Henry Penn

Treg cell function in rheumatoid arthritis is compromised by ctla-4 promoter methylation resulting in a failure to activate the indoleamine 2,3-dioxygenase pathway.

Functionally impaired Treg cells expressing abnormally low levels of CTLA‐4 have been well documented in rheumatoid arthritis (RA). However, the molecular defect underlying this reduced expression is unknown. The aims of this study were to assess the role of DNA methylation in regulating CTLA‐4 expression in Treg cells isolated from RA patients and to elucidate the mechanism of their reduced suppressor function.

Methotrexate Restores Regulatory T Cell Function Through Demethylation of the FoxP3 Upstream Enhancer in Patients With Rheumatoid Arthritis.

We have previously shown, in a cohort of untreated rheumatoid arthritis (RA) patients, that the suppressive function of Treg cells is defective. However, other studies in cohorts of patients with established RA have shown that Treg cell function is normal. We hypothesized that treatment may restore Treg cell function and lead to reduced disease activity. The aim of this study was to investigate whether treatment with methotrexate (MTX) can result in epigenetic changes that lead to restoration of the Treg cell suppressive function in RA.

A novel upstream enhancer of FOXP3, sensitive to methylation-induced silencing, exhibits dysregulated methylation in rheumatoid arthritis Treg cells.

Treg‐cell function is compromised in rheumatoid arthritis (RA). As the master regulator of Treg cells, FOXP3 controls development and suppressive function. Stable Treg‐cell FOXP3 expression is epigenetically regulated; constitutive expression requires a demethylated Treg‐specific demethylated region. Here, we hypothesised that methylation of the FOXP3 locus is altered in Treg cells of established RA patients. Methylation analysis of key regulatory regions in the FOXP3 locus was performed on Treg cells from RA patients and healthy controls. The FOXP3 Treg‐specific demethylated region and proximal promoter displayed comparable methylation profiles in RA and healthy‐donor Treg cells. We identified a novel differentially methylated region (DMR) upstream of the FOXP3 promoter, with enhancer activity sensitive to methylation‐induced silencing. In RA Treg cells we observed significantly reduced DMR methylation and lower DNA methyltransferase (DNMT1/3A) expression compared with healthy Treg cells. Furthermore, DMR methylation negatively correlated with FOXP3 mRNA expression, and Treg cells isolated from rheumatoid factor negative RA patients were found to express significantly higher levels of FOXP3 than Treg cells from RhF‐positive patients, with an associated decrease in DMR methylation. In conclusion, the novel DMR is involved in the regulation of Treg‐cell FOXP3 expression, but this regulation is lost post‐transcriptionally in RA Treg cells.

Inhibition of histone H3K27 demethylase selectively modulates inflammatory phenotypes of natural killer cells

Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets. The prototypic JMJD3/UTX (Jumonji domain–containing protein 3) H3K27 demethylase inhibitor GSK-J4 increased global levels of the repressive H3K27me3 mark around transcription start sites of effector cytokine genes. Moreover, GSK-J4 reduced IFN-γ, TNFα, granulocyte–macrophage colony-stimulating factor (GM-CSF), and interleukin-10 levels in cytokine-stimulated NK cells while sparing their cytotoxic killing activity against cancer cells. The anti-inflammatory effect of GSK-J4 in NK cell subsets, isolated from peripheral blood or tissue from individuals with rheumatoid arthritis (RA), coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggested that histone demethylase inhibition has broad utility for modulating immune and inflammatory responses. Overall, our results indicate that H3K27me3 is a dynamic and important epigenetic modification during NK cell activation and that JMJD3/UTX-driven H3K27 demethylation is critical for NK cell function.

A retrospective series of conditions and mortality associated with extreme hyperferritinaemia in adults

Serum ferritin is commonly used in the diagnosis of iron deficiency anaemia. However, extreme hyperferritinaemia suggests a significant illness, including the differential diagnosis of haemophagocytic lymphohistiocytosis (HLH), which is rare and associated with a high mortality, particularly if untreated. This series aims to identify the causes and associated mortality of severe hyperferritinaemia in patients seen at a teaching hospital in London, UK.

Fatal cardiac involvement complicating antisynthetase syndrome

A 35-year-old Afro-Caribbean woman presented with dyspnoea, urticarial rash and myalgia 1 month after treatment for a community-acquired respiratory tract infection. Investigations revealed raised antisynthetase antibodies, lung fibrosis and an inflammatory myopathy. The patient was diagnosed with antisynthetase syndrome (ASS) and started on immunosuppressive medication. Despite treatment she died 4 weeks after presentation from a fulminant cardiomyopathy. ASS is a rare condition and is not typically associated with a cardiomyopathy. This case report intends to raise awareness that cardiomyopathy is a potentially fatal complication of ASS.

Losing all sense: a case of meningeal carcinomatosis

Meningeal carcinomatosis (MC) is diffuse infiltration of the meninges by metastatic carcinoma. Though a known complication of solid tumours, it is rarely seen as a presenting feature of such cancers. Here, the authors describe the case of a 64-year-old lady who presented with rapid-onset hearing loss and progressive visual loss, among other cranial nerve palsies. A primary non-small cell lung cancer was later identified by CT, but the diagnosis of MC was only confirmed after cytological analysis of a repeat lumbar puncture. Immunophenotyping of cells from the lung biopsy correlated with cells obtained from cerebrospinal fluid. In view of her rapid clinical deterioration, chemotherapy was not pursued, and the patient was transferred to a hospice 3 weeks after admission.

Unusual cause of flare in antineutrophil cytoplasmic antibody-associated vasculitis

A 53-year-old woman attended for a routine outpatient appointment for follow-up of antineutrophil cytoplasmic antibody-positive vasculitis. Her disease had relapsed despite appropriate medical management with mycophenolate mofetil (MMF), as evidenced by rising acute phase response and antimyeloperoxidase titre with ongoing symptoms. On further questioning, she had been taking oral charcoal as part of a detoxification diet, which we postulate was causing significantly impaired MMF absorption. This case report summarises the presentation and highlights the importance of a thorough drug history, and should prompt the reader to keep an open mind with regard to drug interactions and treatment regimen adherence when treatment is, unexpectedly, seemingly failing.