The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography–tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR–CK2α complex could be a novel therapeutic target for various inflammatory diseases.
Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR.
Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1-enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.
ABSTRACT:Cytomegalovirus (CMV) infection is the most common infectious complication following solid organ transplantation. Ganciclovir (GCV)-resistant CMV infection may be fatal, and is difficult to treat while avoiding allograft rejection. A 31-year-old woman received a second ABO-incompatible kidney transplant, from her father. Induction therapy consisted of basiliximab and rituximab followed by maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone. Her CMV serostatus was D + /R -at second transplant and she received prophylactic low-dose valganciclovir (VGCV). BK polyoma virus nephropathy (BKVN) developed 7 months after transplant concurrent with CMV hepatitis and retinitis. VGCV was increased to a therapeutic dose combined with reduced immunosuppression with minimal methylprednisolone (2 mg/day) and everolimus (0.5 mg/day). However, pp65 antigenaemia continued to increase for 6 weeks. Her CMV was defined as ganciclovir (GCV)-resistant. Foscarnet was therefore administered and her CMV disease resolved within 2 weeks. Kidney allograft dysfunction developed 9 months after transplant, and graft biopsy showed tubulointerstitial injury with crystal deposition suggesting foscarnet nephrotoxicity, with no findings of BKVN or rejection. Kidney function recovered after cessation of foscarnet and the patient had good graft function 18 months after transplant. This case demonstrates the successful use of foscarnet to treat GCV-resistant CMV infection after ABO-incompatible kidney transplant complicated with BKVN, without acute allograft rejection. This case further highlights the need to establish appropriate management for CMV D + /R -patients to avoid the acquisition of GCV-resistant gene mutations.
The presence of highly immunogenic mismatched eplets is associated with development of CAAMR.
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