Autoimmunity and Tolerance Overview

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Questions and Answers

What defines autoimmunity?

An appropriate response of the immune system against self antigens

An inappropriate response of the immune system against self antigens (correct)

A state of tolerance in T and B cells

A response of the immune system to foreign antigens

Which process involves the elimination of self-reactive lymphocytes during their development?

Positive selection

Central tolerance (correct)

Peripheral tolerance

Activation-induced apoptosis

What role does the transcription factor AIRE play in T cell central tolerance development?

Enhances expression of self-antigens in the thymus (correct)

Inhibits Treg differentiation

Promotes apoptosis of autoreactive T cells

Facilitates positive selection of T cells

What is the primary function of FOXP3 in regulatory T cells?

Regulate Treg cell development (C) Signup and view all the answers

Which mechanism is NOT involved in peripheral tolerance for T and B cells?

Production of antibodies against self-antigens (B) Signup and view all the answers

What is the main function of central tolerance in T cells?

To eliminate immature T cells that react to self-antigens (D) Signup and view all the answers

What is the outcome when there is strong or no binding of TCR to MHC?

Deletion of T cells (A) Signup and view all the answers

Which of the following describes the role of AIRE in T cell development?

To express various peripheral tissue antigens in the thymus (C) Signup and view all the answers

What mechanism is responsible for peripheral tolerance?

Deletion of self-reactive T cells via apoptosis (C) Signup and view all the answers

What is a potential consequence of a mutation in the AIRE gene?

Defective negative selection (C) Signup and view all the answers

Which type of cells are primarily involved in maintaining peripheral tolerance?

Regulatory T cells (Treg) (A) Signup and view all the answers

Which mechanism is NOT a main mechanism of T cell peripheral tolerance?

Activation (C) Signup and view all the answers

During which stage does central tolerance primarily occur?

In the thymus during T cell maturation (A) Signup and view all the answers

Which happens when T cells experience anergy?

T cells become incapable of responding to antigens (C) Signup and view all the answers

What happens to self-reactive CD4+ T cells that do not undergo deletion in the thymus?

They differentiate into Treg cells (B) Signup and view all the answers

What is a potential effect of reduced Treg cell populations?

Development of autoimmunity (D) Signup and view all the answers

What role do Treg cells play in the immune system?

Regulating responses against self antigens (A) Signup and view all the answers

What is the ultimate goal of exposing immature T cells to various self-antigens during their development?

To minimize autoimmune reactions (D) Signup and view all the answers

Which statement best describes peripheral tolerance?

It includes mechanisms like Treg cell-mediated suppression (A) Signup and view all the answers

How do T cells become anergic?

By binding to APCs without costimulation (A) Signup and view all the answers

What effect does weak TCR-MHC binding have on T cell function?

Pathway towards helper T cell development (B) Signup and view all the answers

What is the result when tolerance mechanisms fail in the immune system?

Autoimmune responses against self antigens (D) Signup and view all the answers

Which process is NOT a part of central tolerance during T and B cell development?

Proliferation of autoreactive T cells (A) Signup and view all the answers

How do Treg cells maintain peripheral tolerance?

By expressing inhibitory receptors and secreting immunosuppressive cytokines (D) Signup and view all the answers

What is one mechanism proposed for breaking tolerance leading to autoimmune conditions?

Molecular mimicry with foreign antigens (C) Signup and view all the answers

Which statement best describes the role of anergic T and B cells?

They fail to respond to further stimulation by antigens (A) Signup and view all the answers

What is the potential effect of exposing epitopes during protein denaturation?

Epitopes may be mistaken for foreign antigens (D) Signup and view all the answers

What happens to immature T cells that recognize MHC+self-Ag during development?

They undergo apoptosis or differentiate into Treg cells (A) Signup and view all the answers

What may happen to B cells in response to self-antigens to maintain tolerance?

They may express inhibitory receptors (B) Signup and view all the answers

What is the primary role of CD25 in T cell regulation?

It binds and sequesters IL-2. (A) Signup and view all the answers

What are the three cytokines secreted by Treg cells that inhibit immune responses?

IL-10, TGF-β, and IL-35 (D) Signup and view all the answers

How do immature B cells that bind self-antigens with high avidity achieve central tolerance?

By undergoing receptor editing or apoptosis. (A) Signup and view all the answers

What happens to immature B cells that bind with low avidity to self antigens?

They remain in an anergic state. (B) Signup and view all the answers

What is one proposed mechanism of B cell peripheral tolerance?

Repeated stimulation by self-antigens can lead to anergy or deletion. (D) Signup and view all the answers

What is the role of the inhibitory receptor CD22 in B cell regulation?

It inhibits B cell activation against self-antigens. (C) Signup and view all the answers

How do Treg cells generally affect self-reactive lymphocytes?

They inhibit their activation, activity, and survival. (B) Signup and view all the answers

Which of the following statements is true regarding receptor editing in B cells?

It modifies the B cell receptor to prevent self-recognition. (D) Signup and view all the answers

Study Notes

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.

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Description

This quiz covers the principles of autoimmunity and the concepts of central and peripheral tolerance. Learn about the mechanisms of immune response, the classification of autoimmune diseases, and the role of Treg cells in regulating lymphocyte activity. Test your understanding of how tolerance develops in T cells and B cells.