Tolerance, autoimmunity and the pathogenesis of immunemediated inflammatory diseases

Abul K. Abbas UCSF

Balancing lymphocyte activation and control

Activation 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

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
CD28 APC TCR

T cell

Activated T cells

Anergy

APC

TCR

Off signals

Functional unresponsiveness

Deletion
APC

Activated T cell

Apoptosis (activation-induced cell death)

Suppression
APC

Block in activation
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 Failure of self-tolerance Persistence of functional self-reactive lymphocytes Activation of self-reactive lymphocytes Environmental trigger (e.g. infections, tissue injury)

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

Host defense: many microbes Systemic and organ-specific autoimmune diseases

Th1 cells (IFN-)

Th2 cells (IL-4, IL-5)

Nave 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

Host defense: many microbes Systemic and organ-specific autoimmune diseases

Th1 cells (IFN-)

Th2 cells (IL-4, IL-5)

Nave CD4 T cell
: IL-4 tat6 , S 3 A GAT

Host defense: helminths Allergic diseases

TGF-, IL-2: Foxp3, Stat5

TGF ROR + IL-6: t , S tat3

Th17 cells (IL-17)

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 nave 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) 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

Differences from human diseases:

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:

Nevertheless, emerging successes:

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 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