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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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  • 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


  • 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


  • 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


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



B

Menu

F


B

Menu

F


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)


Loss of Thymic Selection lead to Autoimmunity

AIRE-Deficient Mice

Normal Mice

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



B-Cell Development are negatively selected.

Sensitive to Negative Selection – Central Tolerance


B-Cell Selection in the Bone Marrow are negatively selected.

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 are negatively selected.

  • 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)


Survival are negatively selected.

Death by

Neglect

Negative selection

Positive selection

Death

Signal Strength

Co-stimulation

Inhibition (attenuation)


Peripheral tolerance
Peripheral Tolerance are negatively selected.

  • 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



  • Peripheral Tolerance: are negatively selected.

    • 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.


Anergy are negatively selected.

and/or

Apoptosis


T regulatory cells t r
T Regulatory Cells (T are negatively selected.r)

CD4+

CD25+

Maloy and Powrie, Nature Immunol. 2:816


T suppressor cells and inhibitory molecules
T suppressor cells and Inhibitory Molecules are negatively selected.

Feinberg & Silvestri, Nature Immunol, 3:215


Tolerance induction by dendritic cells
Tolerance Induction by Dendritic Cells are negatively selected.

Lutz and Schuler, Trends Immunol: 23:9




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 Disease

  • 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 Disease

  • 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





Susceptibility to Autoimmune Diseases Disease

  • Genetic Predisposition

    • MHC genes – eg. HLA DR4 in Diabetes

    • Other susceptibility genes

  • Sex Differences



Therapeutic Intervention of Autoimmunity

  • 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)


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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