Toll-like receptor 2 (TLR2) serves as a pattern recognition receptor that signals the presence of cytomegalovirus. Herein, we report that R753Q polymorphism paralyzes TLR2-mediated immune signaling in cells exposed to cytomegalovirus glycoprotein B. This immunologic impairment could serve as a biologic mechanism underlying the association between TLR2 R753Q polymorphism and cytomegalovirus disease in humans.
Background
Hepatitis C virus (HCV) core and nonstructural 3 (NS3) proteins induce inflammation and immunity through a Toll-like receptor 2 (TLR2)-dependent pathway. Individuals with the R753Q single nucleotide polymorphism (SNP) in the TLR2 gene have increased risk of allograft failure after liver transplantation for chronic hepatitis C.
Methods
To test the hypothesis that R753Q SNP impairs TLR2 recognition of HCV proteins, a series of in vitro experiments were performed wherein stable clones of wild-type TLR2-deficient HEK293 cells, and HEK293 cells transfected with wild-type (HEK293-TLR2) or variant TLR2 genes (HEK293-TLR2-R753Q) were stimulated with HCV core and NS3 proteins. Cellular activation was assessed by nuclear factor-kappa B (NFκB)-driven luciferase activity, cytokine secretion, and gene upregulation.
Results
Compared to TLR2-deficient HEK293 cells, HEK293-TLR2 cells had marked NFκB-driven luciferase activity, had modest to marked upregulation in TLR2 signaling-associated genes, and secreted large quantities of interleukin-8 during exposure to HCV core and NS3 proteins. In contrast, HEK293-TLR2-R753Q cells did not respond to stimulation with HCV, and behaved similarly like the TLR2-deficient HEK293 cells.
Conclusion
R753Q SNP impairs TLR2-mediated immune recognition of HCV core and NS3 proteins. This biologic defect may account for the predisposition of patients to develop allograft failure after liver transplantation for chronic hepatitis C.
Background: Plasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes with molecular heterogeneity. Although therapy-related myeloid neoplasms are common in plasma cell myeloma patients after chemotherapy, transdifferentiation of plasma cell myeloma into myeloid neoplasms has not been reported in literature. Here we report a very rare case of myeloid neoplasm transformed from plasma cell myeloma. Case presentation: A 60-year-old man with a history of plasma cell myeloma with IGH-MAF gene rearrangement and RAS/RAF mutations developed multiple soft tissue lesions one year following melphalan-based chemotherapy and autologous stem cell transplant. Morphological and immunohistochemical characterization of the extramedullary disease demonstrated that the tumor cells were derived from the monocyte-macrophage lineage. Next generation sequencing (NGS) studies detected similar clonal aberrations in the diagnostic plasma cell population and post-therapy neoplastic cells, including IGH-MAF rearrangement, multiple genetic mutations in RAS signaling pathway proteins, and loss of tumor suppressor genes. Molecular genetic analysis also revealed unique genomic alterations in the transformed tumor cells, including gain of NF1 and loss of TRAF3. Conclusion: To our knowledge, this is the first case of myeloid sarcoma transdifferentiated from plasma cell neoplasm. Our findings in this unique case suggest clonal evolution of plasma cell myeloma to myeloma neoplasm and the potential roles of abnormal RAS/RAF signaling pathway in lineage switch or transdifferentiation.
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