Μάθημα_7_Immune Tolerance & Autoimmunity

Immunologic Tolerance & Autoimmunity

Definition of Immunologic Tolerance

  • Immunologic Tolerance: Specific unresponsiveness induced by an antigen.

  • Tolerogens vs. Immunogens:

    • Tolerogens are antigens that induce tolerance.

    • Immunogens stimulate an immune response.

Consequences of Tolerance Failure

  • Self-tolerance: Mechanism by which the immune system does not attack its host tissues.

  • Autoimmunity: An immune response against self-antigens leading to tissue damage.

Mechanisms of Immunologic Tolerance

Central Tolerance

  • Occurs in generative lymphoid organs (thymus, bone marrow).

  • Thymus Role:

    • Negative Selection: Deletion of T-cells that strongly recognize self-antigens.

    • Generation of Regulatory T cells (Tregs).

Peripheral Tolerance

  • Occurs in peripheral tissues.

  • Mechanisms:

    • Anergy: Functional unresponsiveness of T-cells.

    • Apoptosis: Deletion of self-reactive lymphocytes.

    • T-regulatory cells (Tregs): Suppress unwanted immune responses.

Inducing and Maintaining Tolerance

Significance

  • All individuals are generally tolerant to their own antigens.

  • Breakdown of self-tolerance can lead to autoimmune diseases.

  • Therapeutic Potential: Inducing tolerance can prevent graft rejection and treat autoimmune diseases.

Features of Self Tolerance

  • Self antigens induce central tolerance through:

    • Cell deletion (apoptosis).

    • Clonal anergy and the development of Tregs in peripheral tissues.

  • Mechanisms:

    • Receptor Editing: Altering B-cell receptors to avoid self-reactivity.

    • Development of CD4+ Tregs.

The Role of Antigen-Presenting Cells (APCs)

  • APC Activation: Critical for T-cell tolerance; applies to presentation of both self and foreign antigens.

  • Immunogenic APCs: Present antigens with high co-stimulation that activates T-cells.

  • Tolerogenic APCs: Present self-antigens with low co-stimulation, leading to anergy or deletion of self-reactive T-cells.

Autoimmunity Overview

Definition

  • Autoimmunity occurs when the immune system improperly attacks the body’s own tissues without a clear external trigger.

Mechanisms Leading to Autoimmunity

  • Genetic Susceptibility: Certain genetic factors increase the risk of autoimmune diseases.

  • Environmental Triggers: Infections and inflammation can trigger the activation of self-reactive lymphocytes.

  • Potential association with specific HLA alleles influencing susceptibility.

Examples of Autoimmune Diseases

  • **Organs: **

    • Thyroid: Hashimoto's thyroiditis, Graves’ disease.

    • Blood: Leukemia.

    • Neurological: Multiple sclerosis, Guillain-Barré syndrome.

    • Skin: Psoriasis, Scleroderma.

    • GI Tract: Celiac disease, Crohn’s disease.

Genetic Factors in Autoimmunity

  • Susceptibility Genes: Various genes contribute to autoimmune disease susceptibility, often related to immune system regulation.

  • Single-Gene Autoinflammatory Diseases: Disorders caused by mutations in a single gene, e.g., AIRE, CTLA4, FOXP3.

Pathogenic Mechanisms of Autoimmunity

  • Failure of Self-Tolerance: Increased activity of self-reactive lymphocytes leading to tissue injury.

  • Cross-Reactivity: Immune response to pathogens that resemble self-antigens, confusing the immune system.

Conclusion

  • Treg Mechanisms: Regulatory T cells are crucial for maintaining tolerance and preventing autoimmunity. Their dysfunction or loss can lead to autoimmune diseases.