1. IMMUN441 Week 9 AC Quiz Section
Autoimmunity
Transplantation

2. Announcements Final Exam Wednesday Dec. 14th
8:30-10:20 in room T-435
Covers lectures 17-26
Final Exam Review Tuesday Dec. 13th
10:30-12:20 in room T-733
Complete your course evaluations
Extra 0.1 added to your GPA

3. Zero or little amount of Ag Zero or little amount of Ag
mTEC
MHC II
CENTRAL TOLERANCE
Thymus
Naïve T cell
TCR
High amount of Ag
Deletion
High avidity
mTEC
High affinity TCR
Zero or little amount of Ag
Escape
Low avidity
mTEC
MHC II
High amount of Ag
Escape
Naïve T cell
TCR
Low avidity
mTEC
Low avidity
Low affinity TCR
Zero or little amount of Ag
Deletion

4. AIRE induces tissue-restricted antigen expression to aid central tolerance
Answers question of how developing T cells see localized self antigen?

5. Recessive Peripheral Tolerance Dominant Peripheral Tolerance
Vs.
Dominant Peripheral Tolerance
Non-inflammatory Environment
mTEC
MHC II
T cell
TCR
APC No
costimulatory signals
Cell Type:
regulatory T Cell
High amount
of Ag
No Ag
TCR specific for what type of Antigen?
Self-Antigen
Intermediate Ag
Effector Function?
Inhibition of other self-reactive T cells via cytokine secretion (IL-10, TGFβ)
Ignorance
Deletion
Anergy
TCR downregulation
TCR
2 Types of Regulatory
T Cells
Inflammatory Environment
T cell
TCR
APC expressing enhanced
costimulatory signals
Type :
Natural Tregs
Type:
Inducible Tregs
Location of Development:
Location of Development:
Thymus
Periphery (post-Ag encounter)
Autoimmunity

6. Mechanisms of dominant tolerance by regulatory T cells

7. Escape of self-reactive lymphocytes from central and peripheral tolerance mechanisms can lead to autoimmunity
mTEC
MHC II
TCR
Treg
Naïve T cell
TCR
T cell
TCR
APC
THYMUS
PERIPHERY
Autoreactive effector T cells
Tissue-specific (T1D) or systemic (SLE)
Any tissue could be a potential target
Involves loss of B cell and/or T cell tolerance
Autoantibodies
Self-reactive T cells

8. Autoantibodies can induce diverse pathology
Activation of cell surface receptors (Graves’ disease)
Cell depletion (autoimmune hemoytic anemia)
Inhibition of cell surface receptors
(myasthenia gravis)
Formation of immune complexes (Systemic lupus erythematosus)

9. Intermediate interaction
Environmental triggers of autoimmune disease
Infection can potentially trigger autoimmunity through multiple mechanisms:
Activation of the innate immune system leads to presentation of self-antigens in more immunogenic context
Non-inflammatory
Low levels of MHC, CD40, CD80, CD86
Weak interaction
What’s a physical way to trigger autoimmune disease?
Intermediate interaction
Strong signal
Deletion or iTreg generation
Ignorance
Anergy
↓ TCR/Co-receptor

10. Environmental triggers of autoimmune disease
Infection can potentially trigger autoimmunity through multiple mechanisms:
Activation of the innate immune system leads to presentation of self-antigens in more immunogenic context
Infection
Co-stimulatory molecules, inflammatory cytokines
Autoimmunity
Genes involved in regulation/activation of innate immune system are associated with some autoimmune diseases – e.g. NOD2/Crohn’s disease

11. Breaking tolerance via viral infection – changing the context of antigen presentation can result autoimmunity
Tolerance broken by physical damage

12. Rheumatoid Arthritis:
T-cell mediated autoimmune disease affecting joints
Clinical Intervention:
TNFα blockade using a monoclonal antibody

13. Myasthenia Gravis Clinical Intervention:
Autoantibodies cause degradation of acetylcholine receptors, preventing Na+ influx and muscle contraction
Weakness of the eyelid muscles, often the first symptom of the disease
Autoantibodies can be transferred across the placenta to the fetus and newborn infant
Clinical Intervention:
drugs to inhibit acetylcholinesterases, the enzyme that degrades acetylcholine
thymectomy

14. CD8 T-cells destroy insulin-producing β cells of the pancreatic islets
Type-1 Diabetes:
CD8 T-cells destroy insulin-producing β cells of the pancreatic islets
Clinical Intervention:
Monoclonal antibody for CD3 to deplete effector T cells while preserving regulatory T cells.
Commonly known as “juvenile diabetes”

15. Systemic Lupus Erythematosus (SLE):
Production of autoantibodies; propagated by epitope spreading
Clinical Intervention:
CD20 monoclonal antibody (depletes B cells)

16. And IL-17-producing TH17 cells.
Multiple Sclerosis:
T-cell mediated inflammatory demyelinating autoimmune disease of the CNS
Clinical Intervention:
Monoclonal antibody for α4 integrin to block cellular migration to inflamed CNS
And IL-17-producing TH17 cells.

17. Graves’ Disease Clinical Intervention:
Autoimmune B cells make antibodies that activate thyroid-stimulating hormone (TSH) receptor, causing hyperthyroidism
Proptosis, a bulging of the eye, is a symptom of Graves’ disease
Clinical Intervention:
antithyroid drugs that reduce the production of thyroid hormone
destruction of the thyroid with radioactive iodine
surgical removal of the thyroid

18. Thyroid autoimmunity: same target cell, different outcome

19. Transplantation

20. Host immune response against foreign grafted tissue
Durability of transplanted tissues remains significant challenge within the field
Host immune response against foreign grafted tissue

21. Subsets of host tolerant immune cells can react with non-self (donor) components

22. What is the evidence that immune system is responsible for graft rejection?
Graft rejection follows principles of self/non-self recognition, and like anti-pathogen responses displays memory.

