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

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

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

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

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

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)

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)

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Infliximab (Remicade®)

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

Etanercept (Enbrel®)

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

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

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

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?

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?

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

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