Hypersensitivity Reactions

1. Type I hypersensitivity (anaphylactic type)

a. Definition: hypersensitivity reactions are characterized by /gE-related release of chemical mediators from mast cells and basophils. The release is triggered by exposure to an antigen b. Requires prior sensitization to the antigen c. Requires cross-linking of IgE Fc receptors on the surface of mast cells and basophils d. Release of chemical mediators i. Histamine and heparin ii. Eosinophil chemotactic factor iii. Leukotriene B4 and neutrophil chemotactic factor iv. Prostaglandin D4, platelet-activating factor (PAF), and leukotrienes C4 and D4

e. Influx of eosinophils amplify and perpetuate the reaction f. Effects may be localized or systemic i. Systemic: anaphylaxis (e.g., bee stings and drugs)

ii. Localized: food allergies, atopy, and asthma

2. Type II hypersensitivity (cytotoxic type)

a. Definition: hypersensitivity reaction characterized by production of an IgG or IgM antibody directed against a specific target cell or tissue b. Complement-dependent cytotoxicity i. Fixation of complement results in osmotic lysis or opsonization of antibody coated cells ii. Example: autoimmune hemolytic anemia c. Antibody-dependent cell-mediated cytoxicity (ADCC)

i. Cytotoxic killing of an. antibody-coated cell ii. Example: pernicious anemia d. Anti-receptor antibodies i. Antibodies activate or interfere with receptors ii. Example: Graves disease

3. Type III hypersensitivity (immune complex disease)

a. Definition: hypersensitivity reaction characterized by the formation of in situ or circulating antibody antigen immune complexes, which deposit in tissue resulting in inflammation and tissue injury b. Examples i. Serum sickness ii. Systemic lupus erythematosus (SLE)

iii. Glomerulonephritis

4. Type IV hypersensitivity (cell-mediated type)

a. Definition: hypersensitivity reaction mediated by sensitized T lymphocytes b. Delayed type hypersensitivity i. CD4+ T-cell lymphocyte mediate granuloma formation ii. PPD skin test and tuberculosis c. Cytotoxic T-cell-mediated i. CD8+ T-cell lymphocytes destroy antigen-containing cells.

ii. Viral infections, immune reaction to tumors, contact dermatitis, and graft rejection

Autoimmune Diseases

1. Systemic lupus erythematosis (SLE)

a. Definition: chronic systemic autoimmune disease characterized by loss of self-tolerance and production of autoantibodies b. Epidemiology i. Females » Males (M:F = 1:9)

ii. Peak incidence: age 20—45

iii. African American > Caucasian c. Autoantibodies i. Anti nuclear antibody (ANA) (>95%)

d. Mechanism of injury: type II and III hypersensitivity reactions e. Distribution of disease i. Hematologic

• Hemolytic anemia

• Thrombocytopenia

■ Neutropenia

• Lymphopenia ii. Arthritis: polyarthralgia and synovitis without joint deformity iii. Skin

■ Malar "butterfly" rash

• Maculopapular rash

• Ulcerations and bullae formation iv. WHO classification of kidney manifestations

• Class II: mesangiai lupus nephritis

• Class III: focal proliferative glomerulonephritis

■ Class IV: diffuse proliferative glomerulonephritis (most common and severe)

■ Class V: membranous glomerulonephritis v. Heart: libman-Sacks endocarditis (nonbacterial verrucous endocarditis)

vi. Serosal surfaces: pericarditis, pleuritis, and pleural effusions vii. CNS: focal neurologic symptoms, seizures, and psychosis f. Treatment: steroids and immunosuppressive agents g. Prognosis i. Chronic, unpredictable course with remissions and relapses ii. Ten-year survival: 85%

iii. Death is frequently due to renal failure and infections

2. Sjögren syndrome (Sicca syndrome)

a. Definition: an autoimmune disease characterized by destruction of the lacrimal and salivary glands resulting in the inability to produce saliva and tears b. Clinical features i. Females > males; age range: 30 to 50

ii. Keratoconjuctivitis sicca (dry eyes) and corneal ulcers iii. Xerostomia (dry mouth)

iv. Mikulicz syndrome: enlargement of the salivary and lacrimal glands c. Often associated with rheumatoid arthritis and other autoimmune diseases d. Anti-ribonucleoprotem antibodies i. SS-A (Ro)

e. Complication: increased risk of developing lymphoma

3. Scleroderma (progressive systemic sclerosis)

a. Definition: autoimmune disease characterized by fibroblast stimulation and deposition of collagen in the skin and internal organs b. Females > males; age range: 20 to 55

c. Pathogenesis: activation of fibroblasts by cytokines interleukin 1 (IL-1), platelet-derived growth factor (PDGF), and/or fibroblast growth factor (FGF) leads to fibrosis d. Diffuse scleroderma i. Anti-DNA topoisomerase 1 antibodies (Scl-70) (70%)

ii. Widespread skin involvement iii. Early involvement of the visceral organs

• Esophagus—dysphagia

• GI tract—malabsorption

• Pulmonary fibrosis—dyspnea on exertion

■ Cardiac fibrosis—arrhythmias

■ Kidney fibrosis—renal insufficiency

In a Nutshell e. Localized scleroderma (CREST syndrome)

i. Anti-centromere antibodies ii. Skin involvement of the face and hands iii. Late involvement of visceral organs iv. Relatively benign clinical course

CREST Syndrome

• Calcinosis

■ Raynaud phenomenon

• Esophageal dysmotility

• Sderodactyly



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