No Slide Title...chemotaxis for neutrophils (extravasation) IL-12: acts with IL-2 in T cell...
Transcript of No Slide Title...chemotaxis for neutrophils (extravasation) IL-12: acts with IL-2 in T cell...
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OPTO 5344
Physiology & Molecular Biology
Immunology
Rachel Redfern, OD, PhD, FAAO
Rm. 244 HBSB
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Reading
Chapter 3 “Immunopathology” in Pathology for the Health-Related Professions by Damjanov
“Immunology”5th Edition, by Riott, Brostoff, Male
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Overview
1. Introduction to the Immune Response2. Cells of the Immune Response3. Primary vs Secondary Lymphoid Tissue4. B cells and Humoral Immunity5. T cells and Cell Mediated Immunity6. Natural Killer (NK) cells7. Complement8. Overview of Immunity9. Immunization
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Discovery of Immunology
• Milk maids would get cow pox from a virus in cow utters
• Milk maids had mild symptoms
• English Physician Edward Jenner observed a protection from small pox in milk maids
• Small pox is caused by pox virus with severe symptoms…
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• Very prevalent in 1700s• Multiple pocks over
entire body
• 10% adult deaths
• 1/3 child deaths
Small Pox
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Jenner’s Provocative Experiment
• Then collected material from cowpox vesicles and injected it James Phipps
• 6 weeks later Phipps was inoculated with small pox and never succumbed to the disease
First vaccine
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Discovery of Immunology
• Vaccination derived from latin word “vacca”
• Extensive vaccinations started 1967
• Small pox officially declared eradicated in 1980s by World Health Organization
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‘immunis’ - free or exempt
Exempt from or protected against somethingdisagreeable or harmful; not susceptible to aspecific disease
To achieve protection:1.) Innate or non-acquired response
-Nonspecific
2.) Acquired or adaptive response-T and B lymphocytes-Memory! Rapid/Robust response!
Introduction
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Innate Immune Response
Non-specific response
Does not improve on subsequent exposures
First line of defense
Four components:1. Physical barriers2. Physiological barriers3. Vascular system4. Phagocytic component
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Physical barriers• Tightly packed
together epithelial cells
• Keratin in skin=waterproof
• Epithelial shedding
• Mucus coat
Innate Immune Response
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Innate Immune Response
Physiological barriers• Fever: ↓ viral
replication• Low pH: ↓ microbes• Cough/sneeze• Blinking• Commensals• Antimicrobial
molecules• Interferon α/β
• ↓infection in neighbor cells
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Interferon
• Released from virus-infected cells
• IFN binds to surface receptors on neighbor cells
• Inducing uninfected cells to synthesize antiviral proteins that interfere with or inhibit viral replication
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Cytokines
Interleukins• Soluble molecules that
mediate interactions between cells
• IL-1 and IL-6: induces fever; ↑immune responseIL-8: chemotaxis for neutrophils (extravasation)IL-12: acts with IL-2 in T cell maturation
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Lysozyme
Lyzozyme• Tears, saliva, in
granules of neutrophils
• Degrades cell wall
• Gram + bacteria succumbs to osmotic gradient
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• Penetration=acute inflammatory response
• Increased vascular permeability
• Phagocytic cells recruited from the blood to remove invading pathogens
Vascular/Phagocytic
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Pathogen Recognition
• Latin “opsono”: to prepare food for…YUM!
