12.3 Types I-IV Hypersensitivity Reactions and Mechanisms of Autoimmunity

12.3 Types I-IV Hypersensitivity Reactions and Mechanisms of Autoimmunity

Hypersensitivity reactions are exaggerated or inappropriate immune responses that result in tissue injury or disease. The standard Gell and Coombs classification categorizes hypersensitivity into four distinct immunologic mechanisms (Types I through IV).

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Gell and Coombs Classification of Hypersensitivity

+-----------+---------------------------------+----------------------------------------+------------------------------------------+
| Type      | Immune Mechanism                | Pathologic Process                     | Classical Clinical Examples              |
+-----------+---------------------------------+----------------------------------------+------------------------------------------+
| Type I    | IgE antibodies on mast cells    | Allergen cross-linking causes mast     | Anaphylaxis, allergic asthma, allergic   |
| (Immediate| and basophils                   | cell degranulation (histamine, LTs)    | rhinitis, urticaria, food allergies      |
+-----------+---------------------------------+----------------------------------------+------------------------------------------+
| Type II   | IgG or IgM against cell-surface | Opsonization/phagocytosis, complement  | AIHA, Goodpasture, Rheumatic fever,      |
| (Cytotoxic| or tissue matrix antigens       | lysis, ADCC, or receptor alteration    | Myasthenia gravis, Graves disease        |
+-----------+---------------------------------+----------------------------------------+------------------------------------------+
| Type III  | Soluble IgG/IgM immune          | Deposit in vessel walls; activates     | SLE, Post-streptococcal glomeruloneph-   |
| (Immune   | complexes                       | complement & recruits neutrophils      | ritis, Serum sickness, Arthus reaction   |
| Complex)  |                                 |                                        |                                          |
+-----------+---------------------------------+----------------------------------------+------------------------------------------+
| Type IV   | Sensitized T lymphocytes        | Th1 cytokine release (IFN-g) activates | Contact dermatitis (poison ivy), PPD test|
| (Delayed) | (CD4+ Th1/Th17 or CD8+ CTLs)    | macrophages; CD8+ direct cytotoxicity  | Type 1 Diabetes, MS, GVHD                |
+-----------+---------------------------------+----------------------------------------+------------------------------------------+

Type I: Immediate (IgE-Mediated) Hypersensitivity

• Sensitization Phase: First exposure to an allergen causes CD4+ T cells to differentiate into Th2 cells. Th2 cells secrete IL-4 and IL-13, stimulating B-cell class switching to IgE. IgE binds high-affinity $Fc\epsilon RI$ receptors on tissue mast cells and circulating basophils, sensitizing them.
• Effector Phase: Re-exposure to allergen cross-links bound IgE molecules, triggering rapid mast cell degranulation:
  • Preformed Mediators (Minutes): Release of histamine (vasodilation, increased vascular permeability, smooth muscle constriction), tryptase (marker of mast cell activation), and heparin.
  • Newly Synthesized Lipid Mediators (Hours): Arachidonic acid metabolites including leukotrienes $LTC_4, LTD_4, LTE_4$ (potent, prolonged bronchoconstrictors and capillary permeability inducers) and prostaglandin $PGD_2$.
  • Late-Phase Reaction (2–24 Hours): Th2 cytokines (IL-5) recruit eosinophils, releasing major basic protein and eosinophil cationic protein, perpetuating tissue damage.
• Clinical Manifestations: Anaphylactic shock (systemic hypotension, laryngeal edema), allergic asthma, allergic rhinitis, urticaria (hives), and angioedema.

