Updates in the diagnosis and management of Takayasu's arteritis.

Takayasu's arteritis is a rare, chronic, large vessel vasculitis which affects the aorta and its large branches. Early diagnosis is important to prevent serious end organ damage, including to stroke and ischemic heart disease. Studies have demonstrated treatment response with methotrexate, azathioprine, and tumor necrosis factor (TNF) inhibitors. This article aims to describe to the reader key features of Takayasu's arteritis and highlights updated evidence in the diagnosis and management of these patients. We also review the 2021 ACR guidelines for Takayasu's arteritis and correlate them to the updated evidence discussed throughout the review. An extensive literature search was conducted via PUBMED, including the words 'Takayasu's diagnostic criteria,' 'Takayasu's treatment,' 'Takayasu's diagnosis,' 'Takayasu's imaging', and 'Takayasu's diagnostic criteria.' Search was filtered to include clinical trials, randomized controlled trials, systematic reviews, and meta-analyses. Articles in the English language or with English translation and published by the date of 20 December 2021 were included.

Prolactin activates IRF1 and leads to altered balance of histone acetylation: Implications for systemic lupus erythematosus.

Objectives: Prolactin is known to be associated with autoimmune disease; however, the mechanisms are incompletely understood. Previous studies have highlighted the effects on B-cell tolerance and monocyte/macrophage activation. One study found that prolactin could activate IRF1, a transcription factor implicated in SLE and interferon responses. We hypothesized that prolactin elicited transcriptional regulation though an epigenetic process related to IRF1 activation in monocytes. This study examined IRF1 activation and downstream epigenetic effects.Methods: Protein analysis, qRT-PCR, and ChIP assays were used in a human monocytic cell line and primary monocytes to define changes related to acute and chronic prolactin exposure.Results: We found that prolactin acutely induced both expression and activation of IRF1. Prolactin induced interactions of IRF1 with the histone acetyltransferase co-activators CBP and p300. Chronic prolactin induced expression of multiple histone modifying proteins and genes within the interferon signature suggesting that the prolonged exposure to prolactin resets the landscape and balance of chromatin modifying enzymes.Conclusion: These data provide insight into the mechanism of the association of prolactin with autoimmunity. We found effects at the level of epigenetics, an area not previously explored. Our data support a role for chronic prolactin regulating the expression of genes setting the landscape of chromatin modifying enzymes and driving the interferon signature. This novel finding is of relevance in systemic lupus erythematosus, where clinical effects of hyperprolactinemia have been recognized.

Monocyte enhancers are highly altered in systemic lupus erythematosus.

OBJECTIVE: Histone modifications set transcriptional competency and can perpetuate pathologic expression patterns. We defined systemic lupus erythematosus (SLE)-specific changes in H3K4me3 and K3K27me3, histone marks of gene activation and repression, respectively. METHODS: We used ChIP-seq to define histone modifications in monocytes from SLE patients and controls. RESULTS: Both promoters and enhancers exhibited significant changes in histone methylation in SLE. Regions with differential H3K4me3 in SLE were significantly enriched in potential interferon-related transcription factor binding sites and pioneer transcription factor sites. CONCLUSION: Enhancer activation defines the character of the cell and our data support extensive disease effects in monocytes, a particularly plastic lineage. Type I interferons not only drive altered gene expression but may also alter the character of the cell through chromatin modifications.

Interferon regulatory factor 1 and histone H4 acetylation in systemic lupus erythematosus.

