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Understanding the Immune System

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Presentation on theme: "Understanding the Immune System"— Presentation transcript:

1 Understanding the Immune System
Andrew E Thompson MD FRCPC Fellow in Rheumatology University of British Columbia

2 OBJECTIVES General overview of the immune system
Introduction to the principal of autoimmune disease

3 Two Types of Immunity Innate Adaptive
“possessed at birth, possessed as an essential characteristic” Always present Adaptive “to make suitable to or fit to a specific use or situation” Created and modified

4 Innate Immunity Protection by Skin and Mucous Membranes
Phagocytic Cells Remove debris (garbage men) Macrophages, Neutrophils, Monocytes Natural Killer Cells Lymphocytes that kill virally infected cells and tumours Complement System “complements antibody in the killing of bacteria” A group of >30 proteins found in the blood

5 Types of White Blood Cells
There are 5 different types of WBCs Neutrophils (60%) kill bacteria Eosinophils (2%) Allergic response Parasite killing Basophils (1%) – Allergic reactions Monocytes (4%) Become macrophages Lymphocytes (33%) Direct the immune system

6 Lymphocytes Two types of lymphocytes T-Cells (Thymus derived)
Natural Killer Cells (Innate Immunity) CD4+ T-Cells (helper cells) CD8+ T-Cells (cytotoxic cells) B-Cells (Bone Marrow derived)

7 Adaptive Immunity Two Components of Adaptive Immune System
Humoral (humoral mediated immunity) B-Cells  Plasma Cells  Antibodies Cellular (cellular mediated immunity) CD8+ T-Cells  Direct Cellular Killing CD4+ T-Cells  Recruitment of other immune cells (inflammatory response)

8 Immune Response Antigen
Antigen – “any substance when introduced into the body stimulates the production of an antibody” Bacteria, fungus, parasite Viral particles Other foreign material Pathogen – an Antigen which causes disease

9 Immune Response Antibodies
Antibody – “a Y-shaped protein, found on the surface of B-Cells or free in the blood, that neutralize antigen by binding specifically to it” Also known as an Immunoglobulin Antigen

10 Humoral Mediated Immunity
T-Cell Cytokines Plasma Cell B-Cell

11 Cellular Mediated Immunity
Via T-Cells CD8+ T-Cell Stimulated  Direct Killing CD4+ T-Cell Th1  Stimulated  Macrophage Activation Th2  Stimulated  B-Cell Activation

12 Cellular Mediated Immunity
B-Cell T-Cell Remember B-Cells have direct surface receptors (immunoglobulins) for antigen! T-Cells do not possess these receptors Instead, T-Cells need to have antigen presented to them (like on a silver platter) Antigen is presented to T-Cells by … Antigen Presenting Cells B-Cell

13 Cellular Mediated Immunity
General APC Professional All Cells B-Cells, Macrophages, Dendritic Cells Present antigen found inside the cell Present antigen found outside the cell Use an MHC class I molecule to present antigen Use an MHC class II molecule to present antigen Interact with CD8+ T-Cells  Cellular Killing Interact with CD4+ T-Cells T-Cell Help Two Types of Antigen Presenting Cells (APCs)

14 General APCs All cells in the body are always “cleaning” themselves
When they find some “dirt” (viral protein, normal cellular debris)  Need to make sure it is not something harmful Attach the “dirt” to an MHC-I molecule Present this “dirt” to a CD8+ T-Cell

15 General APCs & CD8+ T-Cells
Cytotoxins T-Cell Receptor Fas ligand Any Cell Fas Protein Protease Peptides MHC-Class I

16 Professional APCs Professional APCs have the ability to take up (endocytosis) extracellular proteins (self or foreign) Break down this protein into peptides and attach it to an MHC-II molecule Present the peptide to a CD4+ T-Cell

