Type III Hypersensitivity

Last updated: November 12, 2024

Briefly describe Type III hypersensitivity
- Type III hypersensitivity is AKA “immune complex-mediated” hypersensitivity.
- Antibodies bind to antigens forming complexes, which circulate get stuck in vessels and stimulate inflammation.
- The end result is inappropriate inflammation and necrotizing vasculitis
- Diseases produced by immune complexes are those in which antigens persist without being eliminated as:
  - Repeat exposure to extrinsic antigen
  - Injection of large amounts of antigens
  - Persistent infection
  - Autoimmunity to self components
List the diseases associated with Type III hypersensitivity reactions, their antigens and consequence (tissue affected)
- Systemic Lupus Erythematosus: Nuclear antigens → nephritis, skin lesions, arthritis
- Post-streptococcal glomerulonephritis: Streptococcal antigens → nephritis
- Polyarteritis Nodosa (PAN): Hepatitis B surface antigen → Systemic vasculitis
- Acute glomerulonephritis: Bacterial antigens (Treponema), Parasite antigens (Malaria, Schistosomes), Tumor antigens → Nephritis
- Reactive arthritis: Bacterial antigens (Yersinia) → Arthritis
- Serum sickness: Foreign proteins → arthritis, vasculitis, nephritis
- Arthus reaction: Foreign proteins; cutaneous vasculitis
What are the types of Type III hypersensitivity reactions
- Systemic immune complex disease
  - Complexes are formed in circulation and are deposited in several organs
  - Includes:
    - Serum sickness
    - Meningitis
    - Hepatitis
    - Mononucleosis
    - SLE
    - RA
    - Allergies to penicillins and sulfonamides
- Local immune complex disease
  - Complexes are formed at sites of antigen injection and precipitate at the injection (local) site
  - Includes: Arthus reaction
Describe the pathophysiology of Type III hypersensitivity reactions
- Phases of Type III hypersensitivity
  - Phase I: Immune complex formation
  - Phase II: Immune complex deposition
  - Phase III: Immune complex-mediated inflammation
    - Activation of complement
      - Neutrophil and monocyte chemoattraction
      - Increased vascular permeability
      - Anaphylatoxin – mediated activation of mast cells
    - Complex-mediated phagocytosis and release of phagocyte granule enzymes and cytokines into the local microenvironment
      - Fc receptor phagocytosis
    - Release of proteases by neutrophils and monocytes
      - PMN chemotaxis → Tissue damage
    - Activate clotting
      - Results in microthrombi – deposition, platelet aggregation
- Important complement fractions involved
  - C3b: phagocytosis of complexes and bugs
  - C3a, C5a (anaphylatoxins): increase permeability
  - C5a: neutrophil and monocyte chemotaxis
  - C5-9: Membrane damage and cytolysis (MAC)
List the Hypersensitivity Pneumonitis Syndromes and their associated antigens
- Farmers lung: Thermophilic actinomycetes
- Malt worker’s lung: Aspergillus spores
- Pigeon fancier’s disease; Avian proteins
- Cheese washer’s lung: Penicillium spores
- Furrier’s lung: Fox fur
- Laboratory technician’s lung: Rat urine proteins
Briefly describe Localized Type III reactions
- Injection of an antigen
  - Leads to an acute Arthus reaction within 4-8 hours
  - Localized tissue and vascular damage from edema, and erythema
  - Severity varies from mild swelling to redness to tissue necrosis
- Insect bite
  - May first have a rapid type I reaction
  - 4-8 hours later a typical arthus reaction occurs
Describe generalized Type III Hypersensitivity reactions
- Large amounts of antigen enter the bloodstream and bind to antibody → circulating immune complexes formed → cleared by phagocytosis or cause tissue damaging type III reactions
What is the etiology of generalized Type III Hypersensitivity reactions
- Serum sickness → antigen is administered IV
- Infectious disease
  - Meningitis
  - Hepatitis
  - Mononucleosis
- Drug reactions
  - Allergies to penicillin and sulfonamides
- Autoimmune disease
  - SLE
  - RA
Briefly describe the Arthus reaction
- Arthus reaction is a localized area of skin necrosis resulting from immune complex vasculitis.
- An antigen is injected into the skin of previously immunized persons causing pre-existing antibodies to form complexes with the antigens → The complexes precipitate at the site of infection and inflammation causes edema, hemorrhage and ulceration.
- Arthus reactions is a local immune complex deposition phenomenon eg. diabetic patients receiving insulin subcutaneously
- Local reactions: edema, erythema, necrosis
- Immune complex deposition in small blood vessels: vasculitis, microthrombi, vascular occlusion, necrosis
Briefly describe Serum sickness
- Horse serum was used for immunization in the olden days.
- Injecting foreign antigens causes manufacture of antibodies, which form complexes with the antigens.
- The complexes lodge in the kidneys, joints, small vessels and the inflammation causes fever, joint pain and proteinuria.
- Serum sickness is a systemic immune complex phenomenon secondary to injection of large doses of foreign serum.
- Antigens are slowly cleared from circulation and immune complexes deposit at various sites.
List drugs that are notorious for causing Serum sickness
- Cephalosporins, Ciprofloxacin, Furazolidone, Griseofulvin, Licomycin, Metronidazole, Para-aminosalicylic acids, penicillins, streptomycin, sulfonamides, tetracycline, allopurinol, barbiturates, bupropion, captopril, carbamazepine, fluoxetine, penicillamine
What are the clinical features of Serum Sickness
- Purpuric rash, Erythema nodosum, Erythema multiforme
- 10 days post injection: fever, urticaria, arthralgia, lymphadenopathy, splenomegaly, glomerulonephritis
What are the laboratory features of Serum Sickness
- CBC: Neutropenia, eosinophilia, thrombocytopenia
- Hepatitis serology: Asses Hepatitis B infection
- Inflammatory markers; Elevated ESR, CRP
- Complement levels: Low C3, C4 and CH50 levels
- Urinalysis: Mild proteinuria
- Skin lesions biopsy: Leukocytoclastic vasculitis that is non-specific
What are the laboratory features of Hypersensitivity pneumonitis
- CBC: normal peripheral eosinophil
- IgG levels: Elevated
- Precipitating antibodies in serum against suspected causative agent
- CXR: Patchy or homogeneous bilateral interstitial and alveolar nodular infiltrates
- High-res CT: Fibrotic changes on CT
- Bronchoalveolar lavage: >50% lymphocytes
What are the laboratory features of SLE
- ANA: sensitive
- Anti-dsDNA, anti-smith: Specific
- Urinalysis with microscopy and urine spot protein to creatinine ratio: evaluate possible nephritis and quantification of proteinuria
- Renal biopsy: definitive diagnosis and classification of lupus nephritis
- Appropriate imaging: Evaluate pulmonary and joint symptoms

