Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is a disease of lymphocyte homeostasis caused by FAS-mediated apoptotic pathway dysfunction and is characterized by non-malignant lymphoproliferation with an increased number of TCRαβ+CD4−CD8− double-negative T cells (αβDNTs). Conversely, RAS-associated leukoproliferative disease (RALD), which is caused by gain-of-functional somatic variants in KRAS or NRAS, is considered a group of diseases with a similar course. Herein, we present a 7-year-old Japanese female of RALD harboring NRAS variant that aggressively progressed to juvenile myelomonocytic leukemia (JMML) with increased αβDNTs. She eventually underwent hematopoietic cell transplantation due to acute respiratory distress which was caused by pulmonary infiltration of JMML blasts. In general, αβDNTs have been remarkably increased in ALPS; however, FAS pathway gene abnormalities were not observed in this case. This case with RALD had repeated shock/pre-shock episodes as the condition progressed. This shock was thought to be caused by the presence of a high number of αβDNTs. The αβDNTs observed in this case revealed high CCR4, CCR6, and CD45RO expressions, which were similar to Th17. These increased Th17-like αβDNTs have triggered the inflammation, resulting in the pathogenesis of shock, because Th17 secretes pro-inflammatory cytokines such as interleukin (IL)-17A and granulocyte-macrophage colony-stimulating factor. The presence of IL-17A-secreting αβDNTs has been reported in systemic lupus erythematosus (SLE) and Sjögren’s syndrome. The present case is complicated with SLE, suggesting the involvement of Th17-like αβDNTs in the disease pathogenesis. Examining the characteristics of αβDNTs in RALD, JMML, and ALPS may reveal the pathologies in these cases.
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We thank Mayuko Miyake for her excellent assistance for the analysis of surface markers.
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This work has been supported by basic research funds distributed annually by the university.
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T.O., H.K., and S.I. designed the research. D.K., T.O., N.S., and H.K. analyzed and interpreted data and wrote the manuscript. T.O., A.M., N.S., and H.K. performed flow cytometry analysis. D.K. and N.S. prepared the figures. M.T., Y.S., K.S., M.T., S.H., K.N., N.S., N.K., and S.I. treated the case; all authors contributed to the final version of the manuscript.
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Kurita, D., Shiba, N., Ohya, T. et al. Severe RAS-Associated Lymphoproliferative Disease Case with Increasing αβ Double-Negative T Cells with Atypical Features. J Clin Immunol 43, 1992–1996 (2023). https://doi.org/10.1007/s10875-023-01566-9
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DOI: https://doi.org/10.1007/s10875-023-01566-9