Hypersensitivity Part II Flashcards
Type II (Cytotoxic) Hypersensitivity
• Foreign (or self) antigen that is present on a cell surface (fixed) stimulates antibody formation
– IgG or IgM
• Time course: Hours to days
Diagnosis of Type II reactions
• History and clinical signs specific to the disease process:
– e.g., decreased renal function, pulmonary infiltrates, hemoptysis (coughing up of blood), low platelets
– presence of Abs against the appropriate antigen (Direct and Indirect Coombs tests, anti-specific antigen antibodies)
– biopsy findings consistent.
Type II Hypersensitivity Immune Mechanisms
- Foreign (or self) antigen that is present on a cell surface stimulates antibody formation.
- Antibody (IgG or IgM) then binds to the antigen on the surface of those cells, opsonizing - fixes complement & induces lysis & phagocytosis, …or….
- Antibody binds to the cells and its Fc part is bound to Fc receptors on effector killer cells and induces antibody-dependent cell-mediated cytotoxicity (ADCC). …or….
- Antibody recognizes self-antigen and induces abnormal physiologic response without inflammation or injury
Note: Antibody is specific, provides a memory response (adaptive immunity). ADCC effector cells (e. g. NK cells & neutrophils) are nonspecific (bind any antibody with correct Fc regardless of antigen specificity) and have no memory response (intrinsic or innate immunity).
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cell destruction and phagocytosis/lysis
- Acute hemolytic transfusion reaction
- Hemolytic disease of the newborn (Erythroblastosis fetalis)
- Autoimmune hemolytic anemia
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cell destruction and phagocytosis/lysis - Acute hemolytic transfusion reaction
•Preformed antibody in the recipient targets non-compatible RBC’s from donor in transfused blood
a. Result of ABO blood group incompatibility between donor and recipient or host antibody reaction against foreign antigen on donor RBC’s
b. Hemoglobin released into plasma with RBC destruction (hemolysis)
c. Clinical presentation: Fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinuria (due to intravascular hemolysis), jaundice
- May lead to shock or death
d. Prevention: Type and cross match prior to transfusion
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cell destruction and phagocytosis/lysis - Hemolytic disease of the newborn (Erythroblastosis fetalis)
•Antigenic difference between maternal and fetal RBC’s causes IgG from mother to cross placenta and destroy fetal RBCs
i. Most common RBC antigen involved is Rh 1. Rh+ father; Rh- mother
ii. First pregnancy: Fetal Rh+ red blood cells move across placenta and into material circulation, evoke immune response from the mother, principally of IgM type (too large to cross the placental barrier)
1. No effect on fetus
2. Mother is now sensitized (most sensitization happens during labor with largest transfer of RBCs)
iii. Subsequent pregnancies: Repeated maternal exposure to Rh+ RBC results in production of anti-Rh IgG type antibodies, which are capable of crossing the placental barrier
1. Fetus’ Rh+ red blood cells are destroyed in utero
2. Possible effects on fetus (severity depends on degree of hemolysis):
a. Anemia, jaundice (buildup of bilirubin), edema, enlarged liver and spleen, congestive heart failure, kernicterus (deposition of bilirubin in brain), hearing loss, mental/cognitive dysfunction, death
iv. Prevention:
1. Identify Rh status of maternal blood (Indirect Coomb’s Test to detect anti-Rh antibodies in mother)
2. RhoGAM – Anti-Rh antibodies given to Rh- mother during 1st pregnancy. Antibodies bind to Rh+ fetal RBC’s in maternal circulation and cause them to be destroyed before mother can become sensitized
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cell destruction and phagocytosis/lysis - Autoimmune hemolytic anemia
•Patients produce autoantibodies against their own RBC’s (various antigenic targets), which are then destroyed
i. Diagnosis: Presence of hemolysis + positive Direct Coombs’ test (detects antibodies that have adhered to patient’s RBCs)
Type II Hypersensitivity Immune Mechanisms: Antibody mediated injury due to inflammation, complement mediated
- ANCA associated vasculitis
- Anti-GBM disease (Goodpastur’s Syndrome)
- Rheumatic Fever
- Antibody mediated graft rejection
Type II Hypersensitivity Immune Mechanisms: Antibody mediated injury due to inflammation, complement mediated - ANCA associated vasculitis
•Anti-neutrophil cytoplasmic antibodies (ANCA) are associated with neutrophil degranulation and inflammation within capillaries
