Understanding the Understanding the Immune SystemImmune System

Andrew E Thompson MD Andrew E Thompson MD FRCPCFRCPCFellow in RheumatologyFellow in RheumatologyUniversity of British ColumbiaUniversity of British Columbia

OBJECTIVESOBJECTIVES General overview of the immune General overview of the immune

systemsystem Introduction to the principal of Introduction to the principal of

autoimmune diseaseautoimmune disease

Two Types of ImmunityTwo Types of Immunity Innate Innate

– ““possessed at birth, possessed as an possessed at birth, possessed as an essential characteristic”essential characteristic”

– Always presentAlways present AdaptiveAdaptive

– ““to make suitable to or fit to a to make suitable to or fit to a specific use or situation”specific use or situation”

– Created and modifiedCreated and modified

Innate ImmunityInnate Immunity Protection by Skin and Mucous Protection by Skin and Mucous

MembranesMembranes Phagocytic CellsPhagocytic Cells

– Remove debris (garbage men)Remove debris (garbage men)– Macrophages, Neutrophils, MonocytesMacrophages, Neutrophils, Monocytes

Natural Killer CellsNatural Killer Cells– Lymphocytes that kill virally infected cells Lymphocytes that kill virally infected cells

and tumoursand tumours Complement SystemComplement System

– ““complements antibody in the killing of complements antibody in the killing of bacteria”bacteria”

– A group of >30 proteins found in the blood A group of >30 proteins found in the blood

Types of White Blood Types of White Blood CellsCells There are 5 different types of WBCsThere are 5 different types of WBCs Neutrophils (60%)Neutrophils (60%)

– kill bacteriakill bacteria Eosinophils (2%)Eosinophils (2%)

– Allergic response Allergic response – Parasite killingParasite killing

Basophils (1%)Basophils (1%)– – Allergic reactionsAllergic reactions

Monocytes (4%)Monocytes (4%)– Become macrophagesBecome macrophages

Lymphocytes (33%)Lymphocytes (33%)– Direct the immune systemDirect the immune system

LymphocytesLymphocytes Two types of lymphocytesTwo types of lymphocytes

– T-CellsT-Cells (Thymus derived) (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-CellsB-Cells (Bone Marrow derived) (Bone Marrow derived)

Adaptive ImmunityAdaptive Immunity Two Components of Adaptive Two Components of Adaptive

Immune SystemImmune System Humoral (humoral mediated Humoral (humoral mediated

immunity)immunity)– B-CellsB-Cells Plasma Cells Plasma Cells Antibodies Antibodies

Cellular (cellular mediated immunity)Cellular (cellular mediated immunity)– CD8+ T-CellsCD8+ T-Cells Direct Cellular Killing Direct Cellular Killing– CD4+ T-CellsCD4+ T-Cells Recruitment of other Recruitment of other

immune cells (inflammatory response)immune cells (inflammatory response)

Immune Response Immune Response AntigenAntigen AntigenAntigen – “any substance when – “any substance when

introduced into the body stimulates introduced into the body stimulates the production of an antibody”the production of an antibody”– Bacteria, fungus, parasiteBacteria, fungus, parasite– Viral particlesViral particles– Other foreign materialOther foreign material

PathogenPathogen – an Antigen which – an Antigen which causes diseasecauses disease

Immune Response Immune Response AntibodiesAntibodies AntibodyAntibody – “a Y-shaped protein, – “a Y-shaped protein,

found on the surface of B-Cells or found on the surface of B-Cells or free in the blood, that neutralize free in the blood, that neutralize antigen by binding specifically to antigen by binding specifically to it”it”

Also known as an Also known as an ImmunoglobulinImmunoglobulin

Antigen

Humoral Mediated Humoral Mediated ImmunityImmunity

Cellular Mediated Cellular Mediated ImmunityImmunity

Via T-CellsVia T-Cells CD8CD8++ T-Cell T-Cell

– Stimulated Stimulated Direct Killing Direct Killing CD4CD4++ T-Cell T-Cell

– Th1 Th1 Stimulated Stimulated Macrophage Macrophage ActivationActivation

– Th2 Th2 Stimulated Stimulated B-Cell Activation B-Cell Activation

Remember B-Cells have direct Remember B-Cells have direct surface receptors surface receptors (immunoglobulins) for antigen!(immunoglobulins) for antigen!

