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Tolerance, autoimmunity and the pathogenesis of immune-mediated inflammatory diseases Abul K. Abbas UCSF. Balancing lymphocyte activation and control. Activation Effector T cells. Tolerance Regulatory T cells. Normal: reactions against pathogens Inflammatory

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slide1

Tolerance, autoimmunity and the pathogenesis of immune-mediated inflammatory diseases

Abul K. Abbas

UCSF

slide2

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

slide3

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
slide4

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”
slide5

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
slide6

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
slide7

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

slide8

Consequences of self antigen recognition in thymus

From: Abbas & Lichtman, Cellular & Molecular Immunology 5th ed 2003

slide9

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
slide10

APC

APC

APC

APC

Peripheral tolerance

T cell

CD28

Normal T cell

response

Activated

T cells

TCR

Functional

unresponsiveness

Anergy

Off signals

TCR

Activated

T cell

Apoptosis

(activation-induced

cell death)

Deletion

Block in

activation

Suppression

Regulatory

T cell

slide12

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?
slide13

“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

slide14

Regulatory T cells

From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007

slide15

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
slide16

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
slide17

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?
slide18

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
slide19

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
slide20

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
slide21

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
slide22

Pathogenesis of autoimmunity

Environmental trigger

(e.g. infections,

tissue injury)

Susceptibility genes

Failure of

self-tolerance

Activation of

self-reactive

lymphocytes

Persistence of functional

self-reactive lymphocytes

Immune responses against self tissues

slide23

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
genetics of autoimmunity recent successes of genomics
Genetics of autoimmunity: recent successes of genomics
  • 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
slide25

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
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
slide27

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)

Host defense: helminths

Allergic diseases

Naïve CD4

T cell

Th17 cells (IL-17)

Host defense: fungi, bacteria

Organ-specific

autoimmune diseases

Regulatory T cells

slide28

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)

IFN-, IL-12:

T-bet, Stat4

Host defense: helminths

Allergic diseases

IL-4:

GATA3, Stat6

Naïve CD4

T cell

Th17 cells (IL-17)

TGF- + IL-6:RORt, Stat3

TGF-IL-2:

Foxp3, Stat5

Host defense: fungi, bacteria

Organ-specific

autoimmune diseases

Regulatory T cells

subsets of cd4 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?
slide30

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”
slide31

Amplification loop in cell-mediated immunity

Cytokines are

powerful

amplifiers of

immune reactions

slide32

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

slide33

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
slide34

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?
slide35

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
slide36

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