Lymphocyte Selection and Tolerance Chander Raman 2004

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Lymphocyte Selection and ToleranceChander
Raman2004
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• Lecture Focus
• Lymphocyte Selection Central Tolerance
• T-cell selection
• B-cell selection
• Peripheral Tolerance
• Peripheral control of autoreactivity.
• Breakdown of tolerance
• Autoimmune diseases
• Restoration of tolerance
• Treatment of autoimmune diseases

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• Tolerance Inability to respond to antigen
  stimulation OR Immunological unresponsiveness.
• Why do we need tolerance?
• Initial T-cell receptor rearrangement or B-cell
  receptor rearrangement leads to generation of
  repertoire that has the potential to recognize
  all antigens
• DOES NOT DISCRIMINATE BETWEEN SELF-REACTIVITY AND
  REACTIVITY TO FOREIGN ANTIGENS

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• Tolerance
• Central tolerance
• Negative selection of immature lymphocytes by
  clonal deletion of self reactive clones during
  development.
• T cells thymus
• B cells bone marrow

Clonal deletion occurs by induction of programmed
cell death or apoptosis
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T-Cell Selection - Overview
Double Negative
(Positive selection for ability to recognize
antigen)
Death by Neglect
Double Positive CD4CD8
(Negative Selection)
Single Positive CD4 or CD8 (Positive selection
based on MHC reactivity)
Negative Selection
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Death by Neglect
Menu
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B
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Menu
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B
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Evidence for Requirement for Central Tolerance

• AIRE (autoimmune regulator) Transcription Factor
  Master Regulator of Ectopic Expression of
  Peripheral Tissue- Restricted Antigens in stromal
  cells of the thymic Medulla.
• Originally identified as a human autosomal
  recessive disorder known as APECED (autoimmune
  polyendocrinopathy-candidiasis-ectodermal
  dystrophy.
• AIRE-/- mice exhibit wide spread organ-specific
  autoimmunity, such as ovary, retina testis,
  stomach. (Anderson et al, Science)

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Loss of Thymic Selection lead to Autoimmunity
AIRE-Deficient Mice
Normal Mice
Autoantibodies to different organs shown in GREEN
in AIRE-deficient mice
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AIRE allows for the expression of antigens to
which T-cells are negatively selected.
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B-Cell Development
Sensitive to Negative Selection Central
Tolerance
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B-Cell Selection in the Bone Marrow
Binding to self molecules in the bone marrow can
lead to the deletion or inactivation of immature
B cells.
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Factors That Regulate Central Tolerance

• Most Important Strength of Signals initiated by
  antigen receptor
• Intracellular signal strength is dependent on
• Avidity of interaction of between antigen and
  antigen receptor
• Affinity of interaction between antigen and
  antigen receptor
• Co-stimulatory signals that enhance signal
  strength (CD28)
• Signals that attenuate signals strength
  Inhibitory receptors (CD5)

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Survival
Negative selection
Death by Neglect
Positive selection
Death
Signal Strength
Co-stimulation
Inhibition (attenuation)
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Peripheral Tolerance

• Not all self-reactive T or B cells are deleted
  during development. Reasons include
• Need for a peripheral repertoire that will
  protect from pathogens
• Peripheral tissue specific antigens not expressed
  in the thymus.
• Expression of neo-antigens occurring as a result
  of tissue damage.
• Expression of specific endopeptidases that modify
  peptides in thymus.
• Positive selection of specificities that exhibit
  weak self-reactivity but with the propensity for
  pathogenic autoreactivity.

Control of autoreactive T cells in the periphery
is termed Peripheral Tolerance
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Peripheral Tolerance Peripheral control of
autoreactivity
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• Peripheral Tolerance
• Clonal deletion, clonal anergy or clonal
  ignorance of mature self-reactive T and mature or
  transitional B cells.
• Regulated by
• Co-stimulatory molecules (signal 2)
• Cytokines (signal 3)
• Inhibitory molecules
• T-regulatory cells (Tr), T-suppressor cells (Ts)
• Dendritic cells.

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T Regulatory Cells (Tr)
CD4 CD25
Maloy and Powrie, Nature Immunol. 2816
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T suppressor cells and Inhibitory Molecules
Feinberg Silvestri, Nature Immunol, 3215
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Tolerance Induction by Dendritic Cells
Lutz and Schuler, Trends Immunol 239
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Immunity vs Tolerance in Peripheral B Cells
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Breakdown of tolerance Autoimmune diseases
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Venn Diagram Requirements for the Development of
Autoimmune Disease
Focus on Autoimmunity Nature Immunology, Sept
2001 (Vol 2) www.nature.com/ni
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Development of Autoimmunity
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Autoimmune Diseases

• Organ specific autoimmune diseases
• Immune response directed to a specific organ
  leading to cellular damage and organ destruction
• Diabetes Cell mediated immune response to
  pancreatic islet beta cells.
• Goodpastures syndrome Antibody to basement
  membrane of kidney glomeruli.
• Graves disease Stimulating antibody to thyroid
  stimulating hormone receptor (TSHr)

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Autoimmune Diseases

• Systemic autoimmune diseases
• Immune response to wide variety of antigens
  involving several organs and tissues. Often
  involves both cell-mediated and humoral.
• Systemic lupus erythematosus (SLE) Primary
  antibody response to DNA and nucleoproteins and
  progressive development of antibodies to other
  tissues.
• Rheumatoid arthritis (RA) IgM antibodies to Fc
  portion of IgG.
• Multiple sclerosis (MS) T cell response to
  myelin basic protein

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Organ Specific and Systemic Autoimmune Diseases
in Human
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Hypothesis for the Development of Type 1 Diabetes
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Systemic Lupus Erythematosus
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Susceptibility to Autoimmune Diseases

• Genetic Predisposition
• MHC genes eg. HLA DR4 in Diabetes
• Other susceptibility genes
• Sex Differences

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Contribution of Susceptibility Gene Alleles to
Development of Autoimmunity
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Therapeutic Intervention

• Conventional therapeutic approaches
• Anti-inflammatories, immunosuppressive drugs,
  Cytotoxic drugs
• New therapies
• TNFr (EMBREL etanerecept)
• anti-CD20 (depletes B-cells treatment of SLE)
• Experimental/New approaches
• TNF receptor family agonists/antagonists
• Blys/BlysR(s) (Inhibition of activation and
  differentiation)
• TRAIL/TRAILR(s) (Apoptosis inducing)

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Decoy Receptors in Regulation of Lymphocyte
Activation and Autoimmunity
Ware, Nature. 404949
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Decoy Receptors In Treatment of Autoimmune
Diseases