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 – “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
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
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
Cellular Mediated Immunity
TwoGeneral Types of Antigen Presenting Professional Cells (APCs)APC APC All Cells
Present antigen found inside the cell Use an MHC class I molecule to present antigen Interact with CD8+ T-Cells Cellular Killing
B-Cells, Macrophages, Dendritic Cells Present antigen found outside the cell Use an MHC class II molecule to present antigen Interact with CD4+ T-Cells T-Cell Help
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
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
Professional APC CD4+ Th2-Cells
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
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
Click here to run the animation
Mechanisms in Rheumatology Š2001
Rheumatoid Arthritis
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速)
Infliximab: Mechanism of action
Click here to run the animation Mechanisms in Rheumatology Š2001
Etanercept (Enbrel速)
Etanercept: Mechanism of action
Click here to run the animation Mechanisms in Rheumatology Š2001
Ankylosing Spondylitis
Up to 90% of white patients with AS are positive for HLA-B27 HLA-B27 is an MHC Class I molecule
HLA-B27
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 – 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 – 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