Immune mechanisms in the pathogenesis of diseases, disorders of immune tolerance

The immune system protects the body against pathogens through highly regulated innate and adaptive responses. However, dysregulation of immune mechanisms can lead to tissue damage, hypersensitivity reactions, and autoimmune diseases. These pathological processes often arise from failure of immune tolerance or exaggerated immune responses.

Key Definitions

• Immunity: The ability of the body to resist infections and eliminate foreign substances.
• Immune response: The reaction of immune cells and molecules against antigens.
• Antigen: Any substance capable of inducing an immune response.
• Self-antigen: Components of the body recognized as “self.”
• Immune tolerance: The ability of the immune system to avoid attacking self-antigens.
• Autoimmunity: Immune response directed against self-antigens.
• Hypersensitivity: Exaggerated or inappropriate immune response causing tissue damage.

Hypersensitivity Reactions

There are four main types of hypersensitivity reactions, a mnemonic to remember them is

ACID

Allergic Reaction (type 1)

Cytotoxic Reaction (type 2)

Immune Complex Reaction (type 3)

Delayed Reaction (type 4)

Type I Hypersensitivity (Immediate)

Definition: IgE-mediated reaction occurring within minutes after antigen exposure

Mechanism:

• Allergen → activation of Th2 cells
• IL-4, IL-13 → IgE production
• IgE binds mast cells
• Re-exposure → cross-linking of IgE → mast cell degranulation
• Release of histamine, leukotrienes → vasodilation, bronchospasm

Morphology: Edema, eosinophils, mucus secretion

Clinical Examples:

• Anaphylaxis
• Bronchial asthma
• Allergic rhinitis (hay fever)

Type II Hypersensitivity (Antibody-Mediated)

Definition: IgG/IgM antibodies directed against cell surface or ECM antigens

Mechanisms:

1. Opsonization → phagocytosis
2. Complement-mediated lysis
3. Inflammation via Fc/complement
4. Receptor dysfunction (stimulating or blocking)

Morphology: Cell destruction, inflammation

Clinical Examples:

• Autoimmune hemolytic anemia
• Goodpasture syndrome
• Myasthenia gravis (receptor blockade)
• Graves disease (receptor stimulation)

Type III Hypersensitivity (Immune Complex)

Definition: Deposition of antigen-antibody complexes in tissues

Mechanism:

• Circulating Ag-Ab complexes → deposit in vessels
• Activate complement → neutrophil recruitment
• Enzymatic tissue damage

Morphology: Vasculitis, fibrinoid necrosis

Clinical Examples:

• Systemic lupus erythematosus (SLE)
• Poststreptococcal glomerulonephritis
• Serum sickness

Type IV Hypersensitivity (T-cell Mediated)

Definition: Delayed reaction mediated by T lymphocytes (not antibodies)

Mechanisms:

1. CD4+ T cells → cytokines → macrophage activation
2. CD8+ cytotoxic T cells → direct cell killing

Morphology: Mononuclear infiltrate, granulomas

Clinical Examples:

• Tuberculosis (granulomas)
• Contact dermatitis
• Type 1 diabetes mellitus

Disorders of Immune Tolerance

Types of Immune Tolerance

1. Central tolerance
   • Occurs in primary lymphoid organs (thymus, bone marrow)
   • Eliminates self-reactive T and B cells (negative selection)
2. Peripheral tolerance
   • Occurs in peripheral tissues
   • Mechanisms:
     • Anergy (functional inactivation)
     • Suppression by regulatory T cells (Tregs)
     • Deletion via apoptosis

Failure of Tolerance Leads to:

• Autoimmune diseases
• Chronic inflammation
• Hypersensitivity reactions

Autoimmune Diseases

Definition: Autoimmune diseases occur when the immune system attacks self-antigens due to breakdown of tolerance.

Pathogenesis

• Genetic susceptibility (HLA association)
• 
  Environmental triggers (infections, drugs)
• Molecular mimicry (cross-reactivity)
• Loss of regulatory T-cell function

Types of Autoimmune Diseases

1. Organ-specific autoimmune diseases

• Affect a single organ

Examples:

• Type 1 diabetes mellitus
• Hashimoto thyroiditis
• Graves disease

2. Systemic autoimmune diseases

• Affect multiple organs

Examples:

• Systemic lupus erythematosus (SLE)
• Rheumatoid arthritis
• Systemic sclerosis