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