Lysosomes participate, in one way or another, in a tremendous variety of cellular and organismic disorders. Often, their participation is chiefly through the activities of scavenger cells that clear up cellular debris; corresponding changes in hydrolase levels and numbers and activity of phagocytes have been described for inflammatory responses, infectious diseases, tumors and many other pathological conditions (see e.g., Franson and Waite 1973, Gordon and Cohn 1973, Van Furth 1970, Vernon-Roberts 1972, Williams and Fudenberg 1972). For certain disorders there is circumstantial evidence for less indirect lysosomal involvement. But, for very few situations do we have adequate information bearing upon the questions that are most critical from our vantage point—are lysosomes involved as causative agents and if so, through what mechanisms? In other words, it is not difficult to find changes occurring in lysosomes of pathological material but determining the significance of these changes is quite another matter.
KeywordsStorage Disease Chronic Granulomatous Disease Aryl Sulfatase Lysosomal Storage Disease Endocytic Vesicle
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- 19.Rietra et al. 1974 report that in Fabry’s disease the lack of a-galactosidase activity is paralleled by a lack of immunologically detectable enzyme protein. Perhaps the mutant protein is abnormally sensitive to the intralysosomal environment. But the possibility that one is dealing with a mutation in a regulatory gene should not be overlooked. Phenomena resembling induction of certain hydrolases have been encountered (e.g.,phosphate deprivation leads to synthesis of specific phosphatases in Euglena and there may be some similar effects for sulfatases in Aspergillis; APTE et al. 1974, Somer and Blum 1965; see also footnote 9 on p. 99), but what this signifies about the mechanisms that regulate lysosomal hydrolase synthesis has yet to be studied, and other approaches to such mechanisms are badly needed. Flo’s (1975) concept that hydrolases acting on lipids may be regulated by special “activator” proteins also merits mention.Google Scholar
- 20.For examples of the kind of data available on the timing of appearances and changes of hydrolases and potential substrates in developing brain see Gilbert and Johnson 1972, and Verity and Brown 1968. Descriptions of the disorders are provided in Bernson and Grossman (1971), Volk and Aronson (1971), and Hers and VAN Hoof (1973)—see e.g.Google Scholar
- Suzuki and Suzuki’s (1973) account of Krabbe’s leukodystrophy in which a galactocerebroside-(3-galactosidase activity is deficient and apparently as a consequence, myelination is grossly abnormal. DECKER (1974, 1974 b) has done correlated biochemical, cytochemical, and electron microscopic studies on developing amphibian brains.Google Scholar
- 21.Reports bearing on these capacities include the finding by Black et al. 1972 that smooth muscle lysosomal cholesterol esterase is notably less effective with some cholesterol esters involving saturated fatty acids than with the corresponding unsaturated acids. Werb and Cohn (1971, 1972) have demonstrated that cholesterol can exchange between extra-cellular media and the membranes of macrophage lysosomes and they have suggested that the capacities of the exchange system to clear cholesterol from the lysosomes may be overwhelmed when much cholesterol enters the cell as in xanthomas or atherosclerosis. Johnson et al. (1975) have published preliminary findings that macrophages have trouble digesting liposomes that contain high proportions of cholesterol.Google Scholar
- Peters et al. (1972, 1974) have isolated a cholesterol-rich sub-population of lysosomes from atheromatous tissue, and have found these particles to be relatively poor in cholesterol esterase and in some other hydrolase activities. Wolinsky et al. (1975) review work indicating that hypertension induces changes in the lysosomes of arteries, similar to alterations evoked by an atherogenic diet; as do others, these authors propose that one factor in atherosclerosis may be a sequence of events in which lysosomal overloading contributes to cell death, with the dying cells releasing their hydrolases (and lipids) to the extracellular spaces in the artery wall.Google Scholar
- As mentioned earlier, the lysosomal (azurophilic) granules apparently also contribute lysozyme. Interestingly, a strain of rabbits that lacks detectable leukocyte lysozyme, shows little evident effect of the deficiency (Prieust et al. 1974 ).Google Scholar
- According to Marvin and Wachtel (1975), filamentous viruses exit from bacteria, without cellular lysis, through a sequence of events in which viral proteins become inserted in the cell’s plasma membrane, and then the viral DNA interacts with these proteins. Does reovirus use a similar mechanism to get its RNA out of the lysosomes?Google Scholar
- 22.The granulocytes are much shorter lived than the macrophages and the latter cells predominate in the later stages of inflammation; as the influx of macrophages increases one often finds them phagocytosing dead PMN leukocytes; Ross and Odland 1968, WisseGoogle Scholar
- 23.There are other types of situations in which phagocytes have to deal with bodies too large for uptake. When they encounter such bodies, groups of phagocytes may surround them and release hydrolyses onto their surfaces. See e.g.,Kalina et al. (1971) for a description of such handling by macrophages and PMN cells, of yeast encapsulated in a large wall. Hibbs et al. 1974 have also asserted that under some conditions macrophages can kill other cells by somehow releasing hydrolases into them. The existence of this unusual mechanism must be verified by more detailed study.Google Scholar
- 25.Brady and Quarles (1973) have put forth the imaginative suggestion that in normal myelinogenesis, extracellular hydrolases are responsible for altering Schwann cell or glial cell plasma membranes to give rise to membranes of the myelin sheath. If normal membrane modulations actually occur in this way, long-term changes in extracellular hydrolase levels, as in some chronic conditions, could lead to all sorts of mischief.Google Scholar
- 28.The atypical properties of rat lymphocyte lysosomes were alluded to in Section II.6: Bowers has found a cathepsin D-ridh class of lysosomes that seem to be present in lymphocytes of spleen and thymus. He also has noted that thoracic duct lymphocytes contain an unusual form of cathepsin D that is either not particle bound, or is present in a structure that does not survive homogenization. This enzyme differs from the typical cathepsin D in sensitivity to inhibitors and other properties (Bowers 1969, 1970, 1973; species other than rat seem not to have the unusual cathepsin D; Bowers, personal communication).Google Scholar
- Simionescu et al. (1975) have presented evidence that the endothelial-cell vesicles may function, to some extent, by fusing with one another in such patterns as to open patent channels from one cell surface to the other. How this relates to the matters under consideration is not yet clear.Google Scholar