Overview
- Hypersensitivity reaction
- A “hyper” or exaggerated response to what should be considered harmless environmental antigens
- Types I, II, and III are immediate reactions occurring within 24 hours.
- Type IV reaction develops over several days.
- Type III hypersensitivity reaction
- Immune complex (IC)-mediated hypersensitivity: triggered by antigen-antibody (Ag-Ab) complexes deposited in tissues
- Ag: intrinsic (part of the host) or extrinsic (exogenous source such as bacteria, virus)
- As with type II hypersensitivity, cell injury is similar: Complement system leads to a reaction that produces cellular damage.
- Unlike type II hypersensitivity, in type III reactions:
- Antigens are not bound to cell surfaces.
- Ag-Ab complexes form in circulation.
- Target of the immune response is not the tissue or cell.
- Target is the IC deposited in the tissue.
Pathophysiology
Physiology
- Immune complex formation normally results in antigen neutralization.
- The complement system reduces pathologic IC accumulation.
- Antibodies (Ab) have 2 regions:
- Fab region: attaches to antigens
- Fc region: interacts with complement and Fc-bearing receptor (FcR) cells
- C1q: activates complement system and binds Ab Fc region, mediating IC clearance by FcR-bearing cells.
- C3b: makes ICs soluble and tags them for phagocytosis (opsonization).
- Antibodies (Ab) have 2 regions:
Pathogenesis
Immune complex formation: IC formed by the binding of Ag and Ab
Immune complex deposition
Immune complex deposition depends on:
- Physical properties of the IC:
- Affinity of Ab to complement, size, and charge of the IC
- Increased rate of IC formation → overwhelms clearing mechanism → IC freely circulate out to organs
- Antigen-to-antibody ratio:
- Low antibodies or excess antibodies → decreased effector activation
- Tissue-specific hemodynamics
- ICs first localize within blood vessels → vasculitis
- Common areas affected are “permeability”-susceptible tissues:
- Glomeruli (nephritis)
- Joints/synovium (arthritis)
Immune complex inflammatory reaction
- IC deposits activate the complement cascade.
- C3a initiates mast cell degranulation:
- Histamine increases vascular permeability in the involved tissue.
- ICs enter tissue → normal tissue with IC becomes a target for inflammatory response
- C5a (chemoattractant) recruits neutrophils → release lysozymes and inflammatory mediators → cell death and tissue injury
- C3b opsonizes the tissue → phagocytosis and membrane attack complex (MAC)-mediated cell lysis
- Macrophages, natural killer cells → release lytic mediators and injure tissue cells
- Platelet aggregation can occur → micro thrombus formation
Related videos
Clinical Presentation
Manifestations are affected by the route of entry, site(s) of IC deposition, and persistence of antigen(s).
Arthus phenomenon /Arthus reaction
- A locally injected antigen (e.g., immunization like Tdap) causes a localized reaction.
- Due to antigen excess and IC deposition on vascular walls
- Necrosis of affected tissues: pain, redness, induration, and edema at the site of injection
- Self-limited
Systemic lupus erythematosus (SLE)
- Antibodies directed against parts of the nucleus: antinuclear antibodies (ANA), a universal finding in SLE
- Antibodies to other parts of the nucleus:
- Histone (anti-histone Ab)
- DNA (anti-dsDNA Ab)
- Ribonucleoprotein (anti-RNP Ab)
- Extractable nuclear antigen/Smith antigen (Anti-Smith Ab)
- Other: Antibodies against phospholipids in cells (antiphospholipid Ab)
- Present in 30%–40% of patients with SLE
- Increased risk of thrombosis
- Ag-Ab complexes deposit in multiple areas:
- Skin/mucocutaneous (malar rash, photosensitivity, oral ulcers)
- Kidneys (glomerulonephritis)
- Joints (arthritis)
- Blood vessels (vasculitis, Raynaud’s phenomenon, blood clots)
- Pleura (effusion)
- Pericardium (pericarditis)
- Blood cells (anemia, leukopenia, thrombocytopenia)
- Central nervous system (strokes, seizures)
Post-streptococcal glomerulonephritis (PSGN)
- Reaction to nephritogenic antigens of group A beta-hemolytic streptococcus (GAS)
- Can be from streptococcal throat infection or skin infection
- Presentation: hematuria, proteinuria, hypertension, edema, and elevated creatinine
Serum sickness
- Reaction to foreign antisera (e.g., antivenom)
- Higher doses of administered agent more likely to result in a reaction
- 1–2 weeks after exposure: fever, rash, arthritis; proteinuria occurs with renal involvement
Hypersensitivity pneumonitis
- Extrinsic allergic alveolitis
- Antigen: a microbe, protein, or chemical
- IC deposition in alveoli, interstitium, bronchioli, and lung parenchyma
- Farmer’s lung: Ag from thermophilic molds on crops
- Bird fancier’s disease: Ag from intestinal mucin in droppings or feathers
- Note: can also be T-lymphocyte–mediated (type IV reaction)
Polyarteritis nodosa (PAN)
- Etiology mostly idiopathic but can be a reaction to hepatitis B virus surface Ag
- Medium-sized arterial inflammation → ↓ blood flow, ↑ thrombosis; spares the veins
- Kidneys: most commonly involved organ
- Presentation:
- Tender erythematous nodules, hypertension, renal insufficiency, and neuropathy
- Some have abdominal symptoms (mesenteric arteritis)
Type III hypersensitivity immune complex mediated tissue injury in blood vessel wall, vasculitis, which is associated with various conditions.