Type II: Cytotoxic (Antibody-Mediated) Hypersensitivity

IgG or IgM antibodies target specific antigens on cell surfaces or extracellular matrix components. Injury occurs via three principal mechanisms:

1. Opsonization and Phagocytosis / Complement Lysis: Antibodies coat cells, attracting phagocytes via Fc receptors or activating the complement MAC. Examples: Autoimmune Hemolytic Anemia (AIHA), Immune Thrombocytopenia (ITP), ABO hemolytic transfusion reactions, and Erythroblastosis Fetalis.
2. Complement- and Fc Receptor-Mediated Inflammation: Antibodies bind fixed tissue matrix, activating complement ($C5a, C3a$) and recruiting neutrophils. Examples: Goodpasture Syndrome (anti-GBM antibodies against $\alpha_3$ chain of type IV collagen in renal glomeruli and pulmonary alveoli) and Acute Rheumatic Fever (anti-streptococcal M protein antibodies cross-reacting with cardiac myosin).
3. Cellular Dysfunction Without Tissue Destruction: Antibodies bind cell receptors, altering signal transduction without inducing inflammation. Examples: Myasthenia Gravis (autoantibodies block or internalize postsynaptic acetylcholine receptors at the neuromuscular junction) and Graves Disease (autoantibodies stimulate the TSH receptor, causing hyperthyroidism).

Type III: Immune Complex-Mediated Hypersensitivity

Soluble antigen-antibody (IgG/IgM) complexes form in the circulation and deposit in small vessel walls, basement membranes, and tissues (glomeruli, joints, skin).

• Pathogenesis: Antigen-antibody complexes (especially at slight antigen excess) deposit in tissues $\rightarrow$ activate classical complement $\rightarrow$ C5a attracts neutrophils $\rightarrow$ neutrophils release lysosomal enzymes and ROS $\rightarrow$ necrotizing vasculitis, glomerulonephritis, and arthritis.
• Clinical Examples:
  • Systemic Lupus Erythematosus (SLE): Anti-dsDNA/DNA complexes deposit in kidneys (lupus nephritis), joints, and skin.
  • Post-Streptococcal Glomerulonephritis (PSGN): Streptococcal antigen-antibody complexes deposit along the glomerular basement membrane.
  • Serum Sickness: Systemic reaction occurring 1–2 weeks after administration of foreign serum or chimeric monoclonal antibodies. Manifests as fever, urticaria, polyarthralgias, lymphadenopathy, and low serum C3/C4 levels.
  • Arthus Reaction: Localized cutaneous necrotizing vasculitis occurring 4–12 hours after intradermal injection of an antigen into a pre-sensitized individual with high circulating IgG levels (e.g., diphtheria/tetanus booster vaccines).

Type IV: Delayed-Type (Cell-Mediated) Hypersensitivity

Type IV hypersensitivity is uniquely devoid of antibodies, relying entirely on sensitized T lymphocytes.

• Sensitization Phase (1–2 Weeks): APCs present antigen to CD4+ T cells, inducing expansion of memory Th1/Th17 cells.
• Effector Phase (24–48 Hours): Re-exposure prompts memory Th1 cells to secrete IFN-$\gamma$, which recruits and activates macrophages. Macrophages secrete TNF-$\alpha$, ROS, and lysosomal enzymes, causing local tissue damage and forming granulomas (epitheloid macrophages and multinucleated giant cells). Alternatively, CD8+ Cytotoxic T Lymphocytes (CTLs) directly kill target cells presenting antigen.
• Clinical Examples: Contact Dermatitis (urushiol from poison ivy, nickel, cosmetics), PPD (Mantoux) Tuberculin Skin Test, Type 1 Diabetes Mellitus (autoimmune destruction of pancreatic $\beta$-cells by CD8+ CTLs), Multiple Sclerosis, Graft-versus-Host Disease (GVHD), and Hashimoto Thyroiditis (parenchymal destruction by T cells).

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Mechanisms of Autoimmunity

Autoimmunity occurs when immune tolerance to self-antigens breaks down, leading to immune-mediated self-tissue destruction.

