ImmunologyTier 1Medical Sciences concept

Leukocyte adhesion deficiency - mechanism (defective integrins, impaired extravasation)

Core concept

The leukocyte adhesion cascade

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1. Capture / rolling - selectins (L on leukocyte, E and P on endothelium)

binding sialyl-Lewis X

2. Activation - chemokines via G-protein-coupled receptors

-> integrin conformational change

3. Firm adhesion - beta-2 integrins (CD11a/b/c + CD18)

binding endothelial ICAM-1

4. Diapedesis - PECAM-1/CD31, junctional migration

5. Chemotaxis - to the tissue

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Type	Defect	Step blocked
LAD-I	CD18 (ITGB2) - the common beta-2 integrin chain	Firm adhesion
LAD-II	SLC35C1 - GDP-fucose transporter -> no sialyl-Lewis X	Rolling
LAD-III	FERMT3 (kindlin-3) - inside-out integrin activation	Adhesion + platelet aggregation -> Glanzmann-like bleeding

All autosomal recessive
Neutrophils are made and released normally but cannot leave the vessel -> they accumulate in blood

The signature triad
- Delayed umbilical cord separation (>3 weeks; normal <2 weeks) and omphalitis
- Recurrent bacterial and fungal infection with NO PUS - skin, perianal, oral, otitis, periodontitis, poorly healing "cigarette-paper" scars
- Persistent marked neutrophilia (often 15-100 x10^9/L) that rises further with infection
Neutrophilia with recurrent infection and no abscess formation is the exam pattern - the count is high because the cells are stuck in the circulation
Severity tracks residual CD18 expression: <2% (severe) -> death in infancy without transplant; 2-30% (moderate) survives into adulthood
LAD-II adds the Bombay (hh) blood group, growth restriction and intellectual disability (fucosylation is a general glycosylation defect); may respond to oral fucose
Diagnosis: flow cytometry for CD18/CD11b on neutrophils, then genetic confirmation
Contrast with the other neutrophil disorders

Disorder	Defect	Discriminator
CGD	NADPH oxidase	Granulomas, abscesses form; DHR-123/NBT abnormal; catalase-positive organisms and Aspergillus
Chediak-Higashi	LYST	Giant granules, oculocutaneous albinism, accelerated phase (HLH)
Severe congenital neutropenia	ELANE	Neutropenia, not neutrophilia

Delayed cord separation plus neutrophilia in an infant = check CD18 flow cytometry
Definitive treatment is allogeneic haematopoietic stem cell transplantation - curative, and should be done early in severe disease; gene therapy is in trials for LAD-I
Supportive: prophylactic antibiotics (co-trimoxazole) +/- antifungal, aggressive treatment of infection, meticulous dental and skin care
Pus and abscess formation require neutrophil egress - their absence is diagnostic information, not reassurance
The same pathway is exploited therapeutically: natalizumab (anti-alpha-4 integrin) and vedolizumab (anti-alpha4beta7) block leukocyte adhesion deliberately -> natalizumab and PML is the acquired mirror of LAD

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