Type II Hypersensitivity Immune Mechanisms: Antibody mediated injury due to inflammation, complement mediated - Anti-GBM disease (Goodpasture’s Syndrome)
•Antibodies against Type IV collagen target basement membranes of glomerular and pulmonary capillaries, cause inflammation and destruction of basement membranes
a. Clinical presentation: Pulmonary Renal syndrome
i. Rapidly progressive glomerulonephritis
ii. Pulmonary hemorrhage, hemoptysis
b. Morphologic features: Renal biopsy with crescents/necrosis and linear IgG staining of glomerular basement membranes by IF
c. Negative ANCA, positive serum test for anti-GBM antibodies
Type II Hypersensitivity Immune Mechanisms: Antibody mediated injury due to inflammation, complement mediated - Rheumatic Fever
•Follows group A streptococcal infection. Antibodies produced against strep antigen cross-react with antigens in myocardium, cardiac valves, joints and skin (molecular mimicry)
a. Clinical presentation:
i. Myocarditis - heart biopsy shows inflammation with Aschoff nodules
ii. Post-inflammatory cardiac valve disease – involves both mitral and aortic valves; thickened leaflets and shortened/thickened cordae tendinae
iii. Arthritis of the large joints – usually starts in legs and migrates up
iv. Skin rash – erythema marginatum
Type II Hypersensitivity Immune Mechanisms: Antibody mediated injury due to inflammation, complement mediated - Antibody-mediated graft rejection
•Antibodies created by the recipient bind to donor antigens on vascular endothelium within the transplanted organ
a. Inflammation of arteries (vasculitis) and capillaries (capillaritis) leads to thrombosis, hemorrhage and ischemic injury of the graft
b. Forms: Hyperacute (due to pre-formed antibodies), acute (formation of new antibodies de novo) and chronic (ongoing injury coupled with graft fibrosis and loss of viable parenchyma)
c. Diagnosis:
i. Tissue biopsy to look for vasculitis, capillaritis (often with PMN’s) and identify complement deposition in the allograft (by immunofluorescence)
ii. Testing of recipient for presence of antibodies against donor antigens (usually anti-HLA antibodies)
d. Treatment: Plasmapheresis (i.e. plasma exchange), intravenous immunoglobulin (IVIg)
i. Removes anti-donor antibodies from recipient circulation
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cellular dysfunction (non-cytotoxic)
- Myasthenia Gravis
- Graves Disease
- Pernicious Anemia
- Chronic idiopathic urticaria
- Pemphigus vulgaris
- Linear IgA bullous dermatosis
- Guillain-Barre syndrome (axonal variant)
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cellular dysfunction (non-cytotoxic): Myasthenia Gravis
a. Antibody formed against the acetylcholine receptor; presence of antibody inhibits binding of neurotransmitter to receptor
b. Clinical presentation: Weakness/rapid muscle fatigue and paralysis involving face, eyes/eyelids, arms, legs and esophagus
c. Treatment: Cholinesterase inhibitors (enhance neuromuscular function), corticosteroids, other immune suppressants
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cellular dysfunction (non-cytotoxic): Graves disease
a. Antibody formed against TSH receptor; Ab-receptor binding activates the receptor, without presence of TSH
b. Hyperthyroidism symptoms – Anxiety, tremor, weight loss, enlarged thyroid (goiter), protrusion of eyes (exophthalmos)
c. Morphologic features: Multinodular thyroid tissue with hyperplastic follicular epithelium, scalloped colloid
d. Treatment: Radioactive iodine, anti-thyroid medications (propylthiouracil, methimazole), beta-blockers (to relieve symptoms) and surgery (thyroidectomy)
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cellular dysfunction (non-cytotoxic): Pernicous anemia
•anti-intrinsic factor Abs
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cellular dysfunction (non-cytotoxic): chronic idiopathic urticaria with autoimmunity
•anti-FceR antibodies
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cellular dysfunction (non-cytotoxic): Pemphigus vulgaris
•anti-epidermal cell adhesion molecule Abs
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cellular dysfunction (non-cytotoxic): Linear IgA bullous dermatosis
•IgA deposition at dermo-epidermal junction: drug reaction to vancomycin or other
Type II Hypersensitivity Immune Mechanisms: Antibody-mediated cellular dysfunction (non-cytotoxic): Guillain-Barre syndrome (axonal variant)
•IgG mediated and complement against cell membrane covering the axon.