23. Hyperacute rejection relies on pre-formed antibodies
Hyperacute rejection: have premade Abs against ABO blood groups or type I HLA, when solid organ transplanted, needs to get hooked into the blood supply of host, thus once the transplant is complete the Abs could bind to their antigen on the vascular endothelium and induce inflammation and immune cell recruitment that would completely block blood from getting through the vessel, thus the transplant would rapidly be starved of oxygen and die
Acute: takes bit longer, t cell mediated (type IV hypersens), donor APCs migrate to secondary lymphoid organs where they can activate host t cells, because there is likely hla incompatibility some of the host t cells could react very strongly to the foreign hla:self complexes and become activated, this allows them to traffic out to site of transplantation and attack the donor cells (direct recog)
Chronic: takes months to years, caused by activation of Abs specific for donor HLA type I, first cd4s activated via indirect pathway (host apcs present part of donor hla)

24. Acute rejection is T cell-mediated
Hyperacute rejection: have premade Abs against ABO blood groups or type I HLA, when solid organ transplanted, needs to get hooked into the blood supply of host, thus once the transplant is complete the Abs could bind to their antigen on the vascular endothelium and induce inflammation and immune cell recruitment that would completely block blood from getting through the vessel, thus the transplant would rapidly be starved of oxygen and die
Acute: takes bit longer, t cell mediated (type IV hypersens), donor APCs migrate to secondary lymphoid organs where they can activate host t cells, because there is likely hla incompatibility some of the host t cells could react very strongly to the foreign hla:self complexes and become activated, this allows them to traffic out to site of transplantation and attack the donor cells (direct recog)
Chronic: takes months to years, caused by activation of Abs specific for donor HLA type I, first cd4s activated via indirect pathway (host apcs present part of donor hla)

25. Chronic rejection can develop over months/years
Acute: takes bit longer, t cell mediated (type IV hypersens), donor APCs migrate to secondary lymphoid organs where they can activate host t cells, because there is likely hla incompatibility some of the host t cells could react very strongly to the foreign hla:self complexes and become activated, this allows them to traffic out to site of transplantation and attack the donor cells (direct recog)
Chronic: takes months to years, caused by activation of Abs specific for donor HLA type I, first cd4s activated via indirect pathway (host apcs present part of donor hla)

26. Are MHC molecules the only target antigens. No
Are MHC molecules the only target antigens? No! Many other ‘minor’ histocompatibility antigens exist.

27. Targets both Major Histocompatibility (MHC) & Minor Histocompatibility (minor-H) antigens from Donor APCs

28. APCs during graft rejection
Targets mainly minor-H antigens or processed MHC antigens presented by Host APCs
*Rejection delayed/slowed

29. Indirect allorecognition leads to chronic rejection

30. Transplant rejection vs GVHD

31. Mechanism of GVHD

32. Remember this is a balancing act!! Autoimmunity
Tolerance
Many factors play a role in the development of autoimmunity
MHC, FoxP3, AIRE, CTLA4
Genetic Susceptibility
Autoimmunity
Immune Regulation
(loss of)
Environmental Triggers
Stress
Inflammatory setting (increased activation and Ag presentation)
Hormones
Infection
Autoimmunity can be organ specific or systemic, B-cell and/or T-cell mediated

33. Clinical interventions
Immunosuppression:
Cyclosporine or equivalent + steroids
Some biologics:
OKT3 (anti-CD3)
Campath-1h (anti-CD52)
Major problems: Lifelong, expensive, no selectivity (susceptibility to infectious disease!), off-target effects.

34. Clinical interventions
Holy grail – Donor-specific tolerance (DST)
Readily achieved in several animal systems with immune modulating antibodies
Modify immune environment to promote activation/development of alloantigen-specific regulatory T cells.
Still being developed for clinical use.

35. Supplemental slides

37. Autoimmune Disease Immune Effector Reactivity/Target Mechanism
Tolerance Affected
Pathological Outcome
Systemic Lupus Erythematosus (SLE)
Autoantibodies
(Form immune complexes with target)
Chromatin (Histones and DNA)
Lodging of immune complexes in kidney glomeruli
B cell
Kidney inflammation (nephritis); proteinuria
Kidney dysfunction
Deposition of immune complexes in blood vessels; complement activation
Skin inflammation (rash)
Hemolytic Anemia
(Induce complement activation,
phagocytosis of target)
Erythrocytes (RBCs)
Lysis of erythrocytes
Anemia
Graves’ Disease
(Activation of target)
Thyroid stimulating hormone receptor (TSHR)
Consitutive activation of TSHR
Hyperthyroidism; dysregulated metabolism
Myasthenia gravis
Autoantibodies (Inhibition of target)
Acetylcholine receptor
Inhibition of acetylcholine signaling
Peripheral muscle weakness
Type-1 diabetes
Autoreactive CD8+ T cells
Beta islet cells (produce insulin)
Lysis of beta cells in pancreas
T cell
Loss of insulin production; dysregulated blood glucose metabolism
Rheumatoid arthritis
Autoreactive CD4+ T cells
Synovial joint antigens
Production of MMP/RANKL by synovial fibroblasts; recruitment and activation of osteoclasts
Degradation of bone and cartilage in joints
Multiple sclerosis
(MS)
Autoreactive Th1, Th17 CD4+ T cells
Myelin sheath protein
Demyelination of neurons
Neurodegeneration; paralysis