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Tolerance, autoimmunity and thepathogenesis of immune-
mediated inflammatory diseases
Abul K. AbbasUCSF
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ActivationEffector T cells
Normal: reactionsagainst pathogensInflammatorydisease, e.g.
reactions against self
ToleranceRegulatory T cells
No response to selfControlled response topathogens
Balancing lymphocyte activation and control
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The importance of immune regulation
To avoid excessive lymphocyte activation andtissue damage during normal protectiveresponses against infections
To prevent inappropriate reactions against selfantigens (self-tolerance)
Failure of control mechanisms is the underlyingcause of immune-mediated inflammatorydiseases
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General principles of controllingimmune responses
Responses against pathogens decline asthe infection is eliminated Apoptosis of lymphocytes that lose their
survival signals (antigen, etc) Memory cells are the survivors
Active control mechanisms may functionto limit responses to persistent antigens(self antigens, possibly tumors and somechronic infections) Often grouped under tolerance
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Immunological tolerance
Definition: specific unresponsiveness to an antigen that is
induced by exposure of lymphocytes to thatantigen (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, treatautoimmune and allergic diseases, and preventimmune responses in gene therapy
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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
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The principal fate
of lymphocytes thatrecognize self antigensin the generative organsis death (deletion), BUT:
Some B cells may changetheir specificity (calledreceptor editing)
Some CD4 T cells may
differentiate intoregulatory (suppressive)T lymphocytes
Central and peripheral tolerance
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007!
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Consequences of self antigen recognition in thymus
From: Abbas & Lichtman, Cellular & Molecular Immunology 5th ed 2003"
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Central tolerance
Lymphocytes that see self antigensbefore they are mature are eithereliminated or rendered harmless
Probably continues to occur at some level
throughout life (as new lymphocytes areproduced from bone marrow stem cells)
Role of the AIRE protein in thymicexpression of some tissue antigens
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APC TCR
T cellCD28
Activated
T cells
APC TCRFunctional
unresponsiveness
Normal T cell
response
Anergy
Apoptosis(activation-induced
cell death)APCDeletion
APC
Block inactivation
Suppression
Regulatory
T cell
Peripheral tolerance
Off signals
ActivatedT cell
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T cell anergy
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T cell anergy
Multiple mechanisms demonstratedin different experimental systems No clear evidence that natural selfantigens induce T cell anergy(especially in humans)
Therapeutic potential: can weadminister antigens in ways that
induce T-cell anergy?
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Activation-induced cell death: death of matureT cells upon recognition of self antigens
From Abbas and Lichtman. Basic Immunology 2nd ed, 2006!Both pathways cooperate to prevent reactions against self
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Regulatory T cells
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007!
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Properties of regulatory T cells
Phenotype: CD4, high IL-2 receptor(CD25), low IL-7 receptor, Foxp3transcription factor; other markers
Mechanisms of action: multiple secretion of immune-suppressivecytokines (TGF, IL-10, IL-35),
inactivation of dendritic cells orresponding lymphocytes
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Thymic (natural) regulatory T cells(Treg)
Development requires recognition of selfantigen during T cell maturation
Reside in peripheral tissues to preventharmful reactions against self
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Peripheral (adaptive, inducible)regulatory T cells
Develop from mature CD4 T cells that areexposed to persistent antigen in theperiphery; no role for thymus
May be generated in all immune responses,to limit collateral damage
Can be induced in vitro (stimulation of CD4T-cells in presence of TGF + IL-2)
What factors determine the balance ofeffector cells and Treg?
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Signals for the generation andmaintenance of regulatory T cells
Antigen recognition, with or withoutinflammation?
TGF- (source?) Interleukin-2 (originally identified as Tcell growth factor; major function is to
control immune responses by maintainingfunctional Treg; works via Stat5)
Low levels of B7: CD28 costimulation Transcription factor Foxp3
Many activated T cells (not only Treg) maytransiently express Foxp3
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Regulatory T cells
Explosion of information about thegeneration, properties, functions andsignificance of these cells Some autoimmune diseases are associated with
defective generation or function of Tregs orresistance of effector cells to suppression byTregs
Will cellular therapy with ex vivoexpanded Treg become a reality? Therapeutic goal: selective induction or
activation of Treg in immune diseases
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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 selfantigens (autoimmunity) or microbial antigens(Crohns disease?)
May be caused by T cells and antibodies May be systemic or organ-specific
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Features of autoimmune diseases
Fundamental problem: imbalance betweenimmune activation and control Underlying causative factors: susceptibility
genes + environmental influences
Immune response is inappropriately directed orcontrolled; effector mechanisms of injury arethe same as in normal responses to microbes
Nature of disease is determined by thetype of dominant immune response
Many immunological diseases are chronicand self-perpetuating
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Pathogenesis of autoimmunity
Susceptibility genes Environmental trigger(e.g. infections,tissue injury)
Failure of
self-toleranceActivation ofself-reactivelymphocytes
Immune responses against self tissues
Persistence of functionalself-reactive lymphocytes
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Genetics of autoimmunity
Human autoimmune diseases are complexpolygenic traits Identified by genome-wide association mapping Single gene mutations are useful for pathway
analysis
Some polymorphisms are associated withmultiple diseases May control general mechanisms of tolerance
and immune regulation
Other genetic associations are disease-specific May influence end-organ damage
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NOD2: polymorphism associated with~25% of Crohns 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
Genetics of autoimmunity: recentsuccesses of genomics
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Infections and autoimmunity
Infections trigger autoimmune reactions Clinical prodromes, animal models Autoimmunity develops after infection is
eradicated (i.e. the autoimmune disease isprecipitated by infection but is not directlycaused by the infection)
Some autoimmune diseases are prevented byinfections (type 1 diabetes, multiple sclerosis,others? -- increasing incidence in developedcountries): mechanism unknown The hygiene hypothesis
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The nature of the disease is determinedby the type of dominant immune responseTh1 response: inflammation,autoantibody production; autoimmune
diseasesTh2 response: IgE+eosinophil-mediatedinflammation; allergic reactions
Th17 response: acute (and chronic?)inflammation; increasingly recognized inimmune-mediated diseases
Immune-mediated diseases
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Th1 cells (IFN-)
Th2 cells (IL-4, IL-5)
Th17 cells (IL-17)
Nave CD4T cell
CD4 T cell subsets: function
Regulatory T cells
Host defense: many microbesSystemic and organ-specific
autoimmune diseases
Host defense: helminths
Allergic diseases
Host defense: fungi, bacteriaOrgan-specific
autoimmune diseases
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Th1 cells (IFN-)
Th2 cells (IL-4, IL-5)
Th17 cells (IL-17)
Nave CD4T cell
CD4 subsets: generation and function
Regulatory T cells
IL-4:
GATA3,Stat6
TGF-+IL-6:
RORt,Stat3TGF-, IL-2:Foxp3, Stat5
Host defense: many microbesSystemic and organ-specific
autoimmune diseases
Host defense: helminths
Allergic diseases
Host defense: fungi, bacteriaOrgan-specific
autoimmune diseases
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Dominant T cell subsets determinedisease vs protection Many autoimmune and allergic diseases are
associated with imbalance of T cell subsets
Cytokines and transcription factorsinvolved in differentiation of nave Tcells to different subsets are well
defined, especially in vitro Conditions for induction in vivo? in disease?
Stability or plasticity of subsets?
Subsets of CD4+ T cells
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Immune-mediated diseases
Immunological diseases tend to be chronicand self-perpetuating, because --
The initiating trigger can often not beeliminated (self antigen, commensal microbes)
The immune system contains many built-inamplification mechanisms whose normal functionis to optimize our ability to combat infections
Epitope spreading
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Amplification loop in cell-mediated immunity!
Cytokines are
powerfulamplifiers ofimmune reactions
Pathogenesis of organ specific autoimmunity
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Pathogenesis of organ-specific autoimmunity
Current therapiestarget late stagesof the reaction(lymphocyteactivation,
inflammation).
Ultimate goal shouldbe to tackle theunderlying cause and
restore control of theabnormally directedresponse
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Immune-mediated inflammatorydiseases
Immune-mediated inflammatory diseasesdevelop because the normal controls onimmune responses fail
The phenotype of the disease isdetermined by the nature of the immuneresponse
These diseases often become self-perpetuating
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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?
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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 lymphocytesmay be abnormal in control/activation
Use of blood cells, even though the relevantreactions may be in tissues
Nevertheless, emerging successes: Type I interferon signature in lupus
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Immune-mediated inflammatorydiseases
Experimental models are revealingpathways of immune regulation and why itfails
Genetic studies are identifying underlyingdefects in human diseases
Improving technologies are enablinganalyses of patients
Challenges: From genes to pathways (molecular and
functional) Using the knowledge to develop therapies