Reference Intervals ›

Biochemistry

ACTH	P: <80 ng/L
ALT	P: 5–35 U/L
Albumin	P: 35–50 g/L
Aldosterone	P: 100–500 pmol/L
Alk. phosphatase	P: 30–130 U/L
α-Amylase	P: 0–180 IU/dL
α-Fetoprotein	S: <10 kU/L
Angiotensin II	P: 5–35 pmol/L
ADH	P: 0.9–4.6 pmol/L
AST	P: 5–35 U/L
Bicarbonate	P: 24–30 mmol/L
Bilirubin	P: 3–17 μmol/L
BNP	P: <50 ng/L
CRP	P: <10 mg/L
Calcitonin	P: <0.1 mcg/L
Calcium (ionized)	P: 1.0–1.25 mmol/L
Calcium (total)	P: 2.12–2.60 mmol/L
Chloride	P: 95–105 mmol/L
Cholesterol	P: <5.0 mmol/L
VLDL	P: 0.128–0.645 mmol/L
LDL	P: <2.0 mmol/L
HDL	P: 0.9–1.93 mmol/L
Cortisol AM	P: 450–700 nmol/L
Cortisol Midnight	P: 80–280 nmol/L
CK ♂	P: 25–195 U/L
CK ♀	P: 25–170 U/L
Creatinine	P: 70–100 μmol/L
Ferritin	P: 12–200 mcg/L
Folate	S: 2.1 mcg/L
FSH	P: 2–8 U/L ♂; >25 menopause
GGT ♂	P: 11–51 U/L
GGT ♀	P: 7–33 U/L
Glucose (fasting)	P: 3.5–5.5 mmol/L
Growth hormone	P: <20 mu/L
HbA1C (DCCT)	B: 4–6%
HbA1C (IFCC)	B: 20–42 mmol/mol
Iron ♂	S: 14–31 μmol/L
Iron ♀	S: 11–30 μmol/L
Lactate (venous)	P: 0.6–2.4 mmol/L
Lactate (arterial)	P: 0.6–1.8 mmol/L
LDH	P: 70–250 U/L
LH	P: 3–16 U/L
Magnesium	P: 0.75–1.05 mmol/L
Osmolality	P: 278–305 mosmol/kg
PTH	P: 0.8–8.5 pmol/L
Potassium	P: 3.5–5.3 mmol/L
Prolactin ♂	P: <450 U/L
Prolactin ♀	P: <600 U/L
PSA	P: 0–4 mcg/mL
Protein (total)	P: 60–80 g/L
Red cell folate	B: 0.36–1.44 μmol/L
Renin (erect)	P: 2.8–4.5 pmol/mL/h
Renin (recumbent)	P: 1.1–2.7 pmol/mL/h
Sodium	P: 135–145 mmol/L
TBG	P: 7–17 mg/L
TSH	P: 0.5–4.2 mU/L
T4	P: 70–140 nmol/L
Free T4	P: 9–22 pmol/L
TIBC	S: 54–75 μmol/L
Triglycerides	P: 0.50–2.3 mmol/L
T3	P: 1.2–3.0 nmol/L
Troponin T	P: <0.1 mcg/L
Urate ♂	P: 210–480 μmol/L
Urate ♀	P: 150–390 μmol/L
Urea	P: 2.5–6.7 mmol/L
Vitamin B12	S: 0.13–0.68 nmol/L
Vitamin D	S: 50 nmol/L

Arterial Blood Gases

pH	7.35–7.45
PaCO₂	4.7–6.0 kPa
PaO₂	>10.6 kPa
Base excess	±2 mmol/L

Urine

Cortisol (free)	<280 nmol/24h
Hydroxyindole acetic acid	16–73 μmol/24h
Hydroxymethylmandelic acid	16–48 μmol/24h
Metanephrines	0.03–0.69 μmol/mmol cr.
Osmolality	350–1000 mosmol/kg
17-Oxogenic steroids ♂	28–30 μmol/24h
17-Oxogenic steroids ♀	21–66 μmol/24h
17-Oxosteroids ♂	17–76 μmol/24h
17-Oxosteroids ♀	14–59 μmol/24h
Phosphate (inorganic)	15–50 mmol/24h
Potassium	14–120 mmol/24h
Protein	<150 mg/24h
Protein/creatinine ratio	<3 mg/mmol
Sodium	100–250 mmol/24h

Haematology

WCC	4.0–11.0 ×10⁹/L
RBC ♂	4.5–6.5 ×10¹²/L
RBC ♀	3.9–5.6 ×10¹²/L
Hb ♂	130–180 g/L
Hb ♀	115–160 g/L
PCV ♂	0.4–0.54 L/L
PCV ♀	0.37–0.47 L/L
MCV	76–96 fL
MCH	27–32 pg
MCHC	300–360 g/L
RDW	11.6–14.6%
Neutrophils	2.0–7.5 ×10⁹/L (40–75%)
Lymphocytes	1.0–4.5 ×10⁹/L (20–45%)
Eosinophils	0.04–0.44 ×10⁹/L (1–6%)
Basophils	0–0.10 ×10⁹/L (0–1%)
Monocytes	0.2–0.8 ×10⁹/L (2–10%)
Platelets	150–400 ×10⁹/L
Reticulocytes	0.8–2.0% / 25–100 ×10⁹/L
Prothrombin time	10–14 s
APTT	35–45 s

Paediatric

Pulse Rate (bpm)
Neonate	140–160
Infant <1yr	120–140
1–5 years	110–130
5–12 years	80–120
>12 years	70–100
Respiratory Rate (tachypnoea)
0–2 months	≥60/min
2–12 months	≥50/min
1–5 years	≥40/min
>5 years	≥30/min
Blood Pressure (mmHg)
Term	65/45
1 year	75/50
4 years	85/60
8 years	95/65
10 years	100/70
Weight Formulas
3–12 months	(a + 9)/2 kg
1–6 years	2a + 8 kg
>6 years	(7a − 5)/2 kg
Haemoglobin (g/dL)
Term newborn	13–20
1 month	11–18
2 months	10–15
1–2 years	10–13
>2 years	11–14
MUAC (6 months–5 years)
Obese	>17.5 cm
Normal	13.5–17.4 cm
At risk	12.5–13.4 cm
Moderate malnutrition	11.5–12.4 cm
Severe malnutrition	<11.5 cm
Developmental Milestones
Social smile	1.5 months
Head control	4 months
Sits unsupported	7 months
Crawls	10 months
Stands unsupported	10–12 months
Walks	12–13 months
Talks	18 months
CSF WBC (/mm³)
Term newborn	0–25
>2 weeks	0–5

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