17 Professional APCs CD4+ Th1-Cells
IL-2 Protein IFN-gamma Macrophage TNF-alpha

18 Professional APC CD4+ Th2-Cells
IL-5, IL-6, IL-10 Th2-Cell IL-4 Plasma Cell B-Cell

19 Summary of Adaptive Immunity
Humoral Antibody Production – B-Cells Cellular CD8+ T-Cells  MHC-I  Cytotoxic CD4+ Th1-Cells  MHC-II  Activate Macrophages CD4+ Th2-Cells  MHC-II  Activate B-Cells to produce Antibody

20 What Prevents the Body from Attacking Itself?
Two Concepts Central Tolerance Peripheral Tolerance

21 Central Tolerance Occurs during lymphocyte (T & B Cells) maturation in the primary lymphoid organs (thymus & bone marrow) The body presents immature lymphocytes with self-antigen Lymphocytes which react with high affinity to this self-antigen are deleted (apoptosis) Lymphocytes which react with low affinity are positively selected to mature

22 Central Tolerance Immature Positive Selection Lymphocyte Self-Antigen
Dendritic Cell (Professional APC) Self-Antigen Immature Lymphocyte Negative Selection

23 Peripheral Tolerance During maturation, lymphocytes cannot be presented with every self-antigen Some antigens are found in low concentrations in specific locations New antigens are formed during life Therefore, lymphocytes come in contact with new antigen Particular importance to the cytokine environment present when lymphocytes encounter this new antigen

24 Rheumatoid Arthritis (RA)
RA is thought to be T-Cell mediated Most widely accepted hypothesis: Professional APC encounters some “unknown” antigen It presents this “unknown” antigen to a CD4 T-helper Cell In a genetically predisposed individual, this starts an immune chain reaction

25 Cellular components of synovial inflammation
Rheumatoid Arthritis by Boulos Haraoui & Edward Keystone 5-2 (animation) Click here to run the animation Mechanisms in Rheumatology ©2001

26 Rheumatoid Arthritis Cytokine: A large family of low molecular weight
soluble proteins involved in regulating cellular activity within the immune system Certain cytokines are important in driving the inflammatory process in RA Two important cytokines are Tumour Necrosis Factor – alpha (TNF-α) Interleukin-1 (IL-1) Rheumatologists have developed new medications which target these cytokines


28 Rheumatoid Arthritis Drugs which inhibit TNF-α
Infliximab (Remicade®) – Chimeric monoclonal antibody directed against TNF-α Etanercept (Enbrel®) – Soluble receptor which “floats” around and mops up any TNF-α

29 Infliximab (Remicade®)

30 Infliximab: Mechanism of action
Biologic Agents by Edward Keystone 23-2 (animation) Click here to run the animation Mechanisms in Rheumatology ©2001

31 Etanercept (Enbrel®)

32 Etanercept: Mechanism of action
Biologic Agents by Edward Keystone 23-3 (animation) Click here to run the animation Mechanisms in Rheumatology ©2001


34 Ankylosing Spondylitis
Up to 90% of white patients with AS are positive for HLA-B27 HLA-B27 is an MHC Class I molecule

35 CD8+ T-Cell HLA-B27 Any Cell Peptides MHC-Class I

36 Ankylosing Spondylitis
Remember – MHC is part of the adaptive immune system – so everybody is different Those people with HLA-B27 type of MHC Class I are at higher risk for developing AS But Why?

37 Ankylosing Spondylitis
The HLA-B27 molecule has a specific binding groove Only certain peptide fragments will fit into this binding groove Big Question: What peptide fragment could be responsible for the initiation of Ankylosing Spondylitis?

38 Summary Innate and Adaptive Immunity B-Cells T-Cells
Act as Professional APCs for Th2-Cells Turn into plasma cells and synthesize antibody T-Cells Natural Killer Cells – Innate Immunity

39 Summary CD8 T-Cells CD4 T-Cells Interact with MHC Class I (any cell)
Direct Cellular Killers CD4 T-Cells Interact with MHC Class II (professionals) Th1– Cellular activation - Macrophages Th2– B-Cells - Antibody

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