Histone acetylation modulates gene expression and has been described as increased in systemic lupus erythematosus (SLE). We investigated interferon regulatory factor 1 (IRF1) interactions that influence H4 acetylation (H4ac) in SLE. Intracellular flow cytometry for H4 acetylated lysine (K) 5, K8, K12, and K16 was performed. Histone acetylation was defined in monocytes and T cells from controls and SLE patients. RNA-Seq studies were performed on monocytes to look for an imbalance in histone acetyltransferases and histone deacetylase enzyme expression. Expression levels were validated using real-time quantitative RT-PCR. IRF1 induction of H4ac was evaluated using D54MG cells overexpressing IRF1. IRF1 protein interactions were studied using co-immunoprecipitation assays. IRF1-dependent recruitment of histone acetyltransferases to target genes was examined by ChIP assays using p300 antibody. Flow cytometry data showed significantly increased H4K5, H4K8, H4K12, and H4K16 acetylation in SLE monocytes. HDAC3 and HDAC11 gene expression were decreased in SLE monocytes. PCAF showed significantly higher gene expression in SLE than controls. IRF1-overexpressing D54MG cells were associated with significantly increased H4K5, H4K8, and H4K12 acetylation compared to vector-control D54MG cells both globally and at specific target genes. Co-immunoprecipitation studies using D54MG cells revealed IRF1 protein-protein interactions with PCAF, P300, CBP, GCN5, ATF2, and HDAC3. ChIP experiments demonstrated increased p300 recruitment to known IRF1 targets in D54MG cells overexpressing IRF1. In contrast, p300 binding to IRF1 targets decreased in D54MG cells with IRF1 knockdown. SLE appears to be associated with an imbalance in histone acetyltransferases and histone deacetylase enzymes favoring pathologic H4 acetylation. Furthermore, IRF1 directly interacts with chromatin modifying enzymes, supporting a model where recruitment to specific target genes is mediated in part by IRF1.

Silencing of microRNA-21 in vivo ameliorates autoimmune splenomegaly in lupus mice.

MicroRNAs (miRNAs) have been implicated in B cell lineage commitment, regulation of T cell differentiation, TCR signalling, regulation of IFN signalling, and numerous other immunological processes. However, their function in autoimmunity, and specifically in systemic lupus erythematosus (SLE), remains poorly understood. B6.Sle123 is a spontaneous genetic mouse model of SLE characterized by autoantibody production, lymphosplenomegaly, and glomerulonephritis. We identified several differentially regulated miRNAs in B and T lymphocytes of B6.Sle123 mice. We found that miR-21 expression in lupus B and T cells is up-regulated and that in vivo silencing of miR-21 using a tiny seed-targeting LNA reversed splenomegaly, one of the cardinal manifestations of autoimmunity in B6.Sle123 mice, and de-repressed PDCD4 expression in vivo and in vitro. In addition, treatment with anti-miR-21 altered CD4/CD8 T cell ratios and reduced Fas receptor-expressing lymphocyte populations. Our study shows that tiny LNAs can be used to efficiently antagonize endogenous miRNAs in peripheral lymphocytes in vivo and in primary lymphocytes cultured ex vivo and can alter the course of a spontaneous genetic disease in mice.

Simultaneous measurement of current and calcium in the ultraviolet-sensitive cones of zebrafish.

In rods and visible cone photoreceptors, multiple measurements cannot be made of intracellular Ca2+ concentration from the same cell using fluorescent dyes, because a single exposure of the measuring light bleaches too large a fraction of the rod or cone photopigment. We have therefore identified and characterized UV-sensitive cones of the zebrafish, whose wavelength of maximum sensitivity is at 360 nm which is far enough from the wavelength of our measuring light (514.5 nm) so that it has been possible to make multiple determinations of photocurrent and Ca2+ concentration from the same cells. We show that for a limited number of measurements, for which the bleaching of the cone photopigment is too small to affect flash kinetics, the outer segment Ca2+ concentration closely follows the wave form of the flash response convolved with the dominant time constant for Ca2+ removal by Na+-Ca2+-K+ exchange. For a larger number of measurements, significant acceleration of the response kinetics by pigment bleaching inevitably occurs, but the Ca2+ concentration nevertheless rises and falls in approximate agreement with the flash wave form. During exposure to steady background light, the Ca2+ concentration falls in proportion to the steady-state current for dim backgrounds at all times and for bright backgrounds at steady state. At early times following the onset of bright backgrounds, however, the Ca2+ concentration is markedly higher than expected from the current of the cone. We show this to be the result of light-dependent Ca2+ release by bright background light, which can be abolished by pre-exposure of the cone to the membrane-permeant acetoxymethyl ester of the Ca2+ chelator BAPTA. Our results therefore demonstrate that the cone outer segment Ca2+ concentration is predominantly a function of the rate of influx and efflux of Ca2+ across the plasma membrane, but that a release of Ca2+ in bright light most probably from buffer sites within the cell can transiently elevate the Ca2+ concentration above the level expected from the open probability of the light-dependent channels.