Immunological Tolerance and Autoimmunity PDF

# Immunological Tolerance and Autoimmunity ## Understanding Mechanisms of Self-Regulation and Autoimmune Disease **DR EVANA KAMARUDIN** ## Learning Objectives - Understand the concept of immunological tolerance: Learn how the immune system differentiates between self and non-self and maintains t...

# Immunological Tolerance and Autoimmunity ## Understanding Mechanisms of Self-Regulation and Autoimmune Disease **DR EVANA KAMARUDIN** ## Learning Objectives - Understand the concept of immunological tolerance: Learn how the immune system differentiates between self and non-self and maintains tolerance to self-antigens. - Differentiate between central and peripheral tolerance mechanisms: Explore how tolerance is achieved in both primary and secondary lymphoid organs. - Explain the role of regulatory T cells (Tregs) in maintaining tolerance: Understand how Tregs suppress immune responses to self-antigens. - Identify factors contributing to autoimmunity: Examine genetic and environmental triggers that lead to autoimmune disease. - Describe the role of genetic and environmental factors in autoimmune diseases: Discuss how polymorphisms and environmental influences contribute to the onset of autoimmunity. ## What is Immunological Tolerance? | | **Definition** | **Prevention of Autoimmunity** | **Mechanisms Involved** | |---|---|---|---| | ⚖️ | Immunological tolerance is the immune system's ability to distinguish between self and non-self, preventing attacks on self-antigens. | It is critical in preventing autoimmune diseases, where the immune system mistakenly targets its own tissues. | Achieved through central and peripheral tolerance mechanisms that regulate immune cell selection and response. | ## Central Tolerance | | **Location** | **Negative Selection** | **Role of AIRE Gene** | |---|---|---|---| | 📍 | Central tolerance occurs in primary lymphoid organs, such as the thymus for T cells and the bone marrow for B cells. | Self-reactive lymphocytes are eliminated through negative selection, preventing them from entering the bloodstream. | AIRE facilitates the expression of tissue-specific antigens in the thymus, ensuring the deletion of self-reactive T cells. | ## Peripheral Tolerance | | **Location** | **Anergy** | **Regulatory T Cells (Tregs)** | **Activation-Induced Cell Death (AICD)** | |---|---|---|---|---| | 📍 | Occurs in secondary lymphoid organs such as the spleen and lymph nodes, regulating self-reactive cells that escape central tolerance. | Self-reactive T cells can be rendered inactive if they do not receive the required costimulatory signals, becoming unresponsive. | Tregs suppress self-reactive immune cells through inhibitory cytokines and prevent autoimmunity. | Overactive or chronically stimulated T cells undergo apoptosis through AICD to prevent prolonged immune responses. | ## Role of Regulatory T Cells (Tregs) | | **FOXP3 Expression** | **Suppression of Immune Responses** | **Prevention of Autoimmunity** | |---|---|---|---| | 🧬 | Tregs express the transcription factor FOXP3, which is essential for their development and function. | Tregs produce inhibitory cytokines like IL-10 and TGF-β to suppress immune responses and prevent activation of self-reactive T cells. | Tregs are critical in maintaining self-tolerance by preventing autoimmunity through direct cell-to-cell contact and secretion of suppressive molecules. | ## Mechanisms Preventing Autoimmunity | | **Central Tolerance** | **Peripheral Tolerance** | **Failure of Tolerance Mechanisms** | |---|---|---|---| | ❌ | Involves negative selection of self-reactive T and B cells in the thymus and bone marrow. | Mechanisms like anergy, Treg suppression, and immune privilege sites prevent autoimmunity. | When these mechanisms fail, self-reactive cells can lead to autoimmunity. | ## Immune Privilege | | **Immune Privileged Sites** | **Mechanisms of Protection** | **Significance** | |---|---|---|---| | 👀 | Certain tissues, like the brain, eyes, and testes, are immune privileged, meaning they are protected from immune responses. | Physical barriers, anti-inflammatory cytokines, an Fas ligand expression prevent immune cell infiltration and damage. | These sites are vital for preserving tissue integrity and function by minimizing immune-related damage. | ## What is Autoimmunity? | | **Definition** | **Breakdown of Self-Tolerance** | **Types of Autoimmunity** | |---|---|---|---| | 🧑‍⚕️ | Autoimmunity occurs when the immune system mistakenly attacks the body's