Epitope spreading in animal models: array of hope in rheumatoid arthritis and multiple sclerosis

The paradigm for pathogenic autoimmunity is the generation of high-titre, affinity-matured autoantibodies to a restricted family of autoantigens, in the appropriate genetic context. Genetic determinants of autoimmunity are largely found within the major histocompatibility complex (MHC) and the 'genotype to serotype to phenotype' concept is supported in a number of autoimmune diseases, where both genotype and serotype are well established. The serotype is autoantigen-driven, with evidence of epitope spreading as the disease evolves from asymptomatic to pathogenic autoimmunity. In rheumatoid arthritis and multiple sclerosis, where the autoantigens are poorly characterised, the use of an array in animal models may produce a hint of what happens in human disease. A more complete picture will be obtained from animals transgenic for human MHC, immunised with known human autoantigens

Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis?

Peptidylarginine deiminases (PADs) convert arginine within a peptide (peptidylarginine) into peptidylcitrulline. Citrullination by human PADs is important in normal physiology and inflammation. Porphyromonas gingivalis, a major pathogen in periodontitis, is the only prokaryote described to possess PAD. P. gingivalis infection may generate citrullinated peptides, which trigger anti-citrullinated peptide antibodies. In susceptible individuals, host protein citrullination by human PADs in the joint probably perpetuates antibody formation, paving the way for the development of chronic arthritis. Blockades of bacterial and human PADs may act as powerful novel therapies by inhibiting the generation of the antigens that trigger and sustain autoimmunity in rheumatoid arthritis

Expression of citrulline and homocitrulline residues in the lungs of non-