Tolerance, autoimmunity and the pathogenesis of

immune-mediated inflammatory diseases

Abul K. AbbasUCSF

ActivationEffector T cells

Normal: reactions against pathogens

Inflammatorydisease, e.g.

reactions against self

ToleranceRegulatory T cells

No response to selfControlled response

to pathogens

Balancing lymphocyte activation and control

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

“immune-mediated inflammatory diseases”

• General principles:– Pathogenesis: Susceptibility genes +

environmental triggers– Systemic or organ-specific

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

Central and peripheral tolerance

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

APC TCR

T cellT cellCD28

ActivatedActivatedT cellsT cells

APC TCR

Functionalunresponsiveness

Normal T cellresponse

Anergy

Apoptosis(activation-induced

cell death)APC

Deletion

APC

Block in

activationSuppression

RegulatoryT cell

Peripheral tolerance

Off signals

ActivatedActivatedT cellT 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 genesEnvironmental trigger

(e.g. infections, tissue injury)

Failure ofself-tolerance

Activation ofself-reactive lymphocytes

Immune responses against self tissues

Persistence of functionalself-reactive lymphocytes

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

• 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

Genetics of autoimmunity: recent successes of genomics

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”

• 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

Immune-mediated diseases

Th1 cells (IFN-)

Th2 cells (IL-4, IL-5)

Th17 cells (IL-17)

Naïve CD4T cell

CD4 T cell subsets: function

Regulatory T cells

Host defense: many microbesSystemic and organ-specific

autoimmune diseases

Host defense: helminthsAllergic diseases

Host defense: fungi, bacteria Organ-specific

autoimmune diseases

Th1 cells (IFN-)

Th2 cells (IL-4, IL-5)

Th17 cells (IL-17)

Naïve CD4T cell

CD4 subsets: generation and function

Regulatory T cells

IFN-

, IL-

12:

T-be

t, S

tat4

IL-4:

GATA3, Stat6

TGF- + IL-6:RORt, Stat3TGF-IL-2:

Foxp3, Stat5

Host defense: many microbesSystemic and organ-specific

autoimmune diseases

Host defense: helminthsAllergic diseases

Host defense: fungi, bacteria Organ-specific

autoimmune diseases

• 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?

Subsets of CD4+ T cells

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 self-perpetuating

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