Objective. Kidney podocytes and their slit diaphragms prevent urinary protein loss. T cells from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin-dependent protein kinase IV (CaMKIV). The present study was undertaken to investigate the role of CaMKIV in podocyte function in lupus nephritis (LN). Methods. We treated kidney podocytes with IgG derived from healthy individuals or patients with LN and then analyzed gene expression using a DNA microarray. The localization of IgG in podocytes was analyzed by immunofluorescence staining, with or without silencing of neonatal Fc receptor (FcRn). In addition, we silenced CAMK4 in podocytes and analyzed the expression of selected genes. We also examined the expression of CD86 in kidney podocytes from MRL/lpr, MRL/lpr.camkiv−/−, and MRL/MPJ mice by in situ hybridization. Results. We found that exposure of podocytes to IgG resulted in entry of IgG into the cytoplasm. IgG entered podocytes via the FcRn because less IgG was found in the cytoplasm of podocytes treated with FcRn small interfering RNA. DNA microarray studies of podocytes exposed to LN-derived IgG revealed up-regulation of genes related to the activation of immune cells or podocyte damage. Interestingly, CD86 expression decreased after silencing CAMK4 in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkiv−/− mice. Conclusion. LN-derived IgG enters podocytes and up-regulates CAMK4, which is followed by increased expression of genes known to be linked to podocyte damage and T cell activation. Targeted inhibition of CAMK4 in podocytes may prove to be clinically useful in patients with LN.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious complication in SLE. Although the mechanism of NPSLE remains unclear, cytokines and chemokines are considered to be involved in their pathogenesis. Here we used Bio-Plex Pro assays to examine 27 types of cytokines and chemokines in the cerebrospinal fluid (CSF) of 32 NPSLE patients. We used the CSF of 20 patients with multiple sclerosis (MS) and 22 patients with neuromyelitis optica (NMO) as a disease control group. Fourteen of 27 cytokines/chemokines were significantly higher in the NPSLE patients compared to the MS/NMO patients. We could identify six "minimum predictive markers" by using a weighted-voting algorithm that could distinguish NPSLE from MS and NMO: interleukin (IL)-17, IL-2, interferon (IFN)-γ, IL-5, basic fibroblast growth factor (FGF)-basic and IL-15. The determination of various types of CSF cytokine profiles may contribute to the diagnosis of NPSLE and may help elucidate the mechanisms underlying this disease.

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Primary vulvar clear cell carcinoma (CCC) is extremely rare. In this article, we report a primary vulvar CCC along with immunohistochemical and gene mutation analyses results and literature review to discuss the clinicopathological features and tumorigenesis of this rare tumor. A 70-year-old (gravida 2 para 2) Japanese woman complained of bleeding from a vulvar mass at a past episiotomy site. A 1.8 × 1.8 × 0.5 cm exophytic sessile mass was present on the vestibular area inside the left labium minora. Radical local excision of the tumor and resection of the inguinal lymph nodes on both sides were performed. Histopathology revealed a vulvar CCC with immunohistochemical positivity for PAX8, HNF-1β, ER, and CA125, and negativity for p16, CD10, GATA3, PTEN, and PAX2, suggesting its Müllerian origin. No lymph node metastasis was observed. The tumor was a 5-mm exophytic growth without deep stromal invasion; thus, it was difficult to measure the invasion depth assuming a squamous cell carcinoma. To investigate pathogenic/oncogenic mutations in 50 cancer-related genes, we used the AmpliSeq Cancer Hotspot Panel. However, no pathogenic/oncogenic mutations were detected. Literature review revealed that most cases of vulvar CCC are associated with vulvar endometriosis. In particular, cases with clinically evident endometriosis at the episiotomy scar should be carefully observed. Evidence-based pathological stages of vulvar adenocarcinoma including CCC remain to be established owing to its rarity, with nationwide or global accumulation of cases required in future.