own tissues, leading to chronic inflammation and tissue damage. | It arises from a failure in self-tolerance mechanisms, such as central and peripheral tolerance. | Autoimmune diseases can be organ-specific, affecting one tissue, or systemic, affecting multiple organs. | ## Organ-Specific Autoimmune Diseases - **Type 1 Diabetes Mellitus:** Autoimmune destruction of insulin-producing β-cells in the pancreas, leading to impaired glucose regulation. - **Graves' Disease:** Overactivation of the thyroid gland due to autoantibodies that stimulate the thyroid receptor. - **Multiple Sclerosis:** The immune system attacks the myelin sheath in the central nervous system, impairing nerve signal transmission. ## Systemic Autoimmune Diseases | | **Systemic Lupus Erythematosus (SLE)** | **Rheumatoid Arthritis** | **Sjögren's Syndrome** | |---|---|---|---| | 🌊 | Autoantibodies target multiple organ systems, causing widespread inflammation and damage. | The immune system attacks the joints, leading to chronic inflammation and deformity. | Autoimmune destruction of moisture-producing glands results in dry eyes and mouth. | ## Genetic Factors in Autoimmunity | | **MHC (HLA) Gene Polymorphisms** | **AIRE and FOXP3 Genes** | **Genetic Predisposition** | |---|---|---|---| | 🧬 | Specific HLA alleles like HLA-DR4 (rheumatoid arthritis) and HLA-DR3 (type 1 diabetes) are linked to autoimmune disease susceptibility. | Mutations in these genes disrupt tolerance mechanisms and are associated with increased risk of autoimmunity. | The combination of genetic factors determines an individual's overall susceptibility to developing autoimmune conditions. | ## Environmental Triggers of Autoimmunity | | **Infections** | **Smoking** | **UV Radiation** | |---|---|---|---| | ⭐️ | Infections, such as viral or bacterial, can trigger autoimmunity through mechanisms like molecular mimicry. | Smoking is a well-known environmental risk factor for autoimmune diseases like rheumatoid arthritis. | Exposure to UV radiation has been linked to the onset or exacerbation of autoimmune conditions, particularly lupus. | ## Molecular Mimicry | | **Definition** | **Example: Rheumatic Fever** | **Implications** | |---|---|---|---| | 🔀 | Molecular mimicry occurs when pathogens have antigens similar to self-antigens, leading to cross-reactive immune responses. | Following Streptococcal infection, antibodies against the M protein cross-react with heart tissue, causing rheumatic heart disease. | Molecular mimicry illustrates how infections can inadvertently trigger autoimmunity by confusing the immune system. | ## Autoantibodies in Autoimmune Diseases | | **Autoantibodies** | **Immune Complexes** | **Examples** | |---|---|---|---| | 👁️ | These are antibodies that mistakenly target self-antigens, contributing to tissue damage in autoimmune diseases. | Autoantibodies can form immune complexes with self-antigens, which deposit in tissues and cause inflammation. | Anti-nuclear antibodies (ANAs) in SLE and anti-thyroid antibodies in Graves' disease illustrate how autoantibodies contribute to pathology. | ## Pathogenesis of Autoimmune Diseases | | **Breakdown of Immune Tolerance** | **Chronic Inflammation** | **Autoantibodies and T Cells** | |---|---|---|---| | 🔓 | Autoimmune diseases result from a failure of central and peripheral tolerance mechanisms. | Persistent immune activation leads to chronic inflammation and progressive tissue damage. | Self-reactive T cells and autoantibodies attack normal tissues, driving disease progression. | ## Type IV Hypersensitivity and Autoimmunity | | **Mediated by T Cells** | **Role in Autoimmune Diseases** | **Example: Multiple Sclerosis** | |---|---|---|---| | 🤝 | Type IV hypersensitivity reactions involve T cells rather than antibodies, leading to delayed tissue damage. | Many autoimmune diseases, such as multiple sclerosis, involve Type IV hypersensitivity, where T cells attack healthy tissues. | In MS, CD4+ T cells attack the myelin sheath in the central nervous system, causing neurological dysfunction. | ## Treatment Strategies for Autoimmune Diseases | | **Immunosuppressive Drugs** | **Corticosteroids** | **Biologic Therapies** | |---|---|---|---| | 💊 | Drugs like methotrexate and azathioprine suppress the immune system to prevent further tissue damage. | Anti-inflammatory agents used to reduce inflammation and slow the progression of autoimmune diseases. | Targeted treatments like anti-TNF agents and monoclonal antibodies offer more precision in modulating immune responses. |