• Information
  1. Cell Types
  2. Biochemical Products
  3. Symptoms of Hypersensitivity Reactions
  4. Types of Hypersensitivity
  5. Type I: Immediate Hypersensitivity
  6. Type II: Antibody Mediated
  7. Type III: Immune Complex Mediated
  8. Type IV: Delayed Type Hypersensitivity
  9. Acute Contact Dermatitis

A. Cell Types [1]

1. Mast cell: mononuclear tissue cell capable of cell division, 10-40µm
2. Basophil: blood borne, end-stage, polymorphonuclear cell, 10-20µm
3. IgE secreting plasma cells
4. Activation of Mast Cells and Basophils
   1. Cross-linking of IgE cell surface receptors (IgER)
   2. Binding of complement (C')-derived anaphylatoxins C5a and C3a
   3. Bacterial defived N-formylated peptides
   4. Hyperosmolarity
   5. Physical (cold, excercise) and chemical (for example, codeine) stimuli
5. Complement Activation [2,3]
   1. Plays a major role in nearly all inflammatory reactions
   2. Complement is activated at sites of tissue injury
   3. Activation occurs through immune complexes (IC) and reperfusion injury (lipid release)
   4. Activated C' causes damage through direct injury (membrane attack complex)
   5. Also causes damage by activating lymphocytes bearing C' receptors
   6. This occurs through C4b and C3b C' proteins
   7. In addition, C' amplifies injury through anaphylatoxins C5a and C3a
6. Transient inhibition of C' activation usually reduces inflammatory damage

B. Biochemical Products

1. Preformed Compounds
   1. Histamine
   2. Eosinophil chemotactic factors (ECF)
   3. Kallikrein
   4. Neutrophil chemotactic factors (NCF)
2. Histamine
   1. Arteriolar dilation, capillary leakage
   2. Induces cholinergic reflex bronchoconstriction (bronchospasm)
3. Eosinophil chemotactic factors (ECF)
   1. Two tetrapeptides account for ~50% ECF activity
   2. Note that IL5 is eosinophil maturation and chemotactic factor also
4. Kallikrein
   1. Large MW enzyme
   2. Increases conversion of Kininogen to Bradykinin (pain, dilation)
5. Newly Generated Products
   1. Leukotrienes
   2. Prostaglandins
   3. Platelet Activating Factor (PAF)
6. Leukotrienes (LT) [4]
   1. Especially LTC4, D4, E4 (formally called "slow reacting substance of anaphylaxis")
   2. Venule contraction
   3. Capillary endothelial contraction with vascular leakage: Increased permeability
   4. Slow onset, sustained contraction
   5. Lipoxygenase sulfatidyl peptide-lipids, Glu(Gly)-Cys-C6 linkage
7. Prostaglandins (PG)
   1. Mainly PG D2
   2. Potent inducer of smooth muscle. contraction
   3. Cyclooxygenase pathway
8. PAF
   1. Acetyl-glyceryl-ether of phosphorylcholine (AGEPC)
   2. Increases platelet aggregation, degranulation
   3. Increases vascular permeability
   4. Activates neutrophil secretion

C. Symptoms of Hypersensitivity Reactions

1. Acute Anaphylaxis
   1. Shock: very low blood pressure due to systemic arteriolar dilation
   2. Bradycardia and decreased respiratory rate
   3. Examples: Bee sting, penicillin allergy
   4. Treated with epinephrine IV, high dose fluids, vasopressor agents
2. Urticaria
   1. Hives = Wheel and Flare response
   2. May be localized or systemic
   3. Pruritus, often severe, is common
3. Allergic rhinitis
   1. Rhinorrhea: excessive fluid and mucous secretion
   2. Obstruction and inflammation
4. Asthma
   1. Often with atopy, allergies
   2. Asthma with allergies frequently with eosinophils infiltrating lung
   3. Bronchospasm common, histamine induced
   4. Hypertrophic smooth muscle in airways
5. Atopy
   1. Constellation of atopic dermatitis (eczema), allergic rhinitis, allergic asthma
   2. Patients usually have elevated serum IgE, typically to a variety of antigens
   3. Increased risk of severe and fatal anaphylactic reactions
   4. Increased risk of reaction to aspirin; may be part of "triad asthma"
   5. Aspirin allergies in setting of asthma, rhinosinusitis linked to elevated cysteinyl leukotriene receptor (CysLT1) expression [7]
6. Anaphylactoid Reactions
   1. Radiocontrast Media Reactions
   2. Physical Urticarias
   3. Aspirin Sensitivity
   4. Exercise-induced Asthma / Anaphylaxis
7. Photosensitivity Reactions

