Immune Tolerance

Immunological Tolerance and Autoimmunity

Introduction

  • Context: Lecture presented by Dr. Karl Meszaros.

  • Textbooks Referenced:

    • Robbins: Basic Pathology

    • Current Immunology Textbooks (Janeway’s, Abbas’s, others)

Learning Objectives

  • Understand, memorize, and describe the following key concepts:

    • Receptor Diversity and the concept of self and not-self

    • Central tolerance and Peripheral tolerance

    • Autoimmunity

    • Autoimmune diseases - Distinction between systemic and organ-specific diseases

    • Mechanisms of autoimmunity including contributing factors

    • Immune-complex-mediated tissue injury

    • T-cell mediated tissue injury

    • Detailed examination of Systemic Lupus Erythematosus (SLE)

    • Prevalence

    • Pathogenesis

    • Clinical and laboratory findings

    • Overview of Sjogren syndrome and Scleroderma

    • Concepts surrounding Transplantation immunity

    • Compatibility

    • Rejection of allografts

    • Immunosuppression for prevention of rejection

Key Concepts

Autoimmunity

  • Definition: Autoimmunity refers to an immune response that is misdirected against the body's own tissues, leading to injury and disease.

Immunological Tolerance

Self and Not Self Concept

  • Self refers to the body’s own cells and molecules.

  • Not-self refers to foreign substances that should elicit an immune response.

  • Immunological Tolerance is the state where the immune system does not respond to self-antigens.

Mechanisms of Immunological Tolerance

  1. Central Tolerance

    • Achieved during the maturation of T cells in the thymus and B cells in the bone marrow.

    • Mechanisms include:

      • Deletion: Lymphocytes that react to self-antigens are deleted via apoptosis.

      • Differentiation: Some T cells become regulatory (Treg) cells that help maintain tolerance.

      • AIRE Protein: The autoimmune regulator (AIRE) protein facilitates the presentation of peripheral tissue antigens in the thymus, promoting the deletion of self-reacting T cells.

  2. Peripheral Tolerance

    • Applies to lymphocytes that have escaped central tolerance.

    • Mechanisms include:

      • Regulatory T Cells (Treg): Suppress immune responses by secreting interleukin-10 (IL-10).

      • Anergy: A state of unresponsiveness to antigen stimulation.

      • Apoptosis: Deletion of autoreactive cells in peripheral tissues.

  3. Slippage

    • Refers to the phenomenon where some self-reactive lymphocytes escape deletion and may cause tissue injury if not adequately controlled.

Autoimmune Diseases

Classification

  1. Organ-Specific Autoimmune Diseases (Mediated by Antibodies)

    • Examples:

      • Autoimmune hemolytic anemia

      • Myasthenia gravis

      • Graves disease

  2. Systemic Autoimmune Diseases

    • Examples:

      • Systemic lupus erythematosus (SLE)

      • Rheumatoid arthritis

      • Multiple sclerosis

Mechanisms of Autoimmunity

  • Associated with several factors:

    • Genetic predisposition (e.g., susceptibility genes and specific HLA alleles)

    • Environmental triggers (e.g., infections, tissue damage)

    • Dysregulation leading to immune complex deposition or T-cell mediated injuries.

Systemic Lupus Erythematosus (SLE)

Overview

  • Prevalence: Approximately 1 in 250 people; higher incidence among Blacks and Hispanics.

  • Demographics: Predominantly affects young females aged 20-50 years.

Pathogenesis

  • Involvement of susceptibility genes that impair self-tolerance.

  • Environmental factors (e.g., UV radiation) exposing nuclear antigens, leading to an immune response.

  • Production of various autoantibodies, particularly antinuclear antibodies (ANAs).

Classification Criteria for SLE

  • Requirements: At least 4 of 17 criteria (at least 1 clinical and 1 laboratory).

    • Clinical Criteria:

    • Acute and chronic cutaneous lupus

    • Oral or nasal ulcers

    • Arthritis

    • Serositis

    • Renal involvement

    • Neurologic manifestations

    • Hematological disorders

    • Immunologic Criteria:

    • Presence of antinuclear antibodies (ANA)

    • Anti-dsDNA antibodies

    • Low complement levels (C3, C4, CH50)

Clinical Manifestations

  • Symptoms can be diverse and include:

    • Skin rashes, particularly a butterfly rash on the face

    • Renal inflammation (nephritis)

    • Neurologic symptoms (seizures, psychiatric symptoms)

    • Hematological issues (anemia, thrombocytopenia)

  • Typical clinical presentation includes fatigue, fever, and musculoskeletal pain.

Autoimmunity and Transplantation Immunity

Transplant Rejection

  • Allograft rejection: The immune system recognizes grafted tissue as foreign, invoking an immune response.

    • Types of Rejection:

    • Hyperacute Rejection: Occurs within minutes, often due to preformed antibodies.

    • Acute Rejection: Develops over days or weeks, mediated by T cells and antibodies.

    • Chronic Rejection: Occurs after months to years, characterized by gradual fibrosis and organ failure.

Graft-Versus-Host Disease (GVHD)

  • Occurs when transplanted immune cells attack the host tissues; significant in stem cell transplants.

Conclusion

  • Understanding the mechanisms of autoimmunity and immunological tolerance is crucial for diagnosing and treating autoimmune diseases, and for improving transplant success via immunosuppression.

Recommended Practice Questions

  • Various sources include quizzes and resources at Harvard, URMC, and Khan Academy for deeper understanding of autoimmune diseases.