Lymphocyte Selection and Tolerance Chander Raman 2004
Lymphocyte Selection: Central Tolerance
Peripheral control of autoreactivity.
Breakdown of tolerance
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
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
Death by Neglect Negative Selection T-Cell Selection - Overview Double Negative Double Positive CD4+CD8+ Single Positive CD4+ or CD8+ ( Positive selection based on MHC reactivity ) ( Negative Selection ) (Positive selection for ability to recognize antigen)
Menu F B Death by Neglect
Menu F B
Menu F B
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)
AIRE -Deficient Mice Normal Mice Loss of Thymic Selection lead to Autoimmunity Autoantibodies to different organs shown in GREEN in AIRE -deficient mice
AIRE allows for the expression of antigens to which T-cells are negatively selected.
B-Cell Development Sensitive to Negative Selection – Central Tolerance
Binding to self molecules in the bone marrow can lead to the deletion or inactivation of immature B cells. B-Cell Selection in the Bone Marrow
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)
Signal Strength Survival Death Negative selection Positive selection Death by Neglect Co-stimulation Inhibition (attenuation)
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
Peripheral control of autoreactivity
Clonal deletion, clonal anergy or clonal ignorance of mature self-reactive T and mature or transitional B cells.
Co-stimulatory molecules (signal 2)
Cytokines (signal 3)
T-regulatory cells (Tr), T-suppressor cells (Ts)
Anergy and/or Apoptosis
T Regulatory Cells (T r ) Maloy and Powrie, Nature Immunol. 2:816 CD4 + CD25 +
T suppressor cells and Inhibitory Molecules Feinberg & Silvestri, Nature Immunol, 3:215
Tolerance Induction by Dendritic Cells Lutz and Schuler, Trends Immunol: 23:9
Immunity vs Tolerance in Peripheral B Cells
Breakdown of tolerance
Venn Diagram: Requirements for the Development of Autoimmune Disease Focus on Autoimmunity Nature Immunology, Sept 2001 (Vol 2) www.nature.com/ni
Development of Autoimmunity
Organ specific autoimmune diseases:
Immune response directed to a specific organ leading to cellular damage and organ destruction