Orosomucoid: An update of immune function

Orosomucoid (Om), a major alphalglobulin, is a glycoprotein of approximately 40,000 kD molecular weight. This protein is very acidic in nature and contains as high as 45% of carbohydrates (10), thus also referred to as alphal-acid glycoprotein (AGP). Orosomucoid is an acute phase reactant, since its plasma concentration is markedly elevated in several acute phase responses, such as inflammation, stress, pregnancy, myocardial infarction, neonatal infections, and cancer. Moreover, Om stimulates the growth of human embryonic lung fibroblasts, He La cells, or EBV-transformed lymphoblastoid cells cultured in a serum-free medium (8). Orosomucoid is an extremely polymorphic protein (7, 11). The phenotypes of the variants are designated as SS, FF, and FS, corresponding to the slow, fast, and double electrophoretic pattems, respectively. In addition, various molecular species of Om, such as a heterodimer with albumin and a dimer, have been reported (9). Recent studies (4) using human cDNA probe demonstrated that AGP in plasma exists as a mixture of two gene products, designated as AGP1 and AGP2, in a ratio of 3:1. The AGP1 form is polymorphic with Arg and Gin present at position 20 in SS and FF variants, respectively. Moreover, Om displays sequence similarity with immunoglobulin G, EGF receptor, and two other acutephase proteins (haptoglobin and alpha lantitrypsin). The synthesis of Om occurs primarily in the liver. Human peripheral blood lymphocytes, monocytes, and granulocytes also synthesize and secrete Om in cell cultures (6, 12). Gahmberg and Andersson (6) showed that the molecule is initially synthesized as a larger molecule of 51,000 kD, which is cleaved by an as yet unknown mechanism into a 40,000 kD molecule before its accumulation in the plasma. During an acute phase response, the synthesis in the liver of acute phase proteins, including Om, is markedly elevated. Interleukin1 (IL1) lymphokine and homeostatic hormones are involved in triggering the transcription and synthesis of these proteins (5). Orosomucoid is present on the surface membrane of human T and B lymphocytes, monocytes, lymphoblastoid cells, and myocardium. We recently showed the occurrence of Om on the cell membrane of NCB-20 cells (a hybrid neuroglial tumor cell line) (14) and on 25-45% of normal T lymphocytes (15). As shown in Fig. 1, the percentages of Om-positive T cells in young adults were of about the same order of magnitude as those found in aged individuals. In addition, we found abnormal distribution of Ompositive T lymphocytes (data not included here) in several patients with autistic syndrome, retinitis pigmentosa, chronic EBV syndrome, Alzheimer's disease, Down's syndrome, and other conditions. Our preliminary results of isolation of Om-positive T cells reveal that these cells are T helper cells, as marked phenotypically by positive staining, predominantly of anti-Leu-3a monoclonal antibody (< 10% of the isolated cells were positive with antiLeu-2a). Accordingly, we suggest that Om might serve as a phenotypic marker of a subpopulation of T helper cells. The function of Om remains unknown. This glycoprotein as outlined below can affect several immunologic functions in vitro, however. Orosomucoid is well known to have immunosuppressive activity (1, 3) based on its inhibitory effect (although very weak) on mitogen-induced lymphocyte DNA synthesis, antibody synthesis, antibody response to sheep erythrocytes, cytolytic lymphocyte reactivity to alloantigens, and phagocytosis by macrophages. Stefanini and associates (16) reported about 70% inhibition by rabbit anti-Om of T cell DNA synthesis stimulated with anti-T3 monoclonal antibody or non-T cells in the autologous mixed lymphocyte reaction (AMLR). They suggested that anti-Ore plays a positive role in the T3-T i activation since both anti-T3-induced proliferation and AMLR presumably involve the T3-T i