D. Types of Hypersensitivity

1. Immediate Type (IgE Mediated)
2. Antibody Mediated
3. Immune Complex Mediated
4. Delayed Type (T Helper Cell Mediated)

E. Type I: Immediate Hypersensitivity [5,6]

1. IgE antibody mediated (? of IgG subclasses also) reactions
2. IgE antibodies bind mast cells, basophils, cross link IgE receptors causing degranulation
3. Release of various mediators including histamine
4. Leads to vascular leakage, especially venules
5. The arteriolar dilation leads to hypotension
6. Examples
   1. Common allergies
   2. Allergic Rhinitis
   3. Atopic Asthma (has Type IV components as well)
   4. Anaphylactic reactions
   5. Insect bite hypersensitivity
   6. Allergic Eczema
   7. Urticaria
7. Insect Bite Hypersensitivity [9]
   1. Insects of the order Hymenoptera
   2. Includes ants, bees, hornets, wasps, yellow jackets
   3. Deliver 100ng (fire ants) and 50µg (bees) of venom
   4. ~40 deaths annually from hymenoptera stings in US
   5. Prior stings cause production of specific IgE antibodies
   6. All stings also contain vasoactive components which cause redness, pain, edema
   7. Local reactions may persist for up to 1 week
   8. Swelling in the airway may become life threatening in allergic persons
   9. Treat any severe allergic / anaphylactic reaction with epinephrine, antihistamines
   10. Glucocorticoids should generally be given to prevent late effects but efficacy unclear
   11. Avoidance and immunotherapy with hymenoptera venom should be considered
8. Allergen immunotherapy can reduce specific IgE levels

F. Type II: Antibody Mediated

1. IgG and IgM binding to fixed (not soluble) target antigens
2. Initial sensitization, or cross reaction with infectious agent leading to Ab production
3. Antibody binds to fixed antigen, attracts complement and Ig-Fc receptor bearing cells
4. Complement (C')
   [Figure] "The Complement Cascade"
   1. Human Antibody C' Activation IgM > IgG3 > IgG1 > IgG2 (IgG4 does not activate)
   2. However, IgG4 does stimulate C3a and C5a production, leading to neutrophil activation
   3. IgG antibodies mediate platelet aggregation and neutrophil attraction
   4. The pentameric nature of IgM Abs permit direct C' activation
   5. However, unbound IgM cannot bind C1q due to steric effects (alleviated on Ag binding)
5. Platelet Aggregation
   1. Due to C3 attraction, platelet activating factor release
   2. Leads to thrombus formation and vessel occlusion
   3. Fibrinous inflammation?
6. Fc Receptor (FcR+) Positive Effector Cells
   1. There are three main types of Fc Receptors for IgG (Fc-Gamma-RI, Fc-G-RII, Fc-G-RIII)
   2. IgG subclasses G1 and G3 bind FcR best, with G2 and G4 of lower affinity
   3. Neutrophils, macrophages, B cells, and natural killer cells express Fc-G-R
   4. Binding of multiple Fc regions of antibodies to FcR signals these cells
   5. Both positive and negative signals have been identified in different systems
   6. In autoimmune (hypersensitivity) disease, effector cells mediate tissue destruction
7. Examples
   1. Goodpasture's Syndrome: Anti-glomerular basement membrane antibodies
   2. Type I Diabetes Mellitus: anti-ß-cell islet Abs. Glucose intolerance and vasculopathy
   3. Hashimoto's thyroiditis: nonhyperthyroid, large goiter, anti-thyroglobulin Abs
   4. Grave's disease: autoimmune thyroiditis, with hyperthyroid; Anti-TSH-Receptor Abs
   5. Myasthenia gravis: anti-acetylcholine receptor Abs, leads to paralysis
   6. Pemphigus vulgaris: anti-epidermal cell adhesion molecule Abs causing skin lesions
   7. Hyperacute graft rejection: preformed anti-graft Abs in host
   8. Autoimmune Hemolytic Anemia: Coombs' positive antibody mediated red cell destruction
   9. Hemolytic transfusion reaction: from preformed anti-A or anti-B Abs (ABO grouping)
   10. Rheumatic fever: due to antibodies to Streptococcal M proteins
   11. Erythroblastosis fetalis: "Rh-Disease"