Breakdown of Tolerance

• Central Tolerance Breakdown: Defective thymic negative selection or mutations in AIRE allow autoreactive T cells to escape into the periphery.
• Peripheral Tolerance Breakdown: Failure of regulatory T cells ($CD4^+CD25^+\text{FOXP3}^+$) or mutations in apoptotic pathways (e.g., Fas / FasL gene mutations causing Autoimmune Lymphoproliferative Syndrome [ALPS]).
• Molecular Mimicry: Pathogen antigens share structural amino acid sequences or conformational epitopes with host self-antigens. Exposure to the pathogen generates an immune response that cross-reacts with host tissue. The classic example is Group A $\beta$-hemolytic Streptococcus: antibodies generated against bacterial M protein cross-react with human cardiac myosin and valvular endothelium, causing Acute Rheumatic Fever.

Human Leukocyte Antigen (HLA) Associations

Specific HLA alleles confer significantly increased relative risk for developing particular autoimmune diseases:

+------------+--------------------------------------------------------------------------------+
| HLA Allele | Associated Autoimmune Diseases                                                 |
+------------+--------------------------------------------------------------------------------+
| HLA-B27    | Seronegative Spondyloarthropathies: Ankylosing Spondylitis (>90% association),|
|            | Reactive Arthritis (Reiter), Psoriatic Arthritis, IBD-associated arthritis     |
+------------+--------------------------------------------------------------------------------+
| HLA-DR3 /  | Type 1 Diabetes Mellitus (HLA-DR3/DR4 heterozygotes have highest risk),       |
| HLA-DR4    | Rheumatoid Arthritis (HLA-DR4), Systemic Lupus Erythematosus (HLA-DR2/DR3)     |
+------------+--------------------------------------------------------------------------------+
| HLA-DR2    | Multiple Sclerosis, Goodpasture Syndrome, Systemic Lupus Erythematosus         |
+------------+--------------------------------------------------------------------------------+
| HLA-DQ2 /  | Celiac Disease ("DQ2/DQ8 eat gluten at 2 and 8")                              |
| HLA-DQ8    |                                                                                |
+------------+--------------------------------------------------------------------------------+

Autoantibody Diagnostic Panel

Autoantibodies serve as key diagnostic biomarkers for specific autoimmune conditions:

• Antinuclear Antibodies (ANA): Sensitive screening test for Systemic Lupus Erythematosus (SLE) (>95% sensitivity), though low specificity (also elevated in scleroderma, Sjögren, polymyositis).
• Anti-dsDNA and Anti-Smith (Anti-Sm): Highly SPECIFIC for SLE. Anti-dsDNA antibody titers correlate directly with lupus nephritis activity and complement depletion ($C3, C4$).
• Anti-Cyclic Citrullinated Peptide (Anti-CCP): Highly specific (>95%) for Rheumatoid Arthritis (RA) (superior diagnostic specificity compared to Rheumatoid Factor [RF], which is an IgM autoantibody directed against the Fc region of self-IgG).
• Anti-Ro / SSA and Anti-La / SSB: Diagnostic for Sjögren Syndrome (keratoconjunctivitis sicca and xerostomia). Anti-Ro positive mothers carry a risk of transmitting antibodies transplacentally, causing congenital heart block in the fetus.
• Anti-Centromere Antibodies: Diagnostic for Limited Cutaneous Systemic Sclerosis / CREST Syndrome (Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasias).
• Anti-Scl-70 (Anti-Topoisomerase I): Diagnostic for Diffuse Cutaneous Systemic Sclerosis (associated with rapid skin involvement and severe interstitial lung disease).
• Anti-Jo-1 (Anti-Histidyl-tRNA Synthetase): Diagnostic for Polymyositis / Dermatomyositis (associated with interstitial lung disease and "mechanic's hands").
• Anti-Smooth Muscle Antibodies (ASMA): Diagnostic for Type 1 Autoimmune Hepatitis.
• Anti-Mitochondrial Antibodies (AMA): Highly specific for Primary Biliary Cholangitis (PBC).