Immunological Tolerance and Autoimmunity

Tolerance and Autoimmunity

• Immunological tolerance is unresponsiveness to self-antigens.
• It's the lack of response to antigens.
• The immune system doesn't react against one's own (self) antigens.
• All individuals are tolerant/unresponsive to their self-antigens.
• Tolerance allows for discrimination between self and non-self-antigens.
• Failure of tolerance mechanisms can lead to autoimmunity, where the immune system attacks the body's own cells and tissues.

Objectives

• What is immunological tolerance?
• How many types of tolerance exist?
• How is tolerance induced?
• What's the difference between central and peripheral tolerance?
• What are the mechanisms of autotolerance, and how can it lead to auto-reactivity?
• What is autoimmunity?

Tolerance

• Tolerance refers to the specific immunological non-reactivity to an antigen resulting from a previous exposure to the same antigen.
• Two types of tolerance:
  • Autotolerance (self-tolerance, natural tolerance):
    • Non-reactivity (unresponsiveness) to self-antigen
    • The failure of the immune system to attack the body's own proteins and other antigens
    • It's a desired state.
  • Induced tolerance:
    • Tolerance to non-self antigens.
    • Created by manipulating the immune system.
    • An antigen that induces tolerance is called a "tolerogen".

How Tolerance is Induced

• Tolerance can be induced by administering antigens in specific ways.
• Tolerance can be induced to antigenic components on both soluble proteins and cells (tissues) by injecting these materials into a host.
• The induction of tolerance depends on various factors.

Factors Affecting Tolerance Induction

• Immunologic maturity of the host:
  • Neonates are more easily tolerized than mature hosts.
  • Neonates may accept allografts that mature hosts reject.
• Structure and dose of antigen:
  • Simple molecules induce tolerance more readily than complex ones.
  • Very high or very low doses of antigen can result in "immune paralysis," a form of tolerance.
  • Continuous antigen presence helps maintain tolerance.
• Administration of immunosuppressive drugs: Used in transplantation, to enhance tolerance.
• Tolerance can be induced by soluble antigens administered intravenously or orally.

Importance of Induced Tolerance

• Protection against allergic reactions (e.g., food allergies, insect stings).
• Avoidance of graft rejection, allowing transplanted organs to survive.
• Antigen-specific tolerance strategies are used for preventing and treating autoimmune diseases.

Importance of Immunological Tolerance

• Treating immunological diseases
• Treatment of allergies
• Treatment of autoimmune diseases
• Preventing rejection
• Preventing immune responses against newly expressed genes (gene therapy).

Central and Peripheral Tolerance

• Central tolerance: Occurs during development of T and B cells in the thymus and bone marrow.
• Peripheral tolerance: Develops after T and B cells mature and enter peripheral tissues.

Mechanisms of Autotolerance in T Cells

• Clonal deletion (for central tolerance): Self-reactive T cells are deleted or killed (negative selection) in the thymus during development.
• Clonal anergy (for peripheral tolerance): Self-reactive T cells become functionally inactivated outside the thymus due to inappropriate self-antigen presentation, leading to a lack of IL-2 production.
• Suppressor T cells (regulatory T cells):
  • Suppress immune system activity.
  • Maintain tolerance to self-antigens.
  • Induced by both low and high doses of antigens, acting directly or by cytokine production (e.g., IL-10).

Mechanisms of Autotolerance in B Cells

• Clonal deletion
• Clonal anergy
• Suppressor cells
• Receptor editing: May change the affinity and specificity of B cells due to high soluble antigen levels.

Autoimmunity

• Autoimmunity is an immune response against self-antigens.
• Factors influencing autoimmune development include genetic susceptibility and environmental triggers (e.g., infection).
• Results in production of antibodies against self-antigens or activation of T cells reactive with self-antigens.
• Etiology of human autoimmune diseases is still not fully understood.

Autoimmunity Etiology

• Polygenic: Genetic factors influence susceptibility to autoimmunity, likely by affecting self-tolerance maintenance.
• MHC genes: Genetic variations in MHC genes can affect susceptibility.
• Environmental triggers: Infection, tissue injury, inflammation can promote influx of lymphocytes into tissues and activate self-reactive T cells, causing tissue injury.

Autoimmunity - Other Factors

• Normal encounter of mature T cells with self-antigens presented by resting tissue antigen-presenting cells (APCs) can lead to peripheral tolerance through anergy or deletion.
• Microbes can activate APCs, which then present self-antigens to activate specific T cells, leading to autoimmunity.
• Microbial antigens, due to mimicry, can cross-react with self-antigens.
• Therefore, immune responses initiated by microbes may be directed at self-cells and tissues.
• Some antibodies can cross-react with heart tissue, causing conditions like rheumatic fever.
• Autoimmunity can be triggered by infection or trauma and the release of sequestered antigens, contributing to the failure of self-tolerance and autoimmune disease.