title: Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis.
abstract: Leukocyte surface glycoproteins that share a common beta subunit have been found to be congenitally deficient in three unrelated patients with recurring bacterial infection. The glycoproteins, Mac-1, LFA-1, and p150,95, have the subunit compositions alpha M beta, alpha L beta, and alpha X beta, respectively. Using subunit-specific monoclonal antibodies, both the alpha M and beta subunits of Mac-1, the alpha L and beta subunits of LFA-1, and at the least the beta subunit of p150,95, were found to be deficient at the cell surface by the techniques of immunofluorescence flow cytometry, radioimmunoassay, and immunoprecipitation. A latent pool of Mac-1 that can be expressed on granulocyte surfaces in response to secretory stimuli, such as f-Met-Leu-Phe, was also lacking in patients. Deficiency was found on all leukocytes tested, including granulocytes, monocytes, and T and B lymphocytes. Quantitation by immunofluorescence cytometry of subunits on granulocytes from parents of these patients and of a fourth deceased patient showed approximately half-normal surface expression, and, together with data on other siblings and a family with an affected father and children, demonstrate autosomal recessive inheritance. Deficiency appears to be quantitative rather than qualitative, with two patients expressing approximately 0.5% and one patient approximately 5% of normal amounts. The latter patient had alpha beta complexes on the cell surface detectable by immunoprecipitation. Biosynthesis experiments showed the presence of normal amounts of alpha'L intracellular precursor in lymphoid lines of all three patients. Together with surface deficiency of three molecules that share a common beta subunit but have differing alpha subunits, this suggests the primary deficiency is of the beta subunit. The lack of maturation of alpha'L to alpha L and the deficiency of the alpha subunits at the cell surface and in latent pools suggests that association with the beta subunit is required for alpha subunit processing and transport to the cell surface or to latent pools. The molecular basis of this disease is discussed in light of adhesion-related functional abnormalities in patients' leukocytes and the blockade of similar functions in healthy cells by monoclonal antibodies.
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface / Q000172:deficiency*; D002472:Cell Transformation, Viral; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006098:Granulocytes / Q000276:immunology; D004854:Herpesvirus 4, Human; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007223:Infant; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1; D008297:Male
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D016169:Lymphocyte Function-Associated Antigen-1