Macrophage Activation & Cytokine Release. Dendritic Cells & Antigen Presentation. Neutrophils & Innate Defense

Transcription

1 Macrophage Activation & Cytokine Release Dendritic Cells & Antigen Presentation Neutrophils & Innate Defense Neutrophils Polymorphonuclear cells (PMNs) are recruited to the site of infection where they phagocytose invading organisms and kill them intracellularly. In addition, PMNs contribute to collateral tissue damage that occurs during inflammation.

2 Antigen Presenting Cells (APCs) Vascular Permeability The production of increased vascular permeability during inflammation. The presence of prostaglandins, leukotrienes, and histamine causes cells lining venules to pull apart, allowing phagocytes to leave the bloodstream and more easily reach a site of infection. The leakage of fluid and cells causes the edema and pain associated with inflammation Pearson Education, Inc., publishing as Benjamin Cummings An Overview of Inflammation 2008 Pearson Education, Inc., publishing as Benjamin Cummings

3 Production of fever in response to infection 2008 Pearson Education, Inc., publishing as Benjamin Cummings Innate Immune Response! "Antigen-presenting cells (APCs) are activated through pathogen-associated molecular pattern (or PAMPs) by receptors such as TLRs.! "This activation leads to the production of inflammatory cytokines and the expression of co-stimulatory molecules on the cell surface. Pattern recognition receptors - PRRs

4 Mammalian TLR family members & their respective ligands Interplay of Innate & Adaptive Immune Systems

5 Lecture 3: B Cells and Antibodies *FIRST - Finish up on Innate Immunity: Complement System Michele Klingbeil 2 Lecture Objectives - Complement Understand different pathways of C activation Know complement proteins (nomenclature) Know the enzymatic and non-enzymatic mechanisms of complement activation 3 Complement Functions Historically, complement referred to a heat-labile serum component that could lyse bacteria Host benefit: opsonization to enhance phagocytosis phagocyte attraction and activation lysis of bacteria and infected cells regulation of antibody responses clearance of immune complexes clearance of apoptotic cells Host detriment: Inflammation, anaphylaxis 1

6 4 Complement Pathways 5 The Complement System More than 20 serum proteins involved Some components bind to antibody Some components bind to membranes Zymogen cleavage cascade - activation C3 most important - most abundant! 6 Classical Complement Pathway 2

7 7 Classical Complement Pathway See animations at website 8 Mannose Binding Lectin Pathway Mannose containing Polysaccharides Similar to Classical Pathway 9 The Membrane Attack Complex 3

8 10 Terminal Pathway (Lytic Attack) Regulatory Proteins of Complement Pathways 11 Natural Killer Cells 12 Bone marrow Lymphocyte lineage Normal cells are not killed because inhibitory signals from MHC class I molecules override activating signals In tumor cells or virus-infected cells, reduced expression or alteration of MHC molecules interrupts the inhibitory signals, allowing activation of NK cells and lysis of target cells. 4

9 13 Natural Killer Cells 14 Innate Immunity to Viral Infections 15 Timing of innate immunity after infection Barriers Seconds Neutrophils Hours Short-lived Epithelial activation - Complement - Cytokines/chemokines Minutes to days Minutes Minutes Monocytes/macrophages Hours to days NK cells Hours to days Long-lived & connect with adaptive immune system 5

10 16 Summary of Immune Response Immune System Anatomical Barriers Innate (Nonspecific) 1 o line of defense Adaptive (Specific) 2 o line of defense Protects/re-exposure Cellular Components Humoral Components Cellular Components Humoral Components 17 Lecture Objectives: B Cells & Antibodies Discuss the general properties of all immunoglobulins Describe the basic structure of immunoglobulins Relate immunoglobulin structure with function Define immunoglobulin hypervariable and framework regions Define immunoglobulin classes and subclasses 18 Adaptive Immunity Immunity established to adapt to infection Learnt by experience Confers pathogen-specific immunity Enhanced by second exposure Has memory Uses cellular and humoral components Is poorly effective without innate immunity Antibodies reflect infections to which an individual has been exposed: diagnostic for infection 6

11 B Cell Maturation & VDJ Rearrangement 19 Immunoglobulin Diversity 20 When a stem cell changes to become a B cell, DNA segments for both heavy (VDJ) and light (VJ) Immunoglobulin chains are randomly combined. Each B cell ends up with functional genes for making one light and one heavy chain coding for an antibody as a membrane-bound receptor Antibody specificity depends on the gene fragments used. Antibodies are produced that can react with almost any chemical structure in nature, including our own proteins Imprecise recombination and mutation increase the variability into billions of possible combinations Immunoglobulin (Antibody) Structure 21 The basic IgG Ab molecule has a MW of ~150kDa These Abs have a basic structure of 4 peptide chains There are 2 identical light (L) chains ~25kDa There are also 2 identical heavy (H) chains, polypeptides of ~50kDa Each L chain is bound to a H chain by a S-S- and non-covalent interactions (salt linkages, hydrogen bonds and hydrophobic bonds forming a heterodimer Similar S-S- and non-covalent interactions link the identical H-L combinations together to form a complete molecule, a dimer of dimers 7

12 22 Immunoglobulin Fragments Ag Binding Binding to Fc Receptors Complement Binding Site Placental Transfer 23 Immunoglobulin regions Heavy & Light Chains Disulfide bonds Inter-chain Intra-chain Variable & Constant Regions V L & C L V H & C H Hinge Region V L Disulfide bond Carbohydrate C L C C H2 C H3 H1 Hinge Region V H 24 Antibodies and Epitopes 8

13 25 B Cell Response to Antigen 26 B Cell Receptor 2 major parts External Immunoglobulin Specificty for antigen Short cytoplasmic tail - no direct signaling Internal Ig!/Ig" dimer - cytoplasmic tail for intracellular signaling Responder to what mig sees. Other important components (not essential for exam) B Cell Receptor - Additional Complexity 27 CD45 CD21 (C3d receptor) CD19 Ig" Ig! CD81 (TAPA-1) The B cell co-receptor 9

14 28 B Cell Receptor Complex Signaling Concept of complex signaling pathways involved: Do not try to memorize all these pathways! 29 Antibody Isotypes 30 Ig Isotype Functions 10

15 31 Ig Isotype Distribution 32 Cytokine Regulation of Ig Isotypes 33 Humoral Immune Response 11

16 34 Amazing Immunoglobin Diversity 12