Autoimmunity and Autoimmune Diseases Quiz

Autoimmunity & Autoimmune Diseases

• Autoimmunity is immune reactions against self (auto)antigens. These reactions are often benign.
• Immune control mechanisms keep autoimmunity benign and prevent "pathogenic autoimmunity."
• Autoimmune diseases occur when mechanisms maintaining immunological tolerance to self-antigens break down.

Learning Objectives

• 8610: Differentiate autoimmunity from autoimmune disease.
• 8611: Describe genetic and/or environmental factors that may underlie the development of autoimmune diseases.
• 8612: Describe potential immunological mechanisms that may cause autoimmune diseases.
• 8613: Categorize autoimmune diseases according to their immunopathology: Type II hypersensitivity, Type III hypersensitivity, and Type IV hypersensitivity.
• 8614: Discuss immunotherapies for the treatment of autoimmune diseases (specific antibodies, cytokines, anti-cytokines, and anti-inflammatory agents).

Autoimmunity vs Autoimmune Diseases

• Autoimmunity: Immune reactions against self (auto)antigens, commonly benign.
• Autoimmune Diseases: Breakdown in mechanisms maintaining immunological tolerance to self-antigens, leading to disease.

Immunological Tolerance to Self-Antigens

• Central tolerance: Involves generative lymphoid organs (thymus and bone marrow). Self-antigen recognition leads to apoptosis.
• Peripheral tolerance: Involves peripheral tissues. Self-antigen recognition can lead to anergy or apoptosis of mature lymphocytes.

Criteria for Defining a Disease as Autoimmune

• Direct proof: Reproducing the disease by transferring antibodies (transplacental or to animals).
• Indirect proof: Recreating the disease in animal models (spontaneous or experimental).
• Circumstantial evidence: Clinical clues (MHC associations, family history, and/or improvement with immunosuppressive drugs).

Most Autoimmune Diseases Are Multifactorial

• Genetic factors: Mendelian disorders, family clustering, and polygenic MHC (HLA) alleles.
• Environmental factors: Certain drugs, modified environmental antigens, trauma-released antigens, and microbial antigens.
• Immune regulation: Aberrant expression of genes that affect immune responsiveness.

Gender & Hormones in Autoimmune Diseases

• Females are more likely to develop autoimmune diseases than males.
• Some autoimmune diseases worsen during pregnancy, while others improve.

HLA Alleles and Autoimmune Diseases

• Specific HLA alleles are associated with certain autoimmune diseases.
• HLA-B27 is associated with ankylosing spondylitis
• HLA-DRB1*15 is associated with Goodpasture's syndrome.
• HLA-DRB1*03 is associated with Systemic lupus erythematosus.

"Known" Triggers/Mechanisms for Autoimmune Diseases

• Failure of oral tolerance
• Release of sequestered antigens from immune privileged sites
• Molecular mimicry
• Polyclonal B-cell activation

Failure of Oral Tolerance in Celiac Disease

• Gluten is broken down, enters tissue, and is deaminated by transglutaminase
• Naive T-cells respond to deaminated peptides presented by HLA molecules
• Inflammation, leading to villous atrophy (damage), is a result.

Immunologically Privileged Sites

• Locations (brain, testis, fetus/placenta, eye) that exclude naïve lymphocytes.
• Factors include secretion of immunosuppressive factors (like TGF-β) and expression of Fas ligand.
• Antigens from these sites may lead to autoimmune responses if released into the circulation.

Breakdown of Self-Tolerance in the Periphery—T-Cell Help For Autoimmune B-Cells

• Molecular mimicry
• Lack of T-cell help leads to anergy or deletion of self-reactive T cells
• Microbial antigen carrying an epitope mimicking a self-antigen.
• T-cell help for self-antigen B-cells can activate autoantibody production.

Molecular Mimicry and Autoimmune Rheumatic Heart Diseases

• Antibodies produced against bacterial antigens may cross-react with heart tissue.
• Contributing to rheumatic heart disease.

Categorization of Autoimmune Diseases by Immunopathology

• Type II hypersensitivity: Autoimmune hemolytic anemia, autoimmune thrombocytopenia, Goodpasture's syndrome.
• Type III hypersensitivity: Systemic lupus erythematosus.
• Type IV hypersensitivity: Hashimoto's thyroiditis, rheumatoid arthritis, and type 1 diabetes.

Examples of Antibody-Mediated Autoimmune Diseases

• Autoimmune Hemolytic Anemia
• Autoimmune Thrombocytopenia
• Goodpasture's Syndrome
• Myasthenia Gravis
• Graves Disease
• Systemic Lupus Erythematosus (SLE)

Myasthenia Gravis & Graves Disease (Anti-receptor Autoantibodies)

• Antagonist autoantibodies in myasthenia gravis block acetylcholine receptors leading to muscle weakness.
• Agonist autoantibodies in Graves disease stimulate thyroid-stimulating hormone (TSH) receptors causing hyperthyroidism

Characteristics of Graves Disease

• Hyperthyroidism
• Family predisposition
• Antibody titers correlate with disease severity
• Neonatal Transfer (maternal antibodies can affect the newborn)

Immune Complex-Mediated Autoimmune Diseases-e.g systemic lupus erythematosus

• Butterfly-like rash
• Photosensitivity
• High levels of anti-double-stranded DNA antibodies.
• Female-to-male ratio of 10:1
• Exacerbated during pregnancy
• Genetic predisposition (with HLA-DR3 association)

Autoimmune Diseases Are Mostly T-cell Mediated

• Hashimoto's Thyroiditis
• Rheumatoid Arthritis
• Multiple Sclerosis
• Type 1 Diabetes

Rheumatoid Arthritis (RA)

• Chronic inflammation, erosion of synovium and bone.
• Immune infiltrate (T cells, macrophages, B cells)
• Rheumatoid factor (antibodies to IgG)
• Genetic component
• Age of onset is typically 40-60 years

Type 1 Diabetes

• Destruction of insulin-producing beta cells in the pancreas.
• CD8+ T-cells play a major role
• Genetic component (HLA-DQB102:01, HLA-DQB103:01)
• Animal model: NOD mouse.

Treatment of Autoimmune Diseases

• NSAIDs (nonsteroidal anti-inflammatory drugs)
• General immunosuppressive drugs
• Corticosteroids
• Inhibitors of cytokine production
• Cytotoxic drugs
• Inhibitors of nucleotide synthesis (interfering with cellular replication)
• Immunosuppressive agents

Targeting Immune Modulators to Treat Autoimmune Diseases

• Biologics - biological response modifiers, or targeted immune modulators to block pro-inflammatory cytokines (e.g., TNF-α).

Specific Therapies-Including Immunotherapies

• Biologics that target TNF-α, IL1, or block B-cell activation.

Summary of Video Overview and Notes on Autoimmunity

• A video, “A Walk through Autoimmunity,” summarizes immune function, autoimmunity, and treatments of various autoimmune conditions.
• Notes provided highlight central and peripheral tolerance mechanisms, diagnostic criteria, genetic and environmental influences, and crucial therapies.

Test your understanding of autoimmunity versus autoimmune diseases, the immunological mechanisms involved, and their associated therapies. This quiz covers the differentiation of these concepts, along with the genetic and environmental factors contributing to autoimmune diseases. Assess your knowledge on categorizing autoimmune diseases by their immunopathology and therapeutic approaches.