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

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Presentation on theme: "Understanding the Immune System Andrew E Thompson MD FRCPC Fellow in Rheumatology University of British Columbia."— 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 General overview of the immune system Introduction to the principal of autoimmune disease Introduction to the principal of autoimmune disease

3 Two Types of Immunity Innate Innate –“possessed at birth, possessed as an essential characteristic” –Always present Adaptive 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 Protection by Skin and Mucous Membranes Phagocytic Cells Phagocytic Cells –Remove debris (garbage men) –Macrophages, Neutrophils, Monocytes Natural Killer Cells Natural Killer Cells –Lymphocytes that kill virally infected cells and tumours Complement System 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 There are 5 different types of WBCs Neutrophils (60%) Neutrophils (60%) –kill bacteria Eosinophils (2%) Eosinophils (2%) –Allergic response –Parasite killing Basophils (1%) Basophils (1%) – Allergic reactions Monocytes (4%) Monocytes (4%) –Become macrophages Lymphocytes (33%) Lymphocytes (33%) –Direct the immune system

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

7 Adaptive Immunity Two Components of Adaptive Immune System Two Components of Adaptive Immune System Humoral (humoral mediated immunity) Humoral (humoral mediated immunity) –B-Cells  Plasma Cells  Antibodies Cellular (cellular mediated immunity) 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” 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 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” 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 Also known as an Immunoglobulin Antigen

10 Humoral Mediated Immunity

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

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

13 Two Types of Antigen Presenting Cells (APCs) Two Types of Antigen Presenting Cells (APCs) GeneralAPCProfessionalAPC 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

14 General APCs All cells in the body are always “cleaning” themselves 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 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 Attach the “dirt” to an MHC-I molecule Present this “dirt” to a CD8 + T-Cell Present this “dirt” to a CD8 + T-Cell

15 General APCs & CD8 + T-Cells

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

17 Professional APCs CD4 + Th1-Cells

18 Professional APC CD4+ Th2-Cells

19 Summary of Adaptive Immunity Humoral Humoral –Antibody Production – B-Cells Cellular 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 Two Concepts –Central Tolerance –Peripheral Tolerance

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

22 Central Tolerance

23 Peripheral Tolerance During maturation, lymphocytes cannot be presented with every self-antigen 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 Therefore, lymphocytes come in contact with new antigen Particular importance to the cytokine environment present when lymphocytes encounter this 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 RA is thought to be T-Cell mediated Most widely accepted hypothesis: 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 Mechanisms in Rheumatology ©2001 Click here to run the animation Cellular components of synovial inflammation

26 Rheumatoid Arthritis Certain cytokines are important in driving the inflammatory process in RA Certain cytokines are important in driving the inflammatory process in RA Two important cytokines are Two important cytokines are –Tumour Necrosis Factor – alpha (TNF- α) –Interleukin-1 (IL-1) Rheumatologists have developed new medications which target these cytokines Rheumatologists have developed new medications which target these cytokines

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28 Rheumatoid Arthritis Drugs which inhibit TNF- α 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 Mechanisms in Rheumatology ©2001 Infliximab: Mechanism of action Click here to run the animation

31 Etanercept (Enbrel®)

32 Etanercept: Mechanism of action Mechanisms in Rheumatology ©2001 Click here to run the animation

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

35 HLA-B27

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

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

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

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


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