G. Type III: Immune Complex Mediated

1. IgG and IgM bind to circulating antigens (Ag) forming "immune" complexes (IC)
2. IC become extremely large meshworks with Ag bridges [2]
   1. Normal clearance is through C' binding (C3b) which reduces size of complex
   2. C3b-IC then bind to complement receptor 1 (CR1), mainly on erythrocytes
   3. C3b-IC bound to CR1 on erythrocytes are cleared in the spleen
   4. Splenic uptake requires functional C2 protein
   5. IC bind FcR as well on macrophages (mainly liver, some splenic) and can be cleared
3. Failure of normal clearance mechanisms [2,3]
   1. May occur in persons with C' deficiency
   2. May contribute to development of SLE and other immune complex disease
   3. Large, uncleared IC are deposited on vessel walls, especially in the kidney
   4. This leads to local C' and FcR+ cell activation and vessel damage
4. Examples of Immune Complex Disease:
   1. Systemic Lupus Erythematosis (SLE)
   2. Polyarteritis nodosa (PAN)
   3. Wegener's Granulomatosus
   4. Bacterial Endocarditis
   5. Henoch-Schonlein Purpura (Serum Sickness)

H. Type IV: Delayed Type Hypersensitivity (DTH)

1. Tissue damage within days to several weeks after the introduction of antigen
2. Mediated by CD4+ T cells, sometimes called T-DTH
3. Unclear if these cells differ from CD4+ T helper (TH) cells
4. Requires intact antigen presenting cells, including Langerhan's cells of skin
5. At least two exposures to the antigen, first for priming, second gives DTH
6. Examples
   1. Cutaneous sensitivity: reaction to poison ivy and poison sumac
   2. Arthus reaction
   3. Contact Allergic Sensitivities: cosmetics and detergents
   4. Granulomatous Reactions
   5. Delayed drug hypersensitivity reactions
7. Arthus Reaction
   1. First exposure: systemic (intravenous) injection of antigen
   2. Then give subcutaneous (SC) injection
   3. DTH reaction (wheel and flare) typically occurs in ~2 days from SC injection
8. Granulomatous Reactions
   1. Sarcoidosis
   2. Tuburculin skin test: giant cell granulomatous formation
   3. Crohn's Disease
   4. Spirochete diseases, especially Treponema pallidum
   5. Deep Fungal Infections: such as histoplasmosis
9. Delayed Drug Hypersensitivity [8]
   1. Type IVa: T cells recruit primarily monocytes
   2. Type IVb: T cells recruit primarily eosinophils
   3. Type IVd: T cells recruit primarily neutrophils
   4. Type IVc: cytotoxic CD4+ or CD8+ lymphocytes (pariticipate in all above reactions)

I. Acute Contact Dermatitis

1. Type IV hypersensitivity reaction
2. Poison ivy is the prototypical causative agent
   1. Eruption of erythematous, edematous patches occurs 6-12hrs post contact
   2. The patient must have been sensitized; the active agent is Urushiol
   3. Urushiol is taken up by LC
3. Urushiol
   1. Also called pentadecylcatecol; a lipo-protein
   2. Urushiol found on waxy surface of plants in the genus Rhus (Toxicodendron)
   3. Rhus are limited primarily to North America
   4. Urushiol is small and lipophilic, so permeates skin easily
   5. The peptide portion of urushiol is presented by the LC to T lymphocytes
4. LC Presentation to T Cells
   1. LC's are mobile following antigen stimulation
   2. Migrate out of epidermis to lymphatics to regional lymph nodes
   3. Land in T cell rich subcapsular lymph node zone
   4. LC's contact many T cells and present urushiol peptide to them
   5. LC's and T cells are responsible for acute changes seen in contact dermatitis
5. Changes occur in LC's when they leave the epidermal environment
   1. Loss of Birbeck granules (unknown function) and many surface markers
   2. Acquire IL2 receptors
   3. Increased expression of MHC Class I and II surface glycoproteins
   4. Achieve enhanced accessory cell function (and alloreactivity)
6. Other Common Agents
   1. Soaps, detergents
   2. Soil organisms
   3. House dust mites (feces also)
   4. Animals

References

1. Costa JJ, Weller PF, Galli SJ. 1998. JAMA. 278(22):1815
2. Walport MJ. 2001. NEJM. 344(14):1058
3. Walport MJ. 2001. NEJM. 344(15):1140
4. Peters-Golden M and Henderson WR. 2007. NEJM. 357(18):1841
5. Kay AB. 2001. NEJM. 344(1):30
6. Kay AB. 2001. NEJM. 344(2):109
7. Sousa AR, Parikh A, Scadding G, et al. 2002. NEJM. 347(19):1493
8. Pichler WJ. 2003. Ann Intern Med. 139(8):682
9. Freeman TM. 2004. NEJM. 351(19):1978