IFN-α induced systemic lupus erythematosus complicated with hemophagocytic lymphohistiocytosis: a case report and literature review.

Hemophagocytic lymphohistiocytosis (HLH) is a severe and life-threatening hyperinflammatory condition characterized by excessive activation of macrophages and T cells and resulted in multi-organ dysfunction. HLH can be a primary disease or secondary to infections, malignancy, and some autoimmune diseases, including adult-onset Still's disease (AOSD) and systemic lupus erythematosus (SLE). However, it is rare for HLH to occur as a secondary condition to drug-induced lupus erythematosus (DILE). In this report, we present a case of HLH as an unusual complication during SLE treatment in a 31-year-old male patient. The patient initially suffered from active chronic hepatitis B (CHB) and was treated with pegylated INFα-2b (Peg-INFα-2b), tenofovir disoproxil and lamivudine. After 19 months, CHB obtained biochemical and virological response with HBsAg positive to HBsAb. The patient developed fever, headache, and cytopenia after Peg-INFα-2b treatment for 33 months, and laboratory studies revealed that ANA and anti dsDNA were positive. He displayed 5 features meeting the HLH-2004 criteria for diagnosis including fever, pancytopenia, hyperferritinemia, high levels of soluble CD25, and hemophagocytosis on bone marrow biopsy. The patient was initiated with a combination treatment of intravenous methylprednisolone pulse therapy, oral cyclosporine, and etoposide (VP-16), which was followed by a course of oral prednisolone, intravenous cyclophosphamide pulse therapy, and entecavir with complete response. To our knowledge, this is the first report of IFN-α induced SLE complicating with HLH. Physicians should consider the potential autoimmune side effects of IFN-α therapy and be alert to insidious HLH in patients diagnosed with SLE.

Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency Inhibits Pathological Cardiac Hypertrophy.

BACKGROUND: Aberrant amino acid metabolism is implicated in cardiac hypertrophy, while the involvement of tryptophan metabolism in pathological cardiac hypertrophy remains elusive. Herein, we aimed to investigate the effect and potential mechanism of IDO1 (indoleamine 2,3-dioxygenase) and its metabolite kynurenine (Kyn) on pathological cardiac hypertrophy. METHODS: Transverse aortic constriction was performed to induce cardiac hypertrophy in IDO1-knockout (KO) mice and AAV9-cTNT-shIDO1 mice. Liquid chromatography-mass spectrometry was used to detect the metabolites of tryptophan-Kyn pathway. Chromatin immunoprecipitation assay and dual luciferase assay were used to validate the binding of protein and DNA. RESULTS: IDO1 expression was upregulated in both human and murine hypertrophic myocardium, alongside with increased IDO1 activity and Kyn content in transverse aortic constriction-induced mice's hearts using liquid chromatography-mass spectrometry analysis. Myocardial remodeling and heart function were significantly improved in transverse aortic constriction-induced IDO1-KO mice, but were greatly exacerbated with subcutaneous Kyn administration. IDO1 inhibition or Kyn addition confirmed the alleviation or aggravation of hypertrophy in cardiomyocyte treated with isoprenaline, respectively. Mechanistically, IDO1 and metabolite Kyn contributed to pathological hypertrophy via the AhR (aryl hydrocarbon receptor)-GATA4 (GATA binding protein 4) axis. CONCLUSIONS: This study demonstrated that IDO1 deficiency and consequent Kyn insufficiency can protect against pathological cardiac hypertrophy by decreasing GATA4 expression in an AhR-dependent manner.

Successful Treatment of SAPHO Syndrome Complicated with Ankylosing Spondylitis by Secukinumab: A Case Report.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is characterized by a wide range of dermatological and musculoskeletal manifestations, and its outcome has recently been improved greatly by optimizing management. However, the treatment strategies are not standardized and require further refinement. Secukinumab, a fully human monoclonal antibody targeting IL-17A, is approved for the treatment of autoimmune psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Here, a 53-year-old man was diagnosed with AS, and he presented scattered pustulosis in both hands and feet with a 5-year history of recurrent lumbosacral area pain and abnormal pain in the neck and front chest area. Secukinumab improved the patient's cutaneous lesion and prevented musculoskeletal pain by substituting adalimumab. Although only a few cases have been reported that secukinumab can effectively treat SAPHO syndrome complicated with AS, the efficacy remains controversial. Therefore, we hope to provide a novel valuable therapeutic strategy for SAPHO syndrome management, particularly in patients with skin lesions.

CaMKII inhibition protects against hyperthyroid arrhythmias and adverse myocardial remodeling.

Hyperthyroidism can potentiate arrhythmias and cardiac hypertrophy, whereas Ca2+/calmodulin-dependent kinase II (CaMKII) promotes maladaptive myocardial remodeling. However, it remains unclear whether CaMKII contributes to the progression of hyperthyroid heart disease (HHD). This study demonstrated that CaMKII inhibition can relieve adverse myocardial remodeling and reduce sinus tachycardia, isoproterenol-induced atrial fibrillation, and ventricular arrhythmias in hyperthyroid mice with preserved heart function. Hyperthyroid cardiac hypertrophy was promoted by CaMKII upregulation-induced HDAC4/MEF2a activation. Briefly, CaMKII inhibition benefits HHD management greatly in mice by preventing arrhythmias and maladaptive remodeling.

