Autoimmunity and Tolerance Overview

Tolerance & Development of Autoimmunity

• Autoimmunity is an inappropriate immune response against self antigens, resulting in the activation of autoreactive lymphocytes.
• Autoimmune diseases are classified as hypersensitivities.
• Autoimmunity involves a loss of self tolerance in B cells, T cells, or both.
• Tolerance is a state of unresponsiveness by lymphocytes to a particular antigen due to interaction with that antigen.

Central Tolerance

• Central tolerance develops during the selection of immature lymphocytes within the primary lymphatic tissues.

Peripheral Tolerance

• Peripheral tolerance involves the deletion (apoptosis) or anergy of lymphocytes that recognize self-antigens in the periphery and the suppression of responses by regulatory CD4+CD25+ T lymphocytes (Treg cells).

Central Tolerance in T Cells

• Negative selection deletes immature T cells that express a TCR specific for a self antigen.
• Thymic epithelial cells express AIRE (autoimmune regulator), which allows them to express many types of peripheral tissue antigens to immature T cells.
• The goal of central tolerance is to expose immature T cells to as many self antigens as possible to delete self-reactive T cells and develop Treg cells.

Treg Cells

• Treg cells are important in inhibiting self-reactive T cells from responding to self antigens.
• The strength of TCR-MHC binding dictates the outcome of T cell development.
• Strong or "no" binding leads to deletion.
• Weak binding leads to helper T cell development.
• Intermediate binding leads to Treg cell development.

Clinical Application: Mutation in AIRE

• A mutation in the AIRE gene can result in a non-functional AIRE protein leading to autoimmunity.
• Defective negative selection allows self-reactive T cells to be released into circulation.
• Defective Treg development leads to a reduction in Treg cells and increased susceptibility to autoimmunity.
• Patients with null mutations in AIRE are diagnosed with Autoimmune Polyendocrinopathy Syndrome (APS1 or APECED).

Peripheral Tolerance of T Cells

• Peripheral tolerance of T cells is the mechanisms by which mature T cells recognizing self antigens in peripheral tissues become incapable of responding to these antigens.
• Key mechanisms of peripheral T cell tolerance include anergy, deletion, and suppression.

Anergy

• Anergy of T cells develops due to lack of costimulation or by inhibitory signals.
• T cells binding to APCs without B7-CD28 costimulation become anergic.
• APCs expressing self-antigens do not express B7.

Treg Cell Inhibition

• Treg cells inhibit the activation, activity, and survival of self-reactive lymphocytes by binding to APCs to block B7-CD28 interactions, secreting inhibitory cytokines, and down-modulating APCs by binding to B7.

Central Tolerance in B Cells

• Immature B cells that bind with high avidity to a self antigen can undergo receptor editing.
• Immature B cells that bind with low avidity to self antigens are released in an anergic state.
• These anergic cells have downregulated BCRs and reduced signaling capacity.

Peripheral Tolerance of B Cells

• Peripheral tolerance of B cells is not well understood, but proposed mechanisms include anergy and deletion.
• The inhibitory receptor CD22 plays a role in B cell peripheral tolerance, setting a activation threshold and inhibiting B cell activation against host cells via the BCR.

Immune Responses Against Self Antigens

• Both cell-mediated and humoral responses can occur against self antigens when tolerance mechanisms fail.
• Helper T cells can activate macrophages and cytotoxic T cells, leading to inflammation and tissue damage.
• Helper T cells can assist B cell activation, leading to antibody production and tissue damage.

Summary

• Tolerance is a state of unresponsiveness to self antigens.
• Central tolerance is negative selection in primary lymphatics.
• Peripheral tolerance mechanisms involve anergy, deletion, and suppression in secondary lymphatics.
• Breakdown of tolerance leads to autoimmunity.
• Genetic susceptibility plays a role in the development of autoimmunity.
• Breakdown of tolerance can be caused through various mechanisms, including bystander T cell activation, molecular mimicry, altered self, release of sequestered antigens, and cryptic self epitopes.
• Autoreactive B and T cell immune responses against self antigens cause tissue damage.