A 73-year-old woman was diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) with general fatigue and severe neutropenia. Although rituximab monotherapy was initiated, the Show more
A 73-year-old woman was diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) with general fatigue and severe neutropenia. Although rituximab monotherapy was initiated, the neutrophil counts decreased within one week after rituximab administration. Subsequently, a combination of rituximab and bendamustine was initiated, and then her neutrophil counts became consistently within the normal range. The LPL/WM kept complete remission for two years. LPL/WM complicated with severe autoimmune neutropenia is rare. Rituximab and bendamustine brought strong lymphocyte depletion, leading to amelioration of autoimmune neutropenia. In this case, rituximab and bendamustine may have been active in patients with LPL/WM complicated with autoimmune disorders. Show less
With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the auto Show more
With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied by mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance. This decreased clearance was reflected by the accumulation of mitochondria-lysosome-related organelles, which depended on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis. Show less