Relation of Lysosomal Fragility in CLL Lymphocytes to PHA Reactivity

Abstract

AFTER addition of various mitogens such as phytohaemagglutinin (PHA) in vitro lymphocytes shift from a “resting” state to one of rapid enlargement, culminating in DNA synthesis and mitosis. The mechanism initiating transformation and proliferation is not yet fully understood. Some observations, however, suggest that alterations of cellular membranes might be involved in these processes. In their cytochemical studies, Allison and Mallucci¹ observed increased permeability of lysosomes in normal human peripheral blood lymphocytes after exposure to PHA for 5 h. Hirschhorn et al.² demonstrated that during the early phase of stimulation 30–120 min after addition of PHA in normal human blood lymphocytes a redistribution of lysosomal acid hydrolases from a sedimentable into a non-sedimentable form as well as an increased release by agents which disrupt membranes, such as streptolysin S and filipin, of lysosomal enzymes from a subcellular fraction rich in lysosomes are taking place. It has been suggested that these alterations, both reflecting enhanced fragility of lysosomal membranes, might be due to increased endocytosis induced by the mitogen, and the hypothesis was raised that lysosomal hydrolases might be involved in intracellular processes leading to lymphocyte activation². We have therefore studied the fragility of lysosomes in unstimulated and PHA-treated lymphocytes from patients with chronic lymphocytic leukaemia (CLL), because lymphocytes in most patients with this disease show a diminished and/or delayed or even no response to PHA³ and other mitogens^4,5.