Mycoplasma-derived leukocyte mitogens

It is well established that many species of mycoplasmas are potent mitogens for leukocytes from a variety of mammals including humans, rodents, and rabbits. The complexity of mycoplasma-leukocyte interactions necessitates the use of purified mycoplasma mitogens to understand the mechanisms and consequences of mycoplasma-induced leukocyte mitogenesis. This has been the objective of several groups and is the subject of this review. Mitogenic activity has been described for 13 of the 80 known species of mycoplasmas. This phenomenon has been recently extensively reviewed (5). Mycoplasmas are the etiologic agents of primary atypical pneumonia (PAP) in humans, atypical pneumonia and arthritis in rodents, rabbits, swine, ruminants, and fowl, and genitourinary and neurologic infections in humans and rodents. Although the consequences of mycoplasma-induced leukocyte mitogenesis in vivo are poorly understood, it is likely that it plays an important role in the etiology of atypical pneumonia (8), but not arthritis (4) in rodents. The mitogenic membrane fraction of Mycoplasma pulmonis, an etiologic agent of pneumonia in rats, and Concanavalin A both induced pneumonia in rats. These pneumonias were characterized by peribronchial mononuclear cell infiltrates typical of human disease induced by M. pneumoniae. This suggests that mitogenesis may be an important factor in PAP. Mycoplasma infection can be devastating in immunologic studies in vitro. Mycoplasmas are common cell culture contaminants; as many as 10-15% of cell lines in the United States, and up to 25% in Europe are infected. All of the most common cell culture contaminants, M. hyorhinis, M. orale, M. arginini, M. fermentans, and A. laidlawii, are leukocyte mitogens. In addition to being mitogenic, several species of mycoplasmas can induce the secretion of soluble immune-response mediators, including granulocyte/monocyte colony-stimulating factor and alpha interferon. Thus, the presence of mycoplasmas can lead to misinterpretation of immunologic data. M. hyorhinis, the most common cell culture contaminant, is highly mitogenic for lymphocytes from many species including human, mouse, and hamster. Mitogenic stimulation of leukocytes by intact infectious mycoplasmas or mycoplasma products is a complex process involving binding and direct stimulation of T cells, B cells, and macrophages, as well as indirect stimulation of lymphocytes by macrophages. Mycoplasmas bound to the plasma membranes of lymphoid and nonlymphoid tumor cell lines can also activate macrophages (5). Evaluation of the pathophysiologic consequences of mycoplasma induced leukocyte mitogenesis is further complicated by the ability of some species of mycoplasmas to stimulate multiple leukocyte types, such as T cells, B cells, macrophages, and NK cells. Since individual species of mycoplasmas can be mitogenic for multiple leukocyte types, they may possess either individual polyspecific mitogens able to stimulate many different target cell types or, alternatively, multiple monospecific mitogens, or both. Purification of mycoplasma mitogens is crucially needed to understand the nature and consequences of mycoplasmainduced mitogenesis. The data presented below describe our efforts to isolate rodent leukocyte mitogens from M. hyorhinis. Although mycoplasmas are capable of free living, they are often associated with host cells as parasites on the outer plasma membrane surface. The adsorption of mycoplasmas to host plasma membranes is a complex phenomenon that may be mediated by association with membrane glycoproteins, by hydrophobic interactions, or both. The association of mycoplasmas or mycoplasma products with host membranes is a necessary first step in mitogenesis. Many species of mycoplasmas are potent mammalian lymphocyte mitogens. These include mycoplasmas that are mitogenic for both human and rodent lymphocytes (M. hyorhinis, M. pneumoniae, M. fermentans, S. mirum, and A. laidlawii), as well as a variety of other mycoplasma species known to be mitogenic only for rodent lymphocytes (i.e., M. arthritidis and M. pulmonis).