a common virus in the brain which is usually latent. Reactivation of the JC virus usually results in death or severe brain damage. At least one patient with rheumatoid arthritis developed PML after treatment with rituximab. Rituximab has been reported as a possible cofactor in a chronic hepatitis E infection in a person with lymphoma. Hepatitis E infection is normally an acute infection, suggesting the drug in combination with lymphoma may have weakened the body's immune response to the virus. A major concern with continuous rituximab treatment is the difficulty to induce a proper vaccine response. This was brought into focus during the COVID-19 pandemic, where persons with multiple sclerosis and rituximab treatment had higher risk of severe COVID-19. In persons with rituximab treatment for multiple sclerosis, 9 of 10 patients with B cell counts of 40/µL or more developed protective levels of antibodies after vaccination with tozinameran. Mechanisms of action The antibody binds to the cell surface protein CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells. Rituximab is relatively ineffective in elimination of cells with low CD20 cell-surface levels. It tends to stick to one side of B cells, where CD20 is, forming a cap and drawing proteins over to that side. The presence of the cap changes the effectiveness of natural killer (NK) cells in destroying these B cells. When an NK cell latched onto the cap, it had an 80% success rate at killing the cell. In contrast, when the B cell lacked this asymmetric protein cluster, it was killed only 40% of the time. The following effects have been found: The Fc portion of rituximab mediates antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Rituximab has a general regulatory effect on the cell cycle. Preferential elimination of malignant B cells with high CD20 levels and high BCR signaling propensity, especially in chronic lymphocytic leukemia (CLL). It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen). It elicits shedding of CD23. It downregulates the B cell receptor. It induces apoptosis of CD20+ cells. Rituximab also induces a release of some chronic lymphocytic leukemia cells from immune niches, which might