• Host derived opsonins
1. Complement fragments (C3b) bind to C3b receptor on immune cells
2. Antibodies bind Fc receptor on immune cells…Note antibodes are part of the adaptive immune response!
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Pathogen Recognition
PRRPAMP
Opsonin
Recognizes pathogen associated molecular patterns (PAMP) on microbes
• LPS• Flagellin
Pattern recognition receptors (PRR)
• Mannose receptors: sugar on pathogens → phagocytosis
• CD14• Toll-like Receptors (TLR)
pathogen pathogen
What is an opsonin?1. C3b2. Antibodies
Immune Cell
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Innate Immune Response
• Jules Hoffman for initial discoveries of Toll-like Receptors (TLR) in drosophila
• Bruce Beutler identified TLR4, the first mammalian TLR
Beutler Hoffman
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• Stimulates the production of cytokines, chemokines and antimicrobial peptides
• Pattern Recognition Receptor
• Alert the immune system of infection
• Kill pathogens
Redfern and McDermott, Experimental Eye Research, 2010, 90, 679-87
Toll-like Receptors
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Innate Immune Response: Review
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Acquired Immune Response
• Pathogen specific
• Improves on subsequent exposure i.e. memory
•Antigen (immunogen): something that induces immune response
•Hapten: too small for immune response unless attached to larger molecule
•Epitope: 3D molecular arrangement on antigen recognized by immune system
TX size microbe antigen epitopes
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• Mediated by lymphocytes: white blood cells
• B lymphocytes (B cells) produce/secrete antibody• Humoral immunity of fluid
• T lymphocytes (T cells) help B lymphocytes (B cells) produce antibody and help destroy organism/infected cells • Cell mediated immunity
• Memory cells
Acquired Immune Response
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• Granulocytes
• Platelets
• Mononuclear Cells
• Dendritic Cells
• Lymphocytes
Cells of The Immune Response
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Cells of The Immune Response
• All cells derived from Haematopoeitic stem cell (Bone Marrow)
• divide and into different lineages
• “colony stimulating factors” regulate the production of these cells
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Cells of The Immune Response
IL-7
IL-3
Mono-CSF
• IL-3 (multi-colony stimulating factor): either lineage
• IL-7: lymphoid cells
• Granulocyte- monocyte CSF
• Monocyte CSF
• Granulocyte CSF
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Granulocytes In Innate Immune Response
Neutrophils
Eosinophils
• In general, granulocytes…
• Produced in the bone marrow (7mill/min)
• 50 billion in circulation
• Life: 2-3 days
Basophils(and mast cells)
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Granulocytes In Innate Immune Response
Neutrophils
Eosinophils
Basophils(and mast cells)
Neutrophils• 95% of circulating granulocytes• Multilobes nucleus (2-3)• PMN• 10-20µm across• Migrate rapidly to site of infection (C5a)• Phagocytose and destroy foreign
organisms• Myeloperoxidase (MPO) and lysozyme
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Granulocytes in Innate Immune Response
• Neutrophil recognizes pathogen• PRR• Opsonins:C3b or antibodies
• Stimulates phagocytosis
• Reactive oxygen species and lysosomes enzymes, kill the pathogen
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Granulocytes In Innate Immune Response
Neutrophils
Eosinophils
Eosinophils• Bilobed nucleus• Mix of large and small granules• 2-5% WBC• Most reside in connective tissue• Activated by IL-5 (secreted at infection site) • Phagocytosis of bacteria • Main function is binding to Ig coated
parasites that can not be phagocytosed• Produce major basic protein
• TOXIC!Basophils
(and mast cells)
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Granulocytes In Innate Immune Response
Neutrophils
Eosinophils
Basophils• 0.2% WBC• Most reside in blood stream• Mast cells are equivalent in tissue• Produced/mature in the bone marrow→ circulation → infection site
• Release histamine• Allergen must cross link IgE
molecules bound to its surfaceBasophils
(and mast cells)
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Granulocytes In Innate Immune Response
Neutrophils
Eosinophils
Mast cells• Produced in bone marrow and
mature in various sites of the body• Release histamine
• Mucosal mast cell• Connective tissue mast cells
Basophils(and mast cells)
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Platelets
• Blood clotting (AKA thrombocytes)
• Involved in inflammation
• Adhere to endothelial surface of damaged blood vessel and release factors to: • ↑ capillary permeability• ↑ leukocyte recruitment
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Cells of The Immune Response
• Granulocytes
• Platelets
• Mononuclear Cells
• Dendritic Cells
• Lymphocytes
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Mononuclear Phagocytes CSF
• Monocyte to Macrophages (BIG!)(Blood) (tissue)
• Largest in size of the circulating WBC • Capable of phagocytosis• 2-8%• Horse shoe nucleus• Macrophages names vary on location
• Kupffer Cells in Liver• Microglia in Brain
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Mononuclear Phagocytes
Innate Immune Response• Phagocytosis = destroying pathogens
• Release factors chemoattractive for other immune cells to boost immune response
• Release leukotrienes and prostaglandins to increase vascular permeability/ cell recruitment (BURNS lecture)
Acquired Immune Response• Antigen presenting cells (APCs)
- present antigen to T cells
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Mononuclear Phagocytes: Acquired Immune Response
• Macrophage digests pathogen
• Some antigens are saved on MHC
• APC to secondary lymphoid tissue activates T cell that recognizes the antigen to generate an immune response
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Major Histocompatibility Complex (MHC)
• AKA Human Leukocyte Antigens (1st discovered in WBC)
• Class I on ALL nucleated cells
• Class I and II on antigen presenting cells (APCs)•APC: Mononuclear cells, B cells, BV endothelial cells, dendritic cells
• Binding pockets for proteinNormal - filled with self-proteinInfection - filled with antigen from invading organism
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Major Histocompatibility Complex (MHC)
MHC I• Single α chain +• β 2 microglobulin
MHC II• 2 chains: α/β
• Specific T-cell will recognize specific “foreign” antigen in MHC molecule and stimulate an immune response
MHC I MHC II
Unique to APC