T-Cells do not possess these T-Cells do not possess these receptorsreceptors

Instead, T-Cells need to have Instead, T-Cells need to have antigen presented to them (like on antigen presented to them (like on a silver platter)a silver platter)

Antigen is presented to T-Cells by Antigen is presented to T-Cells by … Antigen Presenting Cells… Antigen Presenting Cells

Cellular Mediated Cellular Mediated ImmunityImmunity

Cellular Mediated Cellular Mediated ImmunityImmunity Two Types of Antigen Presenting Cells Two Types of Antigen Presenting Cells

(APCs)(APCs)General General

APCAPCProfessional Professional

APCAPCAll CellsAll Cells B-Cells, Macrophages,B-Cells, Macrophages,

Dendritic Cells Dendritic Cells Present antigen found Present antigen found

inside the cellinside the cellPresent antigen found Present antigen found

outside the celloutside the cellUse an Use an MHC class IMHC class I molecule to present molecule to present

antigenantigen

Use an Use an MHC class IIMHC class II molecule to present molecule to present

antigenantigenInteract with Interact with CD8+ T-CD8+ T-

CellsCells Cellular KillingCellular Killing

Interact with Interact with CD4+ T-CD4+ T-CellsCells

T-Cell HelpT-Cell Help

General APCsGeneral APCs All cells in the body are always All cells in the body are always

“cleaning” themselves“cleaning” themselves When they find some “dirt” (viral When they find some “dirt” (viral

protein, normal cellular debris) protein, normal cellular debris) Need to make sure it is not Need to make sure it is not something harmfulsomething harmful

Attach the “dirt” to an MHC-I Attach the “dirt” to an MHC-I moleculemolecule

Present this “dirt” to a CD8Present this “dirt” to a CD8++ T-Cell T-Cell

General APCs & General APCs & CD8CD8++ T-Cells T-Cells

Professional APCsProfessional APCs

Professional APCs have the ability to Professional APCs have the ability to take up (endocytosis) extracellular take up (endocytosis) extracellular proteins (self or foreign)proteins (self or foreign)

Break down this protein into Break down this protein into peptides and attach it to an MHC-II peptides and attach it to an MHC-II moleculemolecule

Present the peptide to a CD4Present the peptide to a CD4++ T-Cell T-Cell

Professional APCsProfessional APCsCD4CD4++ Th1-Cells Th1-Cells

Professional APCProfessional APCCD4+ Th2-CellsCD4+ Th2-Cells

Summary of Adaptive Summary of Adaptive ImmunityImmunity Humoral Humoral

– Antibody Production – B-CellsAntibody Production – B-Cells CellularCellular

– CD8+ T-CellsCD8+ T-Cells MHC-I MHC-I CytotoxicCytotoxic– CD4+ Th1-CellsCD4+ Th1-Cells MHC-II MHC-II Activate Activate

MacrophagesMacrophages– CD4+ Th2-CellsCD4+ Th2-Cells MHC-II MHC-II Activate Activate

B-Cells to produce AntibodyB-Cells to produce Antibody

What Prevents the What Prevents the Body from Attacking Body from Attacking Itself?Itself? Two ConceptsTwo Concepts

– Central ToleranceCentral Tolerance– Peripheral TolerancePeripheral Tolerance

Central ToleranceCentral Tolerance Occurs during lymphocyte (T & B Cells) Occurs during lymphocyte (T & B Cells)

maturation in the primary lymphoid maturation in the primary lymphoid organs (thymus & bone marrow)organs (thymus & bone marrow)

The body presents immature The body presents immature lymphocytes with self-antigenlymphocytes with self-antigen

Lymphocytes which react with high Lymphocytes which react with high affinity to this self-antigen are deleted affinity to this self-antigen are deleted (apoptosis)(apoptosis)

Lymphocytes which react with low Lymphocytes which react with low affinity are positively selected to matureaffinity are positively selected to mature

Central ToleranceCentral Tolerance

Peripheral TolerancePeripheral Tolerance During maturation, lymphocytes cannot During maturation, lymphocytes cannot

be presented with every self-antigenbe presented with every self-antigen– Some antigens are found in low Some antigens are found in low

concentrations in specific locationsconcentrations in specific locations– New antigens are formed during lifeNew antigens are formed during life

Therefore, lymphocytes come in contact Therefore, lymphocytes come in contact with new antigenwith new antigen

