more quickly than adaptive immune system.Why is a quick response important? • Starting with one bacterium that doubles every thirty minutes --> 100 x 1012 bacteria in one day • 100 x 1012 bacteria equivalent to ~100 liters of a dense culture • Total volume of blood in human ~5 liters • VERY important to check a bacterial infection quickly!

Three components of the innate immune system • Phagocytes (cells) (e.g., macrophages) • Complement proteins • Natural killer (NK) cells Innate immune receptors recognize features common to many pathogens. Receptors are employed by all cells of a given cell type. Response does not lead to immunological memory. Adaptive immune receptors are antigen specific. Antigen receptors of adaptive immune system are clonally distributed on individual lymphocytes. Response can lead to immunological memory.

Macrophages can engulf and digest bacteria Macrophage about to eat a bacterium http://www.biochemweb.org/neutrophil.shtml p. 4 “How the Immune System Works” by Lauren Sompayrac

Question Which component of bacteria serves as a very potent stimulant of the innate immune system? Ribosomes Proteins Carbohydrates DNA RNA Plasmids

Question Carbohydrates on viruses strongly activate the innate immune system. True False

Complement system • Ancient system (found in invertebrates such as sea urchins) • ~20 different proteins that work together to destroy invaders and recruit immune cells • Activated three different ways • “Classical” pathway: by antibodies bound to pathogen (vertebrates only) • “Alternative” pathway: by bacterial surfaces • Lectin activation pathway: by binding of mannose-binding lectin (MBL) to yeast, bacteria, parasites or viruses (e.g., HIV) • Activation of complement system is tightly regulated because end results can be dangerous

Figure 2-18 The three pathways of complement activation converge Combination of adaptive and innate immune responses Innate immunity Innate immunity

Figure 2-11 Binding of mannose-binding lectin, a plasma protein, initiates lectin pathway of complement activation. MBL discriminates self carbohydrates from non-self carbohydrates by recognition of a particular pattern of sugar residues

Figure 2-35 part 3 of 3 One of the end results of complement activation -- the membrane attack complex kills a cell Electron micrographs of ~100 Å diameter membrane attack complex channels

Laboratory uses of complement:isolate one population of cells by killing off another population Example: Have mixture CD4 T-cells and CD8 T-cells Want only CD8 T-cells Add anti-CD4 antibody to mixture of T cells. It binds. Now add complement, and CD4 T-cells will be killed, leaving you with CD8 T-cells only.

Question Which type of pathogen is easier for the innate immune system to deal with: bacteria or viruses? 1) Bacteria 2) Viruses

So far, we’ve talked only about active recognition of features of pathogens… But pathogens have also developed ways to remove some of the cell’s critical proteins, often so that they can escape detection by the immune system. For example, in the adaptive immune system, T lymphocytes (T cells) recognize viral fragments (peptides) bound to MHC proteins. It’s hard for a virus to hide out in a cell if the cell surface MHC proteins contain viral fragments that can be recognized by T cells. What’s a virus to do? Get rid of the host MHC proteins!

For every strategy a virus comes up with, the immune system (usually) has an answer… Natural killer cells recognize cells that do not express adequate levels of MHC proteins on their surface. They respond to “missing self”.

Natural killer (NK) cells • Can kill tumor cells, virus-infected cells, bacteria, parasites, fungi in tissues • Identify targets based on “missing self” • Two types of NK receptors: inhibitory and activating • If inhibitory receptor recognizes a self protein (a class I MHC molecule) on a target cell, the NK cell is turned OFF even if activating receptor binds a ligand on the same target cell • If activating receptor binds a ligand, but inhibitory receptor does not (target cell has down-regulated class I MHC proteins), NK cells kill • Many virally-infected cells and tumor cells down-regulate expression of class I MHC molecules (NK cells important for preventing cancers)

The immune cells we’re talking about are called white blood cells. This means they are in the ____.How do they get to a site of infection?

Figure 1-7

Antibody Secretion Activation of T and B cells, Macrophages, Inflammation Target Cell Lysis Figure 1-5

Phases of Adaptive Immune Responses • Recognition • Activation • Effector • Homeostasis

Figure 1-10

Activation

Figure 2-13

Figure 2-14

Figure 2-16

Figure 2-18

Figure 2-19

Figure 2-20

Antigens

Figure 3-4

Figure 3-8

Introduction

Introduction

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INTRODUCTION/ INTRODUCTION

Introduction

INTRODUCTION

Introduction

Introduction