Autoimmunity Study Notes

Autoimmunity

Tolerance

  • Definition of Tolerance: Refers to the mechanisms that prevent the immune system from attacking self-antigens, thereby avoiding autoimmunity.

  • Development of B/T Cells:

    • During maturation, self-reactive B and T cells are either eliminated or differentiated into regulatory T-cells (Tregs).

    • Regulatory T-cells: Play a critical role in maintaining immune tolerance and preventing autoimmunity.

  • Escape of Self-reactive Cells: Despite rigorous testing, some self-reactive cells manage to evade these mechanisms and enter circulation.

Privileged Antigens

  • Definition: Self antigens from parts of the body that have limited contact with the immune system, thereby minimizing exposure to self-reactive B and T cells.

  • Examples of Privileged Sites:

    • Central Nervous System (CNS)

    • Eyes

    • Testes

Hidden Antigens

  • Definition: Antigens that are typically found within cells or in secreted proteins, making them inaccessible during immune maturation.

  • Maturation Process: B and T cells are not tested against these privileged and hidden antigens, which can lead to autoimmune responses when they are later exposed.

Molecular Mimicry

  • Concept: Some pathogens have evolved to closely resemble human cellular components, potentially as an avoidance strategy against immune activation.

  • Immune Response Activation:

    • Each immune system is unique, meaning some pathogens may be distinct enough to elicit an immune response.

    • However, their similarities can lead to cross-reactivity with self-antigens during the affinity maturation process.

  • Consequences: This phenomenon can activate self-reactive B-cells that passed through the developmental screening.

  • Clinical Relevance: Molecular mimicry is implicated in various organ-specific autoimmune diseases such as:

    • Multiple Sclerosis (MS)

    • Type 1 Diabetes

    • Myasthenia Gravis

    • Systemic Lupus Erythematosus (SLE)

Bystander Activation

  • Mechanism: Antigens within cells, typically hidden from immune surveillance, escape upon cell death, leading to unintended immune activation.

  • Activation Process:

    • Antigen-Presenting Cells (APCs) do not recognize these hidden antigens as threats while healthy.

    • Infection results in cell death, releasing internal antigens and creating an inflammatory environment.

    • Increased activation of APCs by Pathogen-Associated Molecular Patterns (PAMPs) can result in the display of self-antigens, activating autoreactive B and T cells.

  • Impact: Leads to a stronger cytotoxic T-cell response.

How Autoimmunity Causes Damage

  • Mechanisms of Damage:

    • Bad Antibodies: React with self-antigens, disrupting normal function.

    • Angry T-cells: Directly kill host cells and secrete inflammatory cytokines that enhance tissue damage.

    • Immune Complexes: Form by reacting with self or foreign antigens and can circulate in the blood, often being deposited in capillaries, which stimulates the complement pathway.

  • Types of Damage:

    • Cytotoxicity: Direct destruction of cells by autoreactive components.

    • Inflammation: Prolonged inflammation disrupts tissue function, leads to cell death, and depletes resources.

    • Dysregulation: Causes inappropriate cell reactions—either overreacting or failing to respond when needed.

Types of Autoimmune Damage

  • Cytotoxicity

  • Inflammation

  • Dysregulation

Specific Autoimmune Conditions

  • Antobodies Related Conditions:

    • Hashimoto’s Thyroiditis

    • Graves Disease

    • Myasthenia Gravis

  • T-cell Related Conditions:

    • Type 1 Diabetes

    • Multiple Sclerosis

  • Immune Complex Related Condition:

    • Systemic Lupus Erythematosus (SLE)

  • Note: Many autoimmune diseases do not fit into a single category.

Types of Damage: Organ Specific vs. Systemic

  • Organ Specific Autoimmune Disease:

    • Definition: Auto-antigens are localized to a specific organ or tissue causing targeted damage mainly in that area.

    • Examples: Celiac Disease, Type 1 Diabetes, Graves Disease, Hashimoto’s Thyroiditis, Multiple Sclerosis.

  • Systemic Autoimmune Disease:

    • Definition: Auto-antigens are present throughout the body, leading to widespread effects and damage.

    • Examples: Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Myasthenia Gravis.

Organ Specific Autoimmune Diseases

Celiac Disease

  • Mechanism: Antibody production against gluten leads to bowel inflammation.

  • Consequences: Destruction of microvilli and impaired nutrient absorption.

  • Treatment: Lifelong avoidance of gluten; chronic condition, often incurable.

Type 1 Diabetes

  • Mechanism: Cytotoxic T-cell attack on insulin-secreting β-cells of the pancreas.

  • Consequences: Progressive destruction not symptomatic until severe damage occurs.

  • Treatment: Insulin supplementation; permanent cell loss consequences. Associated with viral infections.

Graves Disease

  • Mechanism: Antibodies generated against thyroid-stimulating hormone (TSH) receptors, leading to overproduction of thyroid hormones.

  • Consequences: Persistent hyperthyroidism symptoms and complications.

  • Treatment: Commonly involves destroying thyroid tissue and hormone replacement therapy.

Hashimoto’s Thyroiditis

  • Mechanism: Autoreactive T cells and antibodies attack thyroid follicular cells.

  • Consequences: Gradual reduction in thyroid hormone production leading to symptoms appearing only when substantial damage has occurred.

  • Treatment: Hormone replacement; destruction of thyroid tissue may occur in cases of goiter formation.

Multiple Sclerosis

  • Mechanism: Immune cells breach the CNS barrier, releasing cytokines that inflame neuronal myelin sheaths.

  • Consequences: Symptoms include impaired muscle coordination, altered sensations, cognitive difficulties, and fatigue.

  • Treatment: Steroids for acute episodes; management includes monoclonal antibodies and interferon; challenges in treatment efficacy.

Systemic Autoimmune Diseases

Myasthenia Gravis

  • Mechanism: Autoantibodies targeting acetylcholine receptors in skeletal muscle.

  • Consequences: Muscle weakness, fatigue, potential for partial paralysis.

  • Treatment: Includes acetylcholinesterase inhibitors, steroids, and monoclonal antibodies; plasmapheresis as an option.

Rheumatoid Arthritis

  • Mechanism: Anti-CCP antibodies form immune complexes that accumulate in joints causing inflammation.

  • Consequences: Joint destruction, altered healing, varying levels of chronic pain and movement dysfunction.

  • Treatment: Disease-modifying anti-rheumatic drugs (DMARDs), adjunctive pain management strategies, physical therapy, and sometimes steroids.

Acute Autoimmune Responses
Rheumatic Fever

  • Description: Follows infection by Streptococcus pyogenes.

  • Mechanism: Antibodies against streptococcal M proteins mistakenly attack heart and joint tissues (Type II hypersensitivity).

  • Consequences: Heart valve damage from cell-mediated immune response and systemic symptoms such as fever, rashes, and joint pain.

  • Treatment: Prompt antibiotic treatment of strep infections, followed by symptomatic treatment using NSAIDs and steroids.

Treatment/Therapy Approaches

Hormone Replacement Therapy

  • Application: Conditions like Type 1 Diabetes, Hashimoto’s Thyroiditis, and Addison’s Disease can be managed by supplementing hormones that are no longer produced.

  • Specifics: Graves Disease often requires thyroid ablation and subsequent hormone replacement therapy.

Immune System Modulation

  • Steroids:

    • Commonly used in acute autoimmune disease flare-ups.

    • Function: Primarily work by reducing T-cell activity and inflammation but come with risks of long-term use complications.

  • Monoclonal Antibodies (MABs):

    • These targeted therapies inhibit specific cytokine interactions or activate pathways for immune cell destruction.

  • DMARDs: Utilized for chronic autoimmune conditions like Rheumatoid Arthritis and others.

  • Experimental Therapies:

    • Stem Cell Therapies: Ongoing research into their use for replacing damaged immune cells.

    • Autologous Stem Cell Transplantation: Aims to reboot the immune response by destroying the existing immune system and replacing it with genetically modified or unmodified cells.

Summary of Autoimmunity

  • Characteristics of Autoimmune Diseases:

    • Arise when immune tolerance mechanisms fail or are disrupted.

    • Self-reactive B or T cells wrongly activated and allowed to function.

    • Triggers can include molecular mimicry or bystander effects, leading to improper immune responses.

  • Types of Damage:

    • Autoantibodies: Cause cytotoxicity, dysregulation, and form immune complexes.

    • T-cells contribute to cytotoxicity and inflammation.

  • Disease Outcomes:

    • Organ-specific damage tends to affect confined areas, whereas systemic autoimmune diseases affect multiple tissues, often via circulating immune complexes.