Hypersensitivity Reactions Explained

Introduction to Hypersensitivity Reactions

• Immunity provides defensive power, protecting the body from various infections
• The immune system, when normally protective, can cause abnormal responses called hypersensitivity reactions
• A hypersensitivity reaction involves an inappropriate or exaggerated response to an antigen or allergen
• These reactions can stem from uncontrolled responses to foreign antigens or failure of self-tolerance, leading to autoimmune diseases

Four Types of Hypersensitivity Reactions

• Type I: Immediate or Anaphylactic
• Type II: Cytotoxic Type
• Type III: Immune Complex Disease
• Type IV: Delayed Type or Cell-Mediated HSY

Type I Hypersensitivity: Immediate/Anaphylactic Reaction

• Characterized as a rapidly developing immunologic reaction
• Occurs within minutes of antigen combining with antibodies on mast cells, in previously sensitized individuals
• Commonly referred to as an allergy
• Can manifest as a systemic disorder or as a local reaction
• The systemic reactions typically follows the injection of the sensitizing antigen
• This hypersensitivity is solely mediated by IgE and mast cells
• Atopic or allergic individuals develop this response to inappropriate stimuli
• Culprit antigens often include pet dander and pollen

Pathogenesis of Type I Hypersensitivity

• Sensitization: The antigen enters the body for the first time
• Antigen presenting cells capture and present
• T cells differentiate into TH2 cells
• TH2 cells release mediators, including:
  • IL-4, which activates B cells, leading to IgE release
  • IL-5, responsible for activating eosinophils
  • IL-13, which promotes IgE production and stimulates mucus secretion by epithelial cells
• Secreted IgE binds to mast cells through Fc receptors, mainly present in circulation

Subsequent Exposure and Phases of Type I

• Re-exposure to the same antigen causes reaction to occur in two phases:
  • Initial Phase:
    • Occurs within minutes of antigen exposure
    • Preformed mediators released due to mast cell degranulation, leading to histamine, proteases, and chemotactic factors being dispersed
    • Histamine then causes vasodilation, bronchoconstriction, and increased permeability
  • Late Phase:
    • Occurs 2-24 hours post-exposure
    • Release of secondary mediator from mast cells is seen
    • Secondary mediators include prostaglandins, leukotrienes, cytokines, and platelet-activating factor (PAF)

Impact and Mediators in Type I Pathogenesis

• Secondary mediators cause bronchospasm, increased mucus production, and recruitment of inflammatory cells
• Platelet Activating Factor (PAF) contributes to bronchospasm, heightened permeability, and histamine release, which initiates the late-phase response
• Various mediators are responsible for the clinical features seen in type I hypersensitivity reactions
• Histamine causes;
  • Bronchial smooth muscle contraction
  • Increased vascular permeability
  • Increased secretion by nasal, bronchial and gastric glands.
• Adenosine leads to;
  • Enhanced mast cell mediator release
  • Bronchoconstriction
  • Inhibited platelet aggregation

Type I Hypersensitivity - Localized vs. Systemic

• Localized reactions include bronchial asthma, hay fever/allergic rhinitis, food allergies, atopic dermatitis, urticaria, and angioedema
• Systemic reactions lead to anaphylaxis, often due to antibiotics (specifically penicillin), bee stings, and insect bites

Type II Hypersensitivity: Antibody-Mediated Reactions

• Mediated by antibodies, these are targeted towards endogenous or exogenous specific antigens
• Antigens are present on cell surfaces or in the extracellular matrix
• Pathogenesis involves three mechanisms:
  • Cell depletion or destruction without inflammation
  • Inflammation through complement or Fc receptor activation
  • Cellular dysfunction induced by antibodies

Type II: Cell Depletion/Destruction without Inflammation

• Antibodies, specifically IgG, bind to target cell surfaces
• The Fc portion binds to the Fc receptor on macrophages, acting as an opsonin
• Opsonization activates macrophages, leading to the phagocytosis of the target cell
• Antibodies can activate the complement pathway by binding to the target cell
• This results in the the formation of complement component C3b, acting as an opsonin
• Bound C3b activates macrophages to engulf the cell and cause depletion
• Antibodies binding to the target cell activate the membrane attack complex (MAC)
• MAC involves complement components C5b6789
• MAC creates a channel in the cell, leading to lysis
• A single channel lyses anucleated cells like erythrocytes, nucleated cells require multiple MACs

Type II Hypersensitivity Examples via Opsonization

• Examples resulting from Opsonization, Complement, and Fc Receptor-Mediated Phagocytosis:
  • Transfusion reactions
  • Erythroblastosis fetalis
  • Autoimmune hemolytic anemia
  • Autoimmune thrombocytopenic purpura

Type II Hypersensitivity: Inflammation via Complement/Fc Receptor

• Antibodies bind to self-antigens which activates the complement pathway
• Complement components C3a and C5a are formed
• C3a and C5a are chemotactic factors that recruit neutrophils
• Neutrophils release enzymes and reactive oxygen species, causing tissue damage
• Example: Goodpasture syndrome involves autoantibodies against collagen in glomerular and alveolar basement membranes
• Antibodies against foreign antigens trigger complement activation and inflammation through molecular mimicry
• Acute Rheumatic fever includes antibodies against streptococcal antigens that mimic cardiac myosin and damage the heart

