Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis.

Open Access
Publisher Website
Google Scholar
Abstract
Leukocyte surface glycoproteins that share a common .beta. subunit have been found to be congenitally deficient in 3 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 a 4th 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 2 patients expressing .apprx. 0.5% and 1 patient .apprx. 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 3 patients. Together with surface deficiency of 3 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.