Image by Lecturio..Immune complex disease: Antigen-antibody complexes deposit on either side of the glomerular basement membrane. These elicit an inflammatory reaction and cause glomerular injury.
Image by Lecturio.
Diagnosis and Management
Diagnosis
- Clinical history and findings (Arthus reaction, serum sickness often diagnosed clinically)
- Laboratory tests:
- CBC
- Anemia, thrombocytopenia, leukopenia: SLE
- Eosinophilia: serum sickness, hypersensitivity pneumonitis
- Metabolic panel
- Creatinine is abnormal in reactions involving the kidneys
- Serologies and culture
- Hepatitis panel for polyarteritis nodosa
- Culture: streptococcal infection (only 25% of patients will have positive results because PSGN occurs weeks after the infection)
- Complement levels
- Generally found in low levels in associated conditions
- Antibodies
- ANA, anti-dsDNA Ab, antiSmith Ab, anti-RNP Ab, antiphospholipid Ab: SLE
- PSGN: antistreptolysin O (ASO), streptozyme test
- Urinalysis
- Proteinuria: SLE, PAN, serum sickness
- PSGN: hematuria, proteinuria
- Inflammatory markers
- Generally elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) during active inflammation
- Imaging
- High-resolution computed tomography (CT) (lung): hypersensitivity pneumonitis
- Arteriography or CT/magnetic resonance angiography (MRA): for polyarteritis nodosa
- X-ray: joint involvement
- Surgical procedures
- Renal biopsy: for renal involvement
- Skin biopsy: for cutaneous involvement
- Bronchoscopy: for lung involvement
- CBC
A 27-year-old female patient with a history of exposure to mold. High-resolution CT scans of the chest (lung window) at the level of the lower lobes show extensive ground-glass opacities (asterisks), with overlapping foci of lobular air trapping (arrows).
Image: “Hypersensitivity Pneumonitis” by Torres PP, Moreira MA, Silva DG, da Gama RR, Sugita DM, Moreira MA. License: CC BY 4.0Management
- Remove or avoid offending agent
- Antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs) for symptom relief (rash, itching, joint pains)
- In reactions due to infection (PSGN), antibiotic therapy if infection is still present
- Control of complications such as hypertension (PSGN, PAN), edema (PSGN, SLE), airway symptoms (hypersensitivity pneumonitis)
- Glucocorticoids used in severe cases to suppress inflammation
- Therapeutic options for specific conditions:
- Hypersensitivity pneumonitis: immunosuppressive therapy (mycophenolate, azathioprine)
- SLE:
- Antimalarials (hydroxychloroquine, chloroquine)
- Immunosuppressive therapy: mycophenolate, azathioprine, cyclophosphamide, rituximab
- Long-term anticoagulation if with thrombosis: warfarin, low-molecular-weight heparin
- PAN:
- Methotrexate, a disease-modifying anti-rheumatic drug (DMARD)
- Immunosuppressive therapy (cyclophosphamide, azathioprine)
- Dialysis for end-stage renal disease from SLE
- Organ transplantation:
- Lung transplantation for advanced lung disease in hypersensitivity pneumonitis
- Renal transplantation for end-stage renal disease in SLE
References
- King, T., Flaherty, K. & Hollingsworth, H. (Eds.). (2019). Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis. UpToDate. Retrieved Aug 17, 2020, from https://www.uptodate.com/contents/hypersensitivity-pneumonitis-extrinsic-allergic-alveolitis-treatment-prognosis-and-prevention
- King, T., Flaherty, K. & Hollingsworth, H. (Eds.). (2020). Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention. UpToDate. Retrieved Aug 17, 2020, from https://www.uptodate.com/contents/hypersensitivity-pneumonitis-extrinsic-allergic-alveolitis-treatment-prognosis-and-prevention
- Lu, L., Suscovich, T., Fortune, S., Galit, A. (2017). Beyond Binding: antibody effector functions in infectious diseases. Nature Reviews Immunology, 18, 46–61. https://doi.org/10.1038/nri.2017.106
- Mak, T., Saunders, M., Jett, B. (2007). Primer to the Immune response. Elsevier, 2nd ed.
- Mayadas, T., Tsokos, G., Tsuboi, N. (2009). Mechanisms of Immune Complex-mediated Neutrophil Recruitment and Tissue Injury : official publication of the Circulation, 120(20), 2012–2014. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.108.771170
- Merkel, P., Hunder, G. & Ramirez Curtis, M. (Eds.) (2019). Clinical manifestations and diagnosis of polyarteritis arteritis nodosa in adults. UpToDate. Retrieved 17 Aug 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults
- Wallace, D., Gladman, D., Pisetsky, D.,Shur, P & Ramirez Curtis, M. (Eds.) (2019). Overview of the management and prognosis of systemic lupus erythematosus in adults. UpToDate. Retrieved 17 Aug 2020, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-systemic-lupus-erythematosus-in-adults
- Wallace, D., Pisetsky, D., Shur, P & Ramirez Curtis, M. (Eds.) (2020,). Overview of the management and prognosis of systemic lupus erythematosus in adults. UpToDate. Retrieved 17 Aug 2020, from https://www.uptodate.com/contents/overview-of-the-management-and-prognosis-of-systemic-lupus-erythematosus-in-adults