Leukocyte Adhesion Deficiency Mechanisms and Therapeutic Approaches

Leukocyte adhesion deficiency (LAD) encompasses a group of rare inherited disorders characterised by defects in the multi-step cascade that governs leukocyte extravasation. At its core lies impaired expression or function of adhesion molecules—principally the β2-integrin family—on the surface of neutrophils and other leukocyte subsets. Failure of firm adhesion and subsequent transendothelial migration results in profound susceptibility to bacterial and fungal infections, delayed wound healing, omphalitis and persistent leukocytosis. Three principal subtypes have been delineated: LAD I, arising from ITGB2 mutations that abrogate β2-integrin (CD18) expression; LAD II, due to deficient fucosylation of selectin ligands; and LAD III, reflecting defects in inside-out integrin activation. Clinical severity correlates with residual adhesion molecule function, with the most severe forms leading to mortality in early childhood without curative intervention.

Therapeutic approaches centre on prompt infection control using broad-spectrum antibiotics and meticulous wound management. Haematopoietic stem cell transplantation (HSCT) remains the only established cure for severe LAD I and LAD III, with survival and quality of life markedly improved by early transplantation. Emerging strategies include gene therapy to restore ITGB2 expression, ex vivo gene editing of patient-derived haematopoietic stem cells and induced pluripotent stem cell (iPSC) modelling to facilitate drug screening. Advances in conditioning regimens and graft-versus-host disease prophylaxis have broadened HSCT eligibility. Ongoing research seeks to refine targeted therapies, harness monoclonal antibodies to modulate residual integrin function and develop small-molecule chaperones to stabilise mutant adhesion proteins.

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Leukocyte Adhesion Deficiency Mechanisms and Therapeutic Approaches publication trend

The graph below shows the total number of articles in leukocyte adhesion deficiency mechanisms and therapeutic approaches across all publications each year (not limited to Nature Index journals).

Technical terms

β2-integrin (CD18): A transmembrane heterodimeric receptor essential for firm leukocyte adhesion to endothelium and subsequent migration into tissues.

Leukocyte extravasation: The multi-step process whereby circulating leukocytes adhere to, roll along, and transmigrate through the vascular endothelium toward sites of inflammation.

Chemotaxis: Directed movement of cells in response to chemical gradients, enabling leukocytes to home to sites of infection or injury.

Haematopoietic stem cell transplantation (HSCT): A procedure in which patient bone marrow is replaced or supplemented with healthy donor stem cells to reconstitute normal blood and immune function.

References

1. Analysis of Clinical, Immunological and Molecular Features of Leukocyte Adhesion Deficiency Type I in Egyptian Children. Journal of Clinical Immunology (2024).
2. Case report: HLA-haploidentical hematopoietic cell transplant with posttransplant cyclophosphamide in a patient with leukocyte adhesion deficiency type I. Frontiers in Immunology (2022).
3. Eight induced pluripotent stem cell lines (iPSCs) derived from two patients with Leukocyte adhesion deficiency Type I (LAD I) with mutations in the ITGB2 gene. Stem Cell Research (2024).