Tolerance, autoimmunity and the
pathogenesis of immunemediated inflammatory diseases
Abul K. Abbas
UCSF
Balancing lymphocyte activation and control
Activation
Effector T cells
Normal: reactions
against pathogens
Inflammatory
disease, e.g.
reactions against self
Tolerance
Regulatory T cells
No response to self
Controlled response to
pathogens
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
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”
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
Autoimmunity
• Definition: immune response against self (auto-)
antigen, by implication pathologic
– Disorders are often classified under “immunemediated inflammatory diseases”
• General principles:
– Pathogenesis: Susceptibility genes +
environmental triggers
– Systemic or organ-specific
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
Consequences of self antigen recognition in thymus
From: Abbas & Lichtman, Cellular & Molecular Immunology 5th ed 2003
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
Peripheral tolerance
Normal T cell
response
Anergy
APC
CD28
T cell
TCR
APC
TCR
Off signals
Activated
T cell
Deletion
APC
Activated
T cells
Functional
unresponsiveness
Apoptosis
(activation-induced
cell death)
Block in
activation
Suppression
APC
Regulatory
T cell
T cell anergy
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?
“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
Regulatory T cells
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007
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
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
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?
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
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
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
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
Pathogenesis of autoimmunity
Susceptibility genes
Environmental trigger
(e.g. infections,
tissue injury)
Failure of
self-tolerance
Persistence of functional
self-reactive lymphocytes
Activation of
self-reactive
lymphocytes
Immune responses against self tissues
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 diseasespecific
– May influence end-organ damage
Genetics of autoimmunity: recent
successes of genomics
• NOD2: polymorphism associated with
~25% of Crohn’s disease
– Microbial sensor
• PTPN22: commonest autoimmunityassociated gene; polymorphism in RA,
SLE, others
– Phosphatase
• CD25 (IL-2R): associated with MS,
others; genome-wide association mapping
– Role in Tregs
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”
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
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)
Naïve CD4
T cell
Host defense: helminths
Allergic diseases
Th17 cells (IL-17)
Host defense: fungi, bacteria
Organ-specific
autoimmune diseases
Regulatory T cells
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)
Naïve CD4
T cell
Host defense: helminths
Allergic diseases
Th17 cells (IL-17)
TGF-IL-2:
Foxp3, Stat5
Host defense: fungi, bacteria
Organ-specific
autoimmune diseases
Regulatory T cells
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?
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”
Amplification loop in cell-mediated immunity
Cytokines are
powerful
amplifiers of
immune reactions
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
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 selfperpetuating
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?
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
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