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1.
Case Rep Nephrol Dial ; 11(2): 233-240, 2021.
Article in English | MEDLINE | ID: mdl-34595210

ABSTRACT

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by IgA deposits in the glomerular mesangium. It has a progressive nature and can eventually lead to end-stage kidney failure. It can occur as a potential side effect of treatment with tumor necrosis factor alpha antagonist that has been used for numerous chronic inflammatory conditions, such as Crohn's disease. In this study, the case of a 33-year-old man with renal dysfunction, nephrotic proteinuria, and erythrocyturia is described. He had had a history of Crohn's disease for 8 years and had been treated with adalimumab for the past 7 years. The diagnosis of IgAN was confirmed by kidney biopsy. After discontinuance of adalimumab and the induction of corticosteroid therapy, he made a remarkable recovery. Four years after the first presentation of IgAN and discontinuation of adalimumab, his renal function was normal with no proteinuria and only mild erythrocyturia.

2.
Arthritis Rheumatol ; 73(9): 1720-1730, 2021 09.
Article in English | MEDLINE | ID: mdl-33760395

ABSTRACT

OBJECTIVE: Systemic sclerosis (SSc) is characterized by dysregulation of type I interferon (IFN) signaling. CD52 is known for its immunosuppressive functions in T cells. This study was undertaken to investigate the role of CD52 in monocyte adhesion and type I IFN signaling in patients with SSc. METHODS: Transcriptome profiles of circulating CD14+ monocytes from patients with limited cutaneous SSc (lcSSc), patients with diffuse cutaneous SSc (dcSSs), and healthy controls were analyzed by RNA sequencing. Levels of CD52, CD11b/integrin αΜ, and CD18/integrin ß2 in whole blood were assessed by flow cytometry. CD52 expression was analyzed in relation to disease phenotype (early, lcSSc, dcSSc) and autoantibody profiles. The impact of overexpression, knockdown, and antibody blocking of CD52 was analyzed by gene and protein expression assays and functional assays. RESULTS: Pathway enrichment analysis indicated an increase in adhesion- and type I IFN-related genes in monocytes from SSc patients. These cells displayed up-regulated expression of CD11b/CD18, reduced expression of CD52, and enhanced adhesion to intercellular adhesion molecule 1 and endothelial cells. Changes in CD52 expression were consistent with the SSc subtypes, as well as with immunosuppressive treatments, autoantibody profiles, and monocyte adhesion properties in patients with SSc. Overexpression of CD52 led to decreased levels of CD18 and monocyte adhesion, while knockdown of CD52 increased monocyte adhesion. Experiments with the humanized anti-CD52 monoclonal antibody alemtuzumab in blood samples from healthy controls increased monocyte adhesion and CD11b/CD18 expression, and enhanced type I IFN responses. Monocytic CD52 expression was up-regulated by interleukin-4 (IL-4)/IL-13 via the STAT6 pathway, and was down-regulated by lipopolysaccharide and IFNs α, ß, and γ in a JAK1 and histone deacetylase IIa (HDAC IIa)-dependent manner. CONCLUSION: Down-regulation of the antiadhesion CD52 antigen in CD14+ monocytes represents a novel mechanism in the pathogenesis of SSc. Targeting of the IFN-HDAC-CD52 axis in monocytes might represent a new therapeutic option for patients with early SSc.


Subject(s)
CD52 Antigen/metabolism , Cell Adhesion/physiology , Interferon Type I/metabolism , Monocytes/cytology , Scleroderma, Systemic/mortality , Signal Transduction/physiology , Adult , Female , Humans , Male , Middle Aged , Monocytes/metabolism , Transcriptome
3.
Transplant Proc ; 53(3): 1080-1084, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33358422

ABSTRACT

BACKGROUND: Pregnancy after kidney transplantation is an uncommon event. In addition to the risk to the child and the mother, pregnancy has a certain risk for the transplanted kidney. METHODS: We made a retrospective analysis of pregnancy and kidney function over a 49-year period in women with transplanted kidneys monitored at the National Transplant Centre, University Medical Centre Ljubljana, Ljubljana, Slovenia. RESULTS: We analyzed 22 pregnancies in 18 women (26-39 years old) 78 ± 37 months after transplantation. Serum creatinine before conception was 92 ± 26 µmol/L; 3 years after delivery, it was 117 ± 67 µmol/L. There were no rejections during pregnancy. Three rejections occurred in the first 9 months after delivery. The median duration of pregnancies was 37 weeks. Preeclampsia occurred in 4 women and severe eclampsia occurred in 2 women. In 19 cases, delivery was by caesarean section. One child was born with trisomy of chromosome 21 and 3 children were born with minor congenital anomalies. CONCLUSIONS: Renal function and proteinuria did not deteriorate 3 years after pregnancy, even after 2 pregnancies. Rejections in the early post-pregnancy period were common. Preeclampsia was more frequent than in the average population. The incidence of major congenital anomalies was comparable to that seen in pregnant women without immunosuppression.


Subject(s)
Delivery, Obstetric/statistics & numerical data , Kidney Transplantation/adverse effects , Pregnancy Complications/epidemiology , Pregnancy Outcome/epidemiology , Adult , Creatinine/blood , Female , Humans , Immunosuppression Therapy/adverse effects , Kidney/physiopathology , Postoperative Period , Pregnancy , Pregnancy Complications/etiology , Pregnancy Complications/physiopathology , Retrospective Studies , Risk Factors , Slovenia/epidemiology , Transplants/physiopathology
4.
Front Med (Lausanne) ; 7: 124, 2020.
Article in English | MEDLINE | ID: mdl-32432116

ABSTRACT

The Janus kinase (JAK)-Signal transducer and activator of transcription (STAT) pathway is one of the central signaling hubs in inflammatory, immune and cancer cells. Inhibiting the JAK-STAT pathway with JAK inhibitors (jakinibs) constitutes an important therapeutic strategy in cancer and chronic inflammatory diseases like rheumatoid arthritis (RA). FDA has approved different jakinibs for the treatment of RA, including tofacitinib, baricitinib and upadacitinib, and several jakinibs are being tested in clinical trials. Here, we reviewed published studies of jakinib effects on resolving synovial pathology in inflammatory arthritis. We discussed the results of jakinibs on structural joint damage in clinical trials and explored the effects of jakinibs across different in vitro, ex vivo, and in vivo synovial experimental models. We delved rigorously into experimental designs of in vitro fibroblast studies, deconvoluted jakinib efficacy in synovial fibroblasts across diverse experimental conditions and discussed their translatability in vivo. Synovial fibroblasts can readily activate the JAK-STAT signaling pathway in response to cytokine stimulation. We highlighted rather limited effects of jakinibs on the in vitro cultured synovial fibroblasts and inferred that direct and indirect (immune cell-dependent) actions of jakinibs are required to curb the fibroblast pathology in vivo. These actions have not been mimicked optimally in current in vitro experimental designs, where inflammatory stimuli do not naturally clear out with treatment as they do in vivo. While summarizing the broad knowledge of synovial jakinib effects, our review uniquely challenges future study designs to better mimick the jakinib actions in broader cell communities, as occurring in vivo in the inflamed synovium. This can deepen our understanding of collective synovial activities of jakinibs and their therapeutic limitations, thereby fostering jakinib development in arthritis.

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