Type IV Hypersensitivity

Last updated: November 12, 2024

Briefly describe Type IV Hypersensitivity
- Type IV hypersensitivity is T-cell mediated hypersensitivity.
- Activated T-cells release cytokines that activate macrophages or kill cells directly.
- Type IV hypersensitivity is useful against intracellular organisms (viruses, fungi, parasites, some bacteria).
- Here it results in inflammation, cell destruction, and granuloma formation
What are the Types of Type IV Hypersensitivity reactions
- Delayed-type Hypesensitivity (DTH)
  - CD4+ T cells secrete cytokines, activating macrophages, can lead to granulomatous inflammation
- Direct cell cytotoxicity
  - CD8+ T cells kill target cells
Describe the pathogenesis of delayed-type Type IV Hypersensitivity reactions
- Initial exposure (Sensitization)
  - Mechanism of exposure:
    - Contact sensitization with chemicals and environmental antigens
    - Intradermal or subcutaneous injection of protein antigens
    - Microbial infection
  - APCs (DCs and Macrophage) uptake antigen, are activated and secrete IL-12, IL-1, IL-6, and IL-23
  - The phagocytosed mocs are presented to naive CD4+ T-cells via MHC II
  - Naive CD4+ T-cells are activated:
    - Secrete IL-2: Autocrine growth factor that stimulates proliferation of the antigen responsive t-CELLS
  - APCs secrete IL-12 which converts CD4+ T-cells to Th1 subset
  - APCs secrete IL-1, IL-6 and IL-23 which convert CD4+ T-cells to Th17 subset
  - Effector Th1 and Th17 cells enter circulation and join the pool of memory T-cells which persist for long periods, sometimes even years
- Re-exposure (Effector T-cell function)
  - On repeat exposure Th1 secrete IFN-y
  - IFN-y activates macrophages via the classical pathway in order to eliminate the offending antigen
    - Ability to phagocytose and kill micro-organisms is enhanced
    - Express more class II MHC molecules on the surface enhancing antigen presentation
    - Secrete TNF, IL-1 and chemokines which promote inflammation
    - Produce more IL-12, amplifying the Th1 response
  - Activate Th17 cells secrete IL-12, IL-22, chemokines and other cytokines
    - Function to recruit neutrophils and monocytes to the reaction promoting inflammation
  - Recruited macrophages and neutrophils cause tissue destruction via lysosomal enzymes and reactive oxygen species
  - Prolonged inflammation causes granulomatous inflammation whereby macrophages are activated to become epitheloid or they fuse to form giant cells
  - Granuloma formation
    - Microbe or foreign body persists within macrophages that the cell is unable to destroy
    - Sustained Th1 activation and IFN-y production causes macrophages to undergo morphologic transformation into epitheloid cells with large abundant cytoplasm
    - Some Macrophages fuse to form giant multinucleated cells
    - Examples
      - Infections: Leprosy, Tuberculosis, Schistosomiasis
      - Non-infectious conditions: Sarcodiosis, Crohn disase
      - Foreign body reaction: Berylliosis, Talcosis, Silicosis
- Direct cell cytotoxicity – CD8+ mediated Hypersensitivity
  - CTLs recognize antigens on surface cells.
Give examples of Delayed Type Hypersensitivity reactions (DTH)
- CD4+ Mediated
  - Mantoux test
  - Brucellosis
  - Lepromin test
  - Frei’s test in Lymphogranuloma Venerium
  - Tuberculin (PPD) reaction
  - Contact Dermatitis (Urushiol poison ivy)
  - Autoimmune diseases (Rheumatoid Arthritis, Psoriasis, Multiple sclerosis, IBD – Crohn)
  - Granuloma formation (Leprosy, Tuberculosis, Schistosomiasis, Sarcodiosis, Crohn disease, Berylliosis, Talcosis, Silicosis
- CD8+ mediated
  - Type I Diabetes Mellitus
  - Graft Rejection
Briefly describe contact dermatitis
- Contact dermatitis is a DTH reaction when skin comes into contact with chemical substances or drugs (poison, hair dyes, cosmetics, soaps, neomycin).
- These substances enter the skin as small molecules (haptens) attached to proteins to form immunogenic substances.
- Urushioll: antigenic component of poision ivy or poison oak
- Mechanism
  - Occurs from topical exposure to chemicals and environmental antigens
  - Haptens penetrate the skin and combine with tissue proteins to form neo-antigens
  - Langerhan cells are the principle APCs in recognition of hapten-tissue protein complexes and presentation to T-cells
- DTH leads to : eczema, rash, vesicular eruption
Briefly describe the Tuberculin skin test (PPD)
- PPD is injected intradermally in sensitized persons.
- A local area of induration appears at the injection site 48-72 hours later due to the accumulation of macrophages and lymphocytes.
- Similar reactions in:
  - Brucellosis
  - Lepromin test in Leprosy
  - Frei’s test in Lymphogranuloma venereum
- Morphology: Accumulation of mononuclear cells (Mainly CD4+ T-cells and Macrophages around venules producing perivascular cuffing
What is the mechanism behind the Tuberculin Skin Test (PPD)
- Occurs in individuals who have been exposed to M tuberculosis (Infection, Vaccination?)
- Delayed Type Hypersensitivity evolves over 24-48 hours
- 4 hours after injection in sensitized individuals neutrophils accumulate around the post-capillary venules at the injection site
- 12 hours after the injection T cells and blood monocytes infiltrate the area
- Endothelial cells lining these venules become enlarged and the vessels leak plasma macromolecules
- Fibrinogen escapes from the blood vessels into the surrounding tissue where it is converted into fibrin
- Deposition of fibrin, edema and accumulation of mononuclear cells within the extravascular tissue space around the injection produces an area of induration (swollen and firm)
Describe the procedure and interpretation of the Mantoux test (Tuberculin Skin Test, PPD)
- Inject 0.15mL of 5 TU PD solution intradermally on the volar surface of the lower arm using a 27G needle and tuberculin syringe
- Produce a wheal 6-10mm diameter
- Note the arm in which the test was administered
- Read the skin the skin test 48-72 hours after administration
- Note the are of induration (not erythema) in millimeters in the axis perpendicular to the long axis of the arm
- Interpretation
  - 5mm – Immunosuppressed
  - 10mm – Individuals with risk factor to TB Endemic individuals, Injection drug users MTB lab personnel, Children younger than 4, infants, children and adolescents exposed to high-risk individuals
  - 15mm – Individuals with no known risk factors for TB
Describe the procedure and interpretations of the Lepromin test
- Procedure is same as the one for the Mantoux test
- Read 48 hours = Fernandez reaction
- Read 3-4 weeks = Mitsuda reaction

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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