Why does the body have ADCC and antibody-mediated cytotoxicity?
To kill cells expressing viral or tumor antigens
Type III (Immune Complex) Hypersensitivity
- Immune Complex Mediated
- IgG and IgM bind circulating antigens
- Form “meshwork” with antigen bridges
- Complement mediated destruction – Typically occur at vascular beds
- IgG, IgM Abs combine with soluble antigen to make insoluble complexes, which then can deposit on walls of small blood vessels/capillaries as meshwork.
- Antigen-antibody complexes activate complement, whose byproducts are chemoattractants and anaphylatoxins.
- PMNs recognize antibody; release lysosomal enzymes and damage the vessel and adjacent tissue after infiltration.
Type III (Immune Complex) Hypersensitivity Classic Features
- Neutropenia, thrombocytopenia, elevated ESR/CRP, proteinuria, low complements with elevated c1q-binding
- Skin biopsy: mild lymphocytic/histiocyte infiltrates, rare leukocytoclastic vasculitis
- Starts 5-10 days after starting offending agent; if recurrent exposure, 12-36 hours
- Symptoms may last for 2+ weeks
- Can occur due to heterologous proteins or simple drugs (PCN)
- Risk factors: higher doses, intermittent exposure, hypergammaglobulinemia, older age
Type III (Immune Complex) Hypersensitivity Clinical Example: Glomerulonephritis
•Sometimes observed acutely as a post-Streptococcal complication.
1) Acute glomerulonephritis develops 1-2 weeks after infection (classically due to nephritogenic strains of group A beta-hemolytic streptococcus)
a. Other types of infections can also cause post-infectious GN (staphylococcus, fungi, parasites) although the classic features may be absent or less prominent
2) Antigens: Bacterial antigens, proteins that resemble bacterial antigens (molecular mimicry)
3) Clinical presentation: Acute nephritic syndrome (hematuria, oliguria, hypertension, edema, increased creatinine)
a. Renal biopsy: Proliferative and exudative glomerulonephritis
i. Light microscopy: Glomeruli are hypercellular due to influx of numerous neutrophils
ii. Immunofluorescence: Coarse granular staining primarily for C3, may also have IgG or IgM
iii. Electron microscopy: Large subepithelial “hump-like” immune deposits
4) Diagnosis: Clinical presentation, serum detection of anti-strep antibodies (streptozyme, ASO test), renal biopsy
a. Renal biopsy may not be necessary if presentation is classic and patient improves with supportive care
If one were to biopsy the affected kidney of a patient with acute post-Streptococcal glomerulonephritis (Type III Hypersensitivity), one would observe:
- ”lumpy-bumpy” immune complex deposits, that are in contrast ie. to Goodpasture patients that have a smooth layer of IgG deposit
Type IV ( Delayed Type) Hypersensitivity (DTH)
- Mediated by T cells, delayed onset (>24 hours after exposure)
- Four subtypes of Type IV Hypersensitivity are currently recognized, IVa-d
Type IV Hypersensitivity: Contact hypersensitivity/dermatitis
- Type IVa
- maximum response observed at 48-72 h, characterized by:
- eczema (dermatitis) seen at contact site of antigen
- mostly epidermal in nature
- common Ags include nickel, chromate, rubber/latex, poison ivy (pentatecacatechol) & poison oak, paraphenylenediamine
- major cause of occupational disease- hairdressers, wood workers, mechanics
- test with Patch testing, which applies specific antigens to the skin and assesses cutaneous inflammation after ~72 hours
Type IV Hypersensitivity: Contact hypersensitivity/dermatitis mechanism
- By 8 hours, Langerhans’ cells (LC) have begun to migrate from the epidermis, bearing haptenized self. There is lymphocyte emigration from blood vessels.
- At 24 hours, DTH lymphocytes (T or NK cells) have entered the epidermis and started to interact with LC and secrete cytokines to recruit macrophages.
- By 48h, macrophages present in all areas, including the epidermis. Keratinocytes of the epidermis now express MHC class II molecules and Intraepidermal edema (spongiosis) occurs.
- Disruption and destruction of epidermis area occurs (spongiosis).