Ca2+/calmodulin-dependent protein kinase II inhibition reduces myocardial fatty acid uptake and oxidation after myocardial infarction.

An AMP-activated kinase (AMPK) signaling pathway is activated during myocardial ischemia and promotes cardiac fatty acid (FA) uptake and oxidation. Similarly, the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is also triggered by myocardial ischemia, but its function in FA metabolism remains unclear. Here, we explored the role of CaMKII in FA metabolism during myocardial ischemia by investigating the effects of cardiac CaMKII on AMPK-acetyl-CoA carboxylase (ACC), malonyl CoA decarboxylase (MCD), and FA translocase cluster of differentiation 36 (FAT/CD36), as well as cardiac FA uptake and oxidation. Moreover, we tested whether CaMKII and AMPK are binding partners. We demonstrated that diseased hearts from patients with terminal ischemic heart disease displayed increased phosphorylation of CaMKII, AMPK, and ACC and increased expression of MCD and FAT/CD36. AC3-I mice, which have a genetic myocardial inhibition of CaMKII, had reduced gene expression of cardiac AMPK. In post-MI (myocardial infarction) AC3-I hearts, AMPK-ACC phosphorylation, MCD and FAT/CD36 levels, cardiac FA uptake, and FA oxidation were significantly decreased. Notably, we demonstrated that CaMKII interacted with AMPK α1 and α2 subunits in the heart. Additionally, AC3-I mice displayed significantly less cardiac hypertrophy and apoptosis 2 weeks post-MI. Overall, these findings reveal a unique role for CaMKII inhibition in repressing FA metabolism by interacting with AMPK signaling pathways, which may represent a novel mechanism in ischemic heart disease.

Identification of a novel pathogenic COL4A3 gene mutation in a Chinese family with autosomal dominant Alport syndrome: A case report.

Alport syndrome (AS) is a genetic disease with various manifestations, including hematuria, proteinuria, impaired renal function and potential ocular or auditory abnormalities. Mutations in the collagen type IV α 3 chain (COL4A3), collagen type IV α 4 chain and collagen type IV α 5 chain genes encoding the α3, α4 and α5 chains of type IV collagen may undermine glomerular basement membrane (GBM) integrity and cause persistent renal deterioration. In the present study, the case of a Chinese family diagnosed with AS was examined. Pedigree investigations and whole exome sequencing (WES) revealed the presence of two heterozygous mutations (c.2603G>A; p.G868E, and c.583G>A; p.G195S) in the COL4A3 gene. p.G868E was identified as the 'culprit' mutation, whereas p.G195S was identified as an 'auxiliary' mutation for AS with regards to the manifestations observed in the patients carrying each of the gene mutations. In conclusion, these findings suggested that c.2603G>A may be a novel overt pathogenic mutation site for autosomal dominant AS. In addition, WES may be effective for the early diagnosis and medical intervention of AS, and may be widely used for AS prognosis prediction and pre-implantation genetic diagnosis.

IL-9 aggravates the development of atherosclerosis in ApoE-/- mice.

AIMS: Recently, interleukin (IL)-9 was found to be involved in the pathogenesis of many inflammatory diseases. Here, we tested whether IL-9 was related to atherosclerosis and investigated the underlying mechanisms. METHODS AND RESULTS: IL-9R was expressed in mouse aortic endothelial cells (MAECs) and aortic tissues, and IL-9 levels were elevated in plasma and aortic arches in Apolipoprotein E-deficient (ApoE-/-) mice. ApoE-/- mice fed a western diet for 10 weeks were administered recombinant mouse IL-9 (rIL-9) or anti-IL-9 neutralizing monoclonal antibody (mAb). Mice treated with rIL-9 developed markedly larger plaques in both the aorta and aortic root. Immunohistochemical studies demonstrated increases in both vascular endothelial adhesion molecule-1 (VCAM-1) expression and the infiltration of inflammatory cells, including T cells and macrophages, in plaques. However, treatment with the anti-IL-9 mAb caused the opposite effect. The administration of rIL-9 did not affect the splenic T cell or peripheral monocyte subsets. Meanwhile, IL-9 induced VCAM-1 expression in MAECs mainly via a STAT3-dependent pathway, consequently increasing monocyte-endothelial adhesion. Moreover, treatment with anti-VCAM-1 mAb partially abrogated the IL-9-induced increase in plaque area. In addition, CD4(+)IL-9(+) T cells and IL-9 were increased in patients with acute coronary syndrome, and the levels of IL-9 in culture supernatants and soluble VCAM-1 (sVCAM-1) in plasma were significantly positively correlated in the enrolled patients. CONCLUSION: Our results demonstrated that IL-9 exerted pro-atherosclerotic effects in ApoE-/- mice at least partially by inducing VCAM-1 expression, which mediated inflammatory cell infiltration into atherosclerotic lesions.