The objective of this investigation is the study of human mononuclear phagocyte differentiation and function through the development of monoclonal reagents that identify membrane antigens expressed by monocytes, macrophages, granulocytes, and their precursors. Among the surface antigens identified thus far, Mol, a two-subunit glycoprotein (gp 155, 94) expressed by monocytes, neutrophils, and bone marrow myeloid precursors, has a clear functional significance. In antibody blocking studies, anti-Mol monoclonal antibodies specific for the 155 kilodalton alpha subunit inhibit the binding of C3bi-coated particles to human neutrophils and monocytes. The noncytotoxic enzyme release (histaminase, lysozyme, beta-glucuronidase) from neutrophils stimulated by C3biopsonized zymosan is also blocked by pretreatment of cells with anti-Mol Fab. These results suggest that the Mol-alpha is the C3bi receptor (CR3) on human myeloid cells. Mol may play a role in Fc- and C3 receptor-dependent phagocytosis, since this function is also reduced in antibody blocking experiments. The functional significance of Mol is indicated by its deficient expression on two pediatric patients whose phagocytes exhibit functional defects that include impaired immune phagocytosis, opsonized zymosan-induced degranulation, and substrate spreading/adhesion. While Mol is a constituent plasma membrane glycoprotein, a large intracellular pool of Mol is associated with the specific granular fraction of neutrophils. After exposure of neutrophils to degranulating stimuli, this intracellular granule-associated Mol is translocated to the plasma membrane resulting in a 10-fold increase in surface Mol density. By this mechanism, neutrophils may rapidly increase available membrane receptor sites without the requirement of neosynthesis. In addition to the myelomonocytic markers Mol-Mo6 (see 1983 report), we have since developed additional monoclonal reagents that identify late macrophage-specific differentiation antigens (PAM1 and BMM1). BMM1 is a protease-sensitive two-subunit surface protein (p 40, 46) found on macrophages isolated from human colostrum, while PAM1 is a papain-sensitive 200 kilodalton polypeptide uniquely expressed by pulmonary alveolar macrophages. Neither antigen is found on peripheral blood monocytes or any other circulating or bone marrow cell. Thus, both antigens are highly restricted in their expression by mononuclear phagocytes found in distinct anatomical sites and provide additional evidence for the structural and functional heterogeneity displayed by cells within this lineage. (CS)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA039064-02
Application #
3177787
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1984-07-01
Project End
1990-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kindzelskii, Andrei L; Amhad, Imran; Keller, Donald et al. (2004) Pericellular proteolysis by leukocytes and tumor cells on substrates: focal activation and the role of urokinase-type plasminogen activator. Histochem Cell Biol 121:299-310
Worth, R G; Esper, R M; Warra, N S et al. (2001) Mercury inhibition of neutrophil activity: evidence of aberrant cellular signalling and incoherent cellular metabolism. Scand J Immunol 53:49-55
Mahdi, F; Shariat-Madar, Z; Todd 3rd, R F et al. (2001) Expression and colocalization of cytokeratin 1 and urokinase plasminogen activator receptor on endothelial cells. Blood 97:2342-50
Kindzelskii, A L; Yang, Z; Nabel, G J et al. (2000) Ebola virus secretory glycoprotein (sGP) diminishes Fc gamma RIIIB-to-CR3 proximity on neutrophils. J Immunol 164:953-8
Mizukami, I F; Todd 3rd, R F (1998) A soluble form of the urokinase plasminogen activator receptor (suPAR) can bind to hematopoietic cells. J Leukoc Biol 64:203-13
Sitrin, R G; Pan, P M; Srikanth, S et al. (1998) Fibrinogen activates NF-kappa B transcription factors in mononuclear phagocytes. J Immunol 161:1462-70
Model, M A; Ganelina, L S; Todd 3rd, R F (1998) A microscopic study of Fc gamma RIII-mediated respiratory burst in neutrophils. Immunobiology 199:39-50
Adachi, Y; Kindzelskii, A L; Cookingham, G et al. (1998) Aberrant neutrophil trafficking and metabolic oscillations in severe pyoderma gangrenosum. J Invest Dermatol 111:259-68
Shaya, S; Kindzelskii, A L; Minor, J et al. (1998) Aberrant integrin (CR4;alpha(x)beta2;CD11c/CD18) oscillations on neutrophils in a mild form of pyoderma gangrenosum. J Invest Dermatol 111:154-8
Xue, W; Mizukami, I; Todd 3rd, R F et al. (1997) Urokinase-type plasminogen activator receptors associate with beta1 and beta3 integrins of fibrosarcoma cells: dependence on extracellular matrix components. Cancer Res 57:1682-9

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