Particular importance to the cytokine Particular importance to the cytokine environment present when lymphocytes environment present when lymphocytes encounter this new antigenencounter this new antigen

Rheumatoid Arthritis Rheumatoid Arthritis (RA)(RA) RA is thought to be RA is thought to be T-CellT-Cell mediated mediated Most widely accepted hypothesis:Most widely accepted hypothesis:

– Professional APC encounters some Professional APC encounters some “unknown” antigen“unknown” antigen

– It presents this “unknown” antigen to a It presents this “unknown” antigen to a CD4 T-helper CellCD4 T-helper Cell

– In a genetically predisposed individual, In a genetically predisposed individual, this starts an immune chain reactionthis starts an immune chain reaction

Mechanisms in Rheumatology ©2001

Click here to run the animation

Cellular components of synovial inflammationCellular components of synovial inflammation

Rheumatoid ArthritisRheumatoid Arthritis Certain cytokines are important in Certain cytokines are important in

driving the inflammatory process in driving the inflammatory process in RARA

Two important cytokines are Two important cytokines are – Tumour Necrosis Factor – alpha (TNF-Tumour Necrosis Factor – alpha (TNF-αα) ) – Interleukin-1 (IL-1)Interleukin-1 (IL-1)

Rheumatologists have developed new Rheumatologists have developed new medications which target these cytokinesmedications which target these cytokines

Rheumatoid ArthritisRheumatoid Arthritis

Drugs which inhibit TNF-Drugs which inhibit TNF-αα– Infliximab (Remicade®) – Chimeric Infliximab (Remicade®) – Chimeric

monoclonal antibody directed against monoclonal antibody directed against TNF-TNF-αα

– Etanercept (Enbrel®) – Soluble receptor Etanercept (Enbrel®) – Soluble receptor which “floats” around and mops up any which “floats” around and mops up any TNF-TNF-αα

Infliximab Infliximab (Remicade®)(Remicade®)

Mechanisms in Rheumatology ©2001

Infliximab: Mechanism of action Infliximab: Mechanism of action

Click here to run the animation

Etanercept (Enbrel®)Etanercept (Enbrel®)

Etanercept: Mechanism of actionEtanercept: Mechanism of action

Mechanisms in Rheumatology ©2001

Click here to run the animation

Ankylosing SpondylitisAnkylosing Spondylitis Up to 90% of white patients with Up to 90% of white patients with

AS are positive for HLA-B27AS are positive for HLA-B27 HLA-B27 is an MHC Class I HLA-B27 is an MHC Class I

moleculemolecule

HLA-HLA-B27B27

Ankylosing SpondylitisAnkylosing Spondylitis Remember – MHC is part of the Remember – MHC is part of the

adaptive immune system – so adaptive immune system – so everybody is differenteverybody is different

Those people with HLA-B27 type Those people with HLA-B27 type of MHC Class I are at higher risk of MHC Class I are at higher risk for developing ASfor developing AS

But Why?But Why?

Ankylosing SpondylitisAnkylosing Spondylitis The HLA-B27 molecule has a The HLA-B27 molecule has a

specific binding groove specific binding groove Only certain peptide fragments Only certain peptide fragments

will fit into this binding groovewill fit into this binding groove Big Question: What peptide Big Question: What peptide

fragment could be responsible for fragment could be responsible for the initiation of Ankylosing the initiation of Ankylosing Spondylitis?Spondylitis?

SummarySummary Innate and Adaptive ImmunityInnate and Adaptive Immunity B-CellsB-Cells

– Act as Professional APCs for Th2-CellsAct as Professional APCs for Th2-Cells– Turn into plasma cells and synthesize Turn into plasma cells and synthesize

antibodyantibody T-CellsT-Cells

– Natural Killer Cells – Innate ImmunityNatural Killer Cells – Innate Immunity

SummarySummary CD8 T-CellsCD8 T-Cells

– Interact with MHC Class I (any cell)Interact with MHC Class I (any cell)– Direct Cellular KillersDirect Cellular Killers

CD4 T-CellsCD4 T-Cells – Interact with MHC Class II Interact with MHC Class II

(professionals)(professionals)– Th1– Cellular activation - MacrophagesTh1– Cellular activation - Macrophages– Th2– B-Cells - AntibodyTh2– B-Cells - Antibody