Type II Hypersensitivity: Cellular Dysfunction by Antibodies

• Autoantibodies bind to receptors on target cells, leading to dysfunction without inflammation or destruction
• Graves' disease leads to autoantibodies that bind thyrotropin receptors resulting in thyroid hormone overproduction
• Myasthenia gravis develops due to autoantibodies against nicotinic acetylcholine receptors, preventing acetylcholine binding which causes muscle weakness

Mnemonic for Type II Hypersensitivity Examples

• Myasthenia gravis
• Blood transfusion reactions
• Group - Goodpasture syndrome, Graves' disease
• Is-Insulin resistant diabetes, ITP
• Rheumatic fever
• Hyperacute graft rejection
• Positive- Pernicious anemia and pemphigus vulgaris

Type III Hypersensitivity: Immune Complex Reactions

• Antigen-antibody complexes cause tissue damage by triggering inflammation at the sites of deposition
• The antigen can be endogenous or exogenous
• Immune complexes circulate or deposit in vessels/extravascular sites (in situ immune complexes)
• They may either be generalized or localized
• The reaction has the following phases:
  • Antigen-antibody complex formation (immune complex deposition)
  • Deposition of the immune complex
  • Immune complex mediated inflammation

Phases of Type III Hypersensitivity

• Antigen-antibody complex formation occurs approximately 5 days post antigen introduction
• Small or intermediate immune complexes are the most pathogenic
• Large complexes are rapidly removed by macrophages
• Immune complexes deposit in:
  • Renal glomeruli
  • Skin
  • Serosal surface
  • Joints
  • Heart
  • Small blood vessels

Type III - Immune Complex Mediated Inflammation

• Immune complex mediated inflammation emerges 10 days after antigen administration
• This results in vasculitis, glomerulonephritis, and arthritis
• The immune complexes activate the complement system, causing neutrophilic infiltration, vasodilation, and edema
• Activation of the intrinsic coagulation pathway and the microthrombi formation contribute to tissue ischemia and necrosis
• Morphology includes acute necrotizing vasculitis (necrosis of vessel wall, neutrophilic infiltration)
• Necrotic tissue, immune complexes, complement, and plasma proteins create a smudgy eosinophilic deposit that obscures cellular detail termed fibrinoid necrosis

Mnemonic for Type III Hypersensitivity Examples

• Serum sickness, Schick test, SLE
• Hypersensitivity pneumonitis, Henoch-Schonlein Purpura
• Arthus reaction
• Reactive arthritis and
• Rheumatoid arthritis, Raji assay
• Polyarteritis nodosa (PAN) Post Streptococcal glomerulonephritis

Factors Influencing Deposition of Immune Complexes

• Size of the Immune Complex:
  • Large complexes in great antibody excess are harmless because they are removed from circulation by the mononuclear phagocyte
  • Small or intermediate complexes are the most pathogenic
• Functional Status of the Mononuclear Phagocyte System:
  • Overload or intrinsic dysfunction increases the probability of the immune complexes lasting in circulation

Other Factors Influencing Deposition

• Valency of the antigen
• Avidity of the antibody
• Affinity of the antibody to various tissue components
• Antigen-antibody ratio
• Complement activation

Type IV Hypersensitivity

• Initiated by antigen-activated T lymphocytes
• Forms:
  • Delayed type hypersensitivity reactions (via CD4+ T cells)
  • Direct cell cytotoxicity (via CD8+ T cells)
• Primarily an immunologic response to viruses, fungi, protozoa, and parasites
• Significant in skin sensitivity to chemical agents and graft rejection

Delayed Type Hypersensitivity Reaction Details

• Antigen enters the body, captured by APCs and presented to T cells
• T cells differentiate into TH1 cells
• Sensitized TH1 cells enter circulation and remain in the memory pool
• Re-exposure to the antigen induces the release of cytokines like TNF-α, lymphotoxin, INF-y, IL-2, and IL-12

Delayed Type Hypersensitivity Continued

• Cytokine releases recruit inflammatory cells to the site of inflammation
• Activated macrophages become epithelioid cells, surrounded by lymphocytes, ultimately forming a granuloma
• Granuloma formation occurs in tuberculin tests and in reactions to intracellular pathogens like mycobacterium and some parasites
• Also important in transplant rejection

Morphological Characteristics of Delayed Type Hypersensitivity

• Classic example: The tuberculin reaction from intracutaneous tuberculin injection
• Accumulation of mononuclear cells around small veins and venules producing a perivascular "cuffing"
• Initial perivascular lymphocytic infiltrate is replaced by macrophages over 2-3 weeks
• Accumulation of macrophages undergo morphological transformation into epithelioid cells
• Microscopic aggregation of epithelioid cells, usually surrounded by a collar of lymphocytes which is referred to as a granuloma
• This pattern of inflammation is sometimes seen in type IV hypersensitivity and is called granulomatous inflammation

T-Cell Mediated Cytotoxicity

• Pathogenesis of T cell mediated cytotoxicity includes CD8+ T cells and cytotoxic T lymphocytes (CTL)
• CTLs kill antigen-bearing target cells (tumor cells, infected cells, and allogeneic tissue during graft rejection)
• Two mechanisms:
  • Perforin granzyme dependent killing includes mediators present in the lysosomal granules of the CTLs (like perforin which causes pore formation)
  • Granzyme activates apoptosis when entering the cells via these pores

Examples of Type IV Hypersensitivity

• Include type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, and peripheral neuropathy

Conclusion

• Hypersensitivity reactions are inappropriate immune responses with varied mechanisms and clinical presentations
• An understanding of the mechanism is important for diagnosing and managing affected individuals