•Symptoms are burning, itching, redness, swelling & even blisters due to release of type I IFNs & proinflammatory molecules that synergize with DTH responses to cause symptoms.
Type IV Hypersensitivity: Contact hypersensitivity/dermatitis tuberculin hypersensitivity mechanism
- At 12 hours, lymphocytes begin to migrate from local blood vessels and accumulate around appendages.
- By 48 hours, macrophages are also present and Langerhans cells start to migrate out of the epidermis.
- The cellular traffic continues over the next 24 hours, and class II molecules appear on keratinocytes; there is no spongiosis but erythema and induration occur.
**Alternatively, blood test for TB called Quantiferon Gold testing is an ex-vivo assay of lymphocyte stimulation upon exposure to TB-specific antigens and determines, by cytokine and cell surface marker assays, whether lymphocyte activation is present, suggesting prior infection/exposure.
Type IV Hypersensitivity: Granulomatous Hypersensitivity reaction
•Granuloma formation results from the presence within macrophages, of persistent agent or organism which cannot be killed. Granuloma forms around the organism/foreign body. The above diagram illustrates the basic granuloma reaction.
- Antigen is injected into subcutaneous tissue and processed by local APC (24h)
- A Th1 cell recognizes antigen and releases cytokines that act on vascular endothelium (48h)
- Recruitment of phagocytes, plasma and CTLs to site of antigen injection causes visible lesion (72h)-macrophages and CTL are activated and may cause tissue damage
- Granuloma formation may take weeks to months to develop - Characteristic cell seen is the epitheloid cell that is derived from macrophages. Core of epitheloid cells and macrophages with or without some necrosis (caseating vs noncaseating granuloma)- surrounded by lymphocytes, with lots of fibrosis
Type IV Hypersensitivity: Drug Reactions - Maculopapular aka Mobilliform exanthema
- Type IV b-c
- Account for 95% of drug eruptions, 5-14 days after drug exposure
- Rash starts centrally, spreads centripetally
- Rash is somewhat itchy, fixed, and flakes with resolution
- Improves with topical or systemic steroids and withdrawal of offending agent (1-2 weeks)
- May also see mild peripheral eosinophilia, low fever, elevated ESR/CRP.
Type IV Hypersensitivity: Drug Reactions - DRESS
- Type IVb
- (Drug rash, eosinophilia, systemic symptoms) Syndrome
- potentially life threatening drug reaction
– Fever 38-40C, eosinophilia>1500, rash, systemic involvement (hepatitis, lymphadenopathy, hematologic abnormalities, nephritis)
– Rash is morbilliform, progressing to diffuse confluent infiltrated erythema with follicular accentuation (>50% BSA)
- Facial edema, mucus membrane inflammation – Starts 2-6 weeks after initiation of therapy
- Anticonvulsants, antimicrobials, sulfasalazine, NSAIDs, ACE inhibitors, Beta blockers, dapsone, allopurinol, azathioprine, diltiazem, methimazole, dobutamine
– Marked activation of T lymphocytes (CD8 & CD4)
– Related to HHV6, 7, EBV, CMV reactivation
Type IV Hypersensitivity: Drug Reactions - Stevens Johnson Syndrome
- Type IVc
- a form of toxic epidermal necrolysis, is a life-threatening skin condition, in which cell death causes the epidermis to separate from the dermis.
- Causes include certain medications (e.g., antiepileptics, antibiotics), but it can also be related to the presence of comorbid infection (HSV, CMV, EBV, HHV8).
- Blisters and erosions cover between 3% and 10% of the body and include mucus membranes.
- Incidence of 6 per million.
- Treatment generally involves withdrawal of offending drug, supportive care and pain management.
- Use of immunosuppressive drugs is controversial.
Type IV Hypersensitivity: Cell mediated graft rejection
•T-cells infiltrate graft, recognize donor antigens on epithelial and endothelial cells within the graft
1) Forms: Acute and chronic
2) CD4+ T cells activated by foreign antigens on allograft cells, triggering release of cytokines, recruitment and activation of macrophages and CD8+ lymphocytes, which directly target and destroy graft cells
3) Morphologic features: Mononuclear infiltrates targeting epithelium (i.e. kidney tubules, liver bile ducts), cardiac myocytes (heart allografts), and vascular endothelium
4) Treatment: Corticosteroids, anti-Thymocyte globulin, mycophenolate mofetil (CellCept)
