HIM1201 Wk#2 AutoImmunity Abbas 11711

7/28/2019 HIM1201 Wk#2 AutoImmunity Abbas 11711

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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

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HIM1201 Wk#2 AutoImmunity Abbas 11711

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