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Lymphocyte Selection and Tolerance Chander Raman 2004. 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

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slide2

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
slide3

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
slide4

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

slide5

T-Cell Selection - Overview

Double Negative

(Positive selection for ability to recognize antigen)

Death by Neglect

Double Positive

CD4+CD8+

(Negative Selection)

Single Positive

CD4+ or

CD8+

(Positive selection based on MHC reactivity)

Negative Selection

slide7

B

Menu

F

slide8

B

Menu

F

slide9

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)
slide10

Loss of Thymic Selection lead to Autoimmunity

AIRE-Deficient Mice

Normal Mice

Autoantibodies to different organs shown in GREEN in AIRE-deficient mice

slide12

B-Cell Development

Sensitive to Negative Selection – Central Tolerance

slide13

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.

factors that regulate central tolerance
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)
slide15

Survival

Death by

Neglect

Negative selection

Positive selection

Death

Signal Strength

Co-stimulation

Inhibition (attenuation)

peripheral tolerance
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 termedPeripheral Tolerance

slide17

Peripheral Tolerance

    • Peripheral control of autoreactivity
slide18
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.
slide19

Anergy

and/or

Apoptosis

t regulatory cells t r
T Regulatory Cells (Tr)

CD4+

CD25+

Maloy and Powrie, Nature Immunol. 2:816

t suppressor cells and inhibitory molecules
T suppressor cells and Inhibitory Molecules

Feinberg & Silvestri, Nature Immunol, 3:215

tolerance induction by dendritic cells
Tolerance Induction by Dendritic Cells

Lutz and Schuler, Trends Immunol: 23:9

slide24

Breakdown of tolerance

    • Autoimmune diseases
slide25

Venn Diagram: Requirements for the Development of Autoimmune Disease

Focus on Autoimmunity

Nature Immunology, Sept 2001 (Vol 2)

www.nature.com/ni

autoimmune diseases
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.
      • Goodpasture’s syndrome – Antibody to basement membrane of kidney glomeruli.
      • Graves disease – Stimulating antibody to thyroid stimulating hormone receptor (TSHr)
autoimmune diseases1
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
slide32

Susceptibility to Autoimmune Diseases

  • Genetic Predisposition
    • MHC genes – eg. HLA DR4 in Diabetes
    • Other susceptibility genes
  • Sex Differences
slide34

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)
slide35

Decoy Receptors in Regulation of Lymphocyte Activation and Autoimmunity

Soluble Receptor

Agonist or

antagonist antibody

Pharmacological Inhibitors

Ware, Nature. 404:949

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