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The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation
Abstract:
An inherited syndrome characterized by recurrent or progressive necrotic soft-tissue infections, diminished pus formation, impaired wound healing, granulocytosis, and/or delayed umbilical cord severance was recognized in four male and four female patients. As shown with subunit-specific monoclonal antibodies in immunofluorescence flow cytometry and 125I immunoprecipitation techniques, in addition to a NaB3H4-galactose oxidase labeling assay, granulocytes, monocytes, or lymphocytes from these individuals had a "moderate" or "severe" deficiency of Mac-1, LFA-1, or p150,95 (or a combination)--three structurally related "adhesive" surface glycoproteins. Two distinct phenotypes were defined on the basis of the quantity of antigen expressed. Three patients with severe deficiency and four patients with moderate deficiency expressed less than 0.3% and 2.5%-31% of normal amounts of these molecules on granulocyte surfaces, respectively. The severity of clinical infectious complications among these patients was directly related to the degree of glycoprotein deficiency. More profound abnormalities of tissue leukocyte mobilization, granulocyte-directed migration, hyperadherence, phagocytosis of iC3b-opsonized particles, and complement- or antibody-dependent cytotoxicity were found in individuals with severe, as compared with moderate, deficiency. It is proposed that in vivo abnormalities of leukocyte mobilization reflect the critical roles of Mac-1 glycoproteins in adhesive events required for endothelial margination and tissue exudation. The recognition of phenotypic variation among patients with Mac-1, LFA-1 deficiency may be important with respect to therapeutic strategies.
Insights
This study identifies an inherited syndrome causing severe infections due to deficiencies in key cell adhesion molecules (Mac-1, LFA-1). Clinical severity correlates with the degree of this glycoprotein deficiency.
Area of Science:
- Immunology
- Genetics
- Cell Biology
Background:
- An inherited syndrome presents with recurrent infections, impaired wound healing, and delayed umbilical cord severance.
- This condition is linked to deficiencies in specific cell surface glycoproteins involved in immune cell adhesion.
Observation:
- Eight patients (4 male, 4 female) exhibited varying degrees of deficiency in Mac-1, LFA-1, or p150,95 glycoproteins.
- Two phenotypes were identified: severe deficiency (<0.3% of normal) and moderate deficiency (2.5%-31% of normal).
Findings:
- Patients with severe glycoprotein deficiency showed more profound defects in leukocyte mobilization, migration, and cytotoxicity.
- Clinical infectious complications were directly proportional to the extent of the glycoprotein deficiency.
Implications:
- Deficiencies in Mac-1, LFA-1, and p150,95 glycoproteins critically impair leukocyte adhesion and tissue infiltration.
- Understanding phenotypic variation is crucial for developing targeted therapeutic strategies for this immune disorder.