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Leukocyte adhesion deficiency: molecular basis and functional consequences
A Fischer1, B Lisowska-Grospierre, D C Anderson
1Inserm U 132, Hôpital des Enfants-Malades, Paris, France.
Insights
Leukocyte adhesion deficiency disease results from beta-subunit gene mutations, impairing leukocyte adhesion and causing severe infections. Bone marrow transplantation offers a cure, and LFA-1 antibodies may provide immunotherapy.
Area of Science:
- Immunology
- Genetics
- Cell Biology
Background:
- Leukocyte adhesion deficiency (LAD) is a genetic disorder affecting immune cell function.
- It stems from mutations in the gene for a beta-subunit common to leukocyte adhesion molecules LFA-1, Mac-1, and p150,95.
- This defect impairs phagocytic cell migration to infection sites.
Purpose of the Study:
- To elucidate the molecular basis and clinical manifestations of LAD.
- To explore therapeutic strategies for LAD, including bone marrow transplantation and immunotherapy.
Main Methods:
- Analysis of beta-subunit gene mutations.
- Assessment of leukocyte adhesion molecule expression (LFA-1, Mac-1, p150,95).
- Clinical evaluation of infection susceptibility and treatment outcomes.
Main Results:
- Mutations lead to absent or abnormal beta-subunit expression, causing defective heterodimer function.
- Severe LAD shows absent surface expression, moderate LAD shows low expression.
- Patients experience severe bacterial and fungal infections; bone marrow transplantation is curative.
- Impaired T-lymphocyte adhesion is noted, but alternative pathways exist.
Conclusions:
- LAD is characterized by impaired leukocyte adhesion due to beta-subunit defects, leading to recurrent infections.
- Allogeneic bone marrow transplantation is a definitive treatment.
- The lack of graft rejection in severe LAD suggests potential for LFA-1 targeted immunotherapy.
Abstract:
Leukocyte adhesion deficiency disease is characterized by a mutation in the gene encoding the beta-subunit shared by three adhesive heterodimers, LFA-1, Mac-1 (CR3) and p150,95 expressed by leukocytes. An absent or abnormal beta-subunit leads to defective expression of the three heterodimers. Severe and moderate phenotypes of the disease are defined by absent and low surface expression of the adhesion molecules. The disease causes an inability of phagocytic cells to adhere to endothelial cells and thereafter to migrate to sites of infections. Severe widespread life-threatening bacterial and fungal infections are the consequences of this abnormality. Cure of the disease can be effected by allogeneic bone marrow transplantation. T-lymphocyte adhesion to various cells is also impaired; its consequences are, however, limited because of the existence of other T-cell-adhesive pathways. Nevertheless, haploidentical bone marrow graft rejection does not occur in the severe phenotype, an indication for possible immunotherapy with LFA-1 specific monoclonal antibodies.