1. Tolerance, autoimmunity and the pathogenesis of immune-mediated inflammatory diseases
Abul K. Abbas
UCSF

2. Balancing lymphocyte activation and control
Effector T cells
Tolerance
Regulatory T cells
Normal: reactions against pathogens
Inflammatory
disease, e.g. reactions against self
No response to self
Controlled response to pathogens

3. The importance of immune regulation
To avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections
To prevent inappropriate reactions against self antigens (“self-tolerance”)
Failure of control mechanisms is the underlying cause of immune-mediated inflammatory diseases

4. General principles of controlling immune responses
Responses against pathogens decline as the infection is eliminated
Apoptosis of lymphocytes that lose their survival signals (antigen, etc)
Memory cells are the survivors
Active control mechanisms may function to limit responses to persistent antigens (self antigens, possibly tumors and some chronic infections)
Often grouped under “tolerance”

5. Immunological tolerance
Definition:
specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)
Significance:
All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity
Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases, and prevent immune responses in gene therapy

6. Autoimmunity
Definition: immune response against self (auto-) antigen, by implication pathologic
Disorders are often classified under “immune-mediated inflammatory diseases”
General principles:
Pathogenesis: Susceptibility genes + environmental triggers
Systemic or organ-specific

7. Central and peripheral tolerance
The principal fate
of lymphocytes that
recognize self antigens
in the generative organs
is death (deletion), BUT:
Some B cells may change
their specificity (called
“receptor editing”)
Some CD4 T cells may
differentiate into
regulatory (suppressive)
T lymphocytes
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007

8. Consequences of self antigen recognition in thymus
From: Abbas & Lichtman, Cellular & Molecular Immunology 5th ed 2003

9. Central tolerance
Lymphocytes that see self antigens before they are mature are either eliminated or rendered harmless
Probably continues to occur at some level throughout life (as new lymphocytes are produced from bone marrow stem cells)
Role of the AIRE protein in thymic expression of some tissue antigens

10. Peripheral tolerance Normal T cell response Anergy Apoptosis
APC
CD28
Normal T cell
response
Activated
T cells
TCR
APC
Functional
unresponsiveness
Anergy
Off signals
TCR
Activated
T cell
APC
Apoptosis
(activation-induced
cell death)
Deletion
APC
Suppression
Block in
activation
Regulatory
T cell

11. T cell anergy

12. T cell anergy
Multiple mechanisms demonstrated in different experimental systems
No clear evidence that natural self antigens induce T cell anergy (especially in humans)
Therapeutic potential: can we administer antigens in ways that induce T-cell anergy?

13. “Activation-induced cell death”: death of mature
T cells upon recognition of self antigens
From Abbas and Lichtman. Basic Immunology 2nd ed, 2006
Both pathways cooperate to prevent reactions against self

14. Regulatory T cells
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007

15. Properties of regulatory T cells
Phenotype: CD4, high IL-2 receptor (CD25), low IL-7 receptor, Foxp3 transcription factor; other markers
Mechanisms of action: multiple
secretion of immune-suppressive cytokines (TGF, IL-10, IL-35),
inactivation of dendritic cells or responding lymphocytes

16. Thymic (“natural”) regulatory T cells (Treg)
Development requires recognition of self antigen during T cell maturation
Reside in peripheral tissues to prevent harmful reactions against self

17. Peripheral (adaptive, inducible) regulatory T cells
Develop from mature CD4 T cells that are exposed to persistent antigen in the periphery; no role for thymus
May be generated in all immune responses, to limit collateral damage
Can be induced in vitro (stimulation of CD4 T-cells in presence of TGF + IL-2)
What factors determine the balance of effector cells and Treg?

18. Signals for the generation and maintenance of regulatory T cells
Antigen recognition, with or without inflammation?
TGF- (source?)
Interleukin-2 (originally identified as T cell growth factor; major function is to control immune responses by maintaining functional Treg; works via Stat5)
Low levels of B7: CD28 costimulation
Transcription factor Foxp3
Many activated T cells (not only Treg) may transiently express Foxp3

19. Regulatory T cells
Explosion of information about the generation, properties, functions and significance of these cells
Some autoimmune diseases are associated with defective generation or function of Tregs or resistance of effector cells to suppression by Tregs
Will cellular therapy with ex vivo expanded Treg become a reality?
Therapeutic goal: selective induction or activation of Treg in immune diseases

20. Immune-mediated inflammatory diseases
Chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation
RA, IBD, MS, psoriasis, many others
Affect 2-5% of people, incidence increasing
May result from immune responses against self antigens (autoimmunity) or microbial antigens (Crohn’s disease?)
May be caused by T cells and antibodies
May be systemic or organ-specific

21. Features of autoimmune diseases
Fundamental problem: imbalance between immune activation and control
Underlying causative factors: susceptibility genes + environmental influences
Immune response is inappropriately directed or controlled; effector mechanisms of injury are the same as in normal responses to microbes
Nature of disease is determined by the type of dominant immune response
Many immunological diseases are chronic and self-perpetuating

22. Pathogenesis of autoimmunity
Environmental trigger
(e.g. infections,
tissue injury)
Susceptibility genes
Failure of
self-tolerance
Activation of
self-reactive
lymphocytes
Persistence of functional
self-reactive lymphocytes
Immune responses against self tissues

23. Genetics of autoimmunity
Human autoimmune diseases are complex polygenic traits
Identified by genome-wide association mapping
Single gene mutations are useful for pathway analysis
Some polymorphisms are associated with multiple diseases
May control general mechanisms of tolerance and immune regulation
Other genetic associations are disease-specific
May influence end-organ damage

24. Genetics of autoimmunity: recent successes of genomics
NOD2: polymorphism associated with ~25% of Crohn’s disease
Microbial sensor
PTPN22: commonest autoimmunity-associated gene; polymorphism in RA, SLE, others
Phosphatase
CD25 (IL-2R): associated with MS, others; genome-wide association mapping
Role in Tregs

25. Infections and autoimmunity
Infections trigger autoimmune reactions
Clinical prodromes, animal models
Autoimmunity develops after infection is eradicated (i.e. the autoimmune disease is precipitated by infection but is not directly caused by the infection)
Some autoimmune diseases are prevented by infections (type 1 diabetes, multiple sclerosis, others? -- increasing incidence in developed countries): mechanism unknown
The “hygiene hypothesis”

26. Immune-mediated diseases
The nature of the disease is determined by the type of dominant immune response
Th1 response: inflammation, autoantibody production; autoimmune diseases
Th2 response: IgE+eosinophil-mediated inflammation; allergic reactions
Th17 response: acute (and chronic?) inflammation; increasingly recognized in immune-mediated diseases

27. CD4 T cell subsets: function
Th1 cells (IFN-g)
Host defense: many microbes
Systemic and organ-specific
autoimmune diseases
Th2 cells (IL-4, IL-5)
Host defense: helminths
Allergic diseases
Naïve CD4
T cell
Th17 cells (IL-17)
Host defense: fungi, bacteria
Organ-specific
autoimmune diseases
Regulatory T cells

28. CD4 subsets: generation and function
Th1 cells (IFN-g)
Host defense: many microbes
Systemic and organ-specific
autoimmune diseases
Th2 cells (IL-4, IL-5)
IFN-, IL-12:
T-bet, Stat4
Host defense: helminths
Allergic diseases
IL-4:
GATA3, Stat6
Naïve CD4
T cell
Th17 cells (IL-17)
TGF- + IL-6: RORt, Stat3
TGF-IL-2:
Foxp3, Stat5
Host defense: fungi, bacteria
Organ-specific
autoimmune diseases
Regulatory T cells

29. Subsets of CD4+ T cells
Dominant T cell subsets determine disease vs protection
Many autoimmune and allergic diseases are associated with imbalance of T cell subsets
Cytokines and transcription factors involved in differentiation of naïve T cells to different subsets are well defined, especially in vitro
Conditions for induction in vivo? in disease?
Stability or plasticity of subsets?

30. Immune-mediated diseases
Immunological diseases tend to be chronic and self-perpetuating, because --
The initiating trigger can often not be eliminated (self antigen, commensal microbes)
The immune system contains many built-in amplification mechanisms whose normal function is to optimize our ability to combat infections
“Epitope spreading”

31. Amplification loop in cell-mediated immunity
Cytokines are
powerful
amplifiers of
immune reactions

32. Pathogenesis of organ-specific autoimmunity
Current therapies
target late stages
of the reaction (lymphocyte activation,
inflammation).
Ultimate goal should
be to tackle the underlying cause and restore control of the abnormally directed response

33. Immune-mediated inflammatory diseases
Immune-mediated inflammatory diseases develop because the normal controls on immune responses fail
The phenotype of the disease is determined by the nature of the immune response
These diseases often become self-perpetuating

34. Animal models of human inflammatory diseases: how good are they?
Resemblance to human diseases:
Same target organs involved
Often similar effector mechanisms (antibodies, cytokines, cytotoxic T lymphocytes)
Differences from human diseases:
Unknown underlying susceptibility genes (some similarities, e.g. in type 1 diabetes)
Often induced by experimental manipulation, e.g. overt immunization with tissue antigen, inflammatory stimulus, or transgenic approach
The potential of “humanized” mice?

35. Biomarkers of human immune diseases
Major goal of current research
High-throughput screens for transcripts and proteins associated with disease
Many practical limitations:
Reliance on population assays, even though only a small fraction of total lymphocytes may be abnormal in control/activation
Use of blood cells, even though the relevant reactions may be in tissues
Nevertheless, emerging successes:
Type I interferon “signature” in lupus

36. Immune-mediated inflammatory diseases
Experimental models are revealing pathways of immune regulation and why it fails
Genetic studies are identifying underlying defects in human diseases
Improving technologies are enabling analyses of patients
Challenges:
From genes to pathways (molecular and functional)
Using the knowledge to develop therapies