A patient with recurrent bacterial pneumonias is found to have a mutation in ITGB2 (CD18) gene. This results in absent surface expression of CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), and CD11c/CD18 on leukocytes. What is the specific defect in leukocyte trafficking?

• A Failure of leukocyte rolling — P-selectin/E-selectin interactions are absent because selectins require CD18 as co-receptor
• B Defective chemokine sensing — CD18 is the signalling subunit of CXCR2 receptor required for IL-8 response
• C Impaired phagocytosis only — the transmigration of leukocytes proceeds normally but intracellular killing is impaired
• D Failure of firm adhesion and transmigration — the beta-2 integrins mediate ICAM-1-dependent firm adhesion; without them, leukocytes roll but cannot arrest or emigrate through the endothelium ✓

Explanation

Leukocyte adhesion deficiency type I (LAD-I) is caused by mutations in CD18 (ITGB2), the common beta-2 subunit of the integrin heterodimers LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), and p150,95 (CD11c/CD18). These integrins mediate firm adhesion of rolling leukocytes to endothelial ICAM-1 and ICAM-2, a step essential before leukocytes can transmigrate into tissues. Without firm adhesion, leukocytes remain in circulation (causing profound leukocytosis) and cannot emigrate to infection sites. Rolling via selectin interactions is intact since selectins do not require CD18. Mac-1 also serves as a complement receptor (CR3), so opsonised phagocytosis is additionally impaired, but the primary trafficking defect is failure of firm adhesion.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.