Hypersensitivity & Autoimmunity

What Counts as a Hypersensitivity Reaction

• An immune response that damages the host rather than only clearing a threat
• Trigger can be a harmless foreign substance (pollen, a drug) or a self-molecule
• When the target is self, the process is called autoimmunity specifically

Two Variables That Shape the Outcome

• Which arm of immunity does the damage
  • Antibody-driven vs. cell-driven
• Where the target antigen sits
  • Fixed in one tissue → localized disease
  • Circulating or widely distributed → systemic disease

Shared Timeline Across All Four Patterns

• Reaction is antigen-specific, not a generic overreaction
• Cross-reactive molecules can trigger the same primed response

Core Identity

• Only pattern built on IgE
• Symptoms appear within minutes of re-exposure
• Evolutionarily meant to expel large parasites too big to phagocytose
• About one in five people mount this response against harmless environmental triggers (pet dander, pollen) — termed atopy

How Sensitization Happens

1. Antigen enters via mucosa or skin
2. Helper T cells polarize toward a Th2 program
3. Th2 cytokines (IL-4, IL-13) drive B cells to class-switch to IgE
4. IgE coats mast cells and basophils via high-affinity Fc receptors
5. On re-exposure, antigen bridges adjacent IgE molecules
6. Bridging triggers degranulation

What Comes Out of the Granules

Two Waves

Clinical Faces of Type I

• Allergic rhinitis — nasal edema and mucus from airborne allergens
• Asthma — bronchoconstriction and mucus plugging from inhaled triggers
• Food allergy — hives and GI upset
• Systemic anaphylaxis — widespread vasodilation, airway compromise, can be fatal
• Wheal-and-flare — the local skin reaction used diagnostically

Core Identity

• IgG or IgM binds an antigen fixed to a cell surface or extracellular matrix
• Because the target doesn't circulate, damage stays confined to that tissue
• Antigen is usually self, occasionally a foreign molecule that cross-reacts with self

Three Ways the Antibody Can Hurt

• Opsonization → faster phagocytic clearance of the coated cell
• Complement fixation → membrane attack complex or recruitment of neutrophils/macrophages
• Receptor interference → antibody blocks or stimulates a receptor without killing the cell

Two Functional Subtypes

Core Identity

• Antibody binds soluble antigen while still in circulation, forming a complex
• Complexes lodge wherever blood filters through narrow vessels — kidney glomeruli, joints, skin
• Damage site therefore has little to do with where the antigen originated
• Because the trigger circulates, disease tends to be systemic rather than one-organ

Injury Mechanism

Related Antinuclear-Antibody Diseases

• Diffuse systemic sclerosis → antibody to DNA topoisomerase I
• Limited scleroderma (CREST) → anti-centromere antibody
• Sjögren syndrome → antibody to ribonucleoproteins

Core Identity

• Only pattern with no antibody involvement — driven entirely by T lymphocytes
• Onset is delayed, typically one to three days after re-exposure
• Same machinery normally clears intracellular pathogens, so injury is a side effect of a legitimate defense program

Two Routes to Damage

• Cytokine-mediated
  • CD4+ Th1 cells release interferon-gamma → activates macrophages
  • CD4+ Th17 cells release IL-17 → recruits neutrophils
• Direct cytotoxic killing
  • CD8+ cytotoxic T cells lyse the target cell directly

The Starting Point

• Autoreactive lymphocytes recognize a self-antigen, then activate, expand, and differentiate into damaging effectors
• Requires an upstream failure of central tolerance — the education process lymphocytes undergo in bone marrow and thymus

Peripheral Tolerance — the Backup System

• Anergy
  • B cells: self-recognition without T-cell help drives high surface IgD, exclusion from lymphoid tissue, and eventual death
  • T cells: failure of T-cell-receptor signaling, or engagement of inhibitory receptors CTLA-4 / PD-1
• Deletion
  • Self-reactive T cells undergo apoptosis via caspase or Fas signaling
• Suppression
  • Regulatory T cells secrete IL-10 and TGF-beta to dampen lymphocyte, macrophage, and dendritic cell activation
  • Regulatory T cells express abundant CTLA-4, which sequesters the costimulatory molecule B7 away from other T cells

What Tips the Balance Toward Disease

• Genetic susceptibility — HLA alleles are the strongest known association
• Non-HLA gene polymorphisms
• Environmental triggers, including infection
• Hormonal influences

Why Autoimmune Disease Tends to Persist

• Infection or tissue damage can change how self-antigens are displayed, providing the initial trigger
• Injury to one self-antigen can expose additional self-antigens to the immune system
• This spreading exposure is why these diseases are typically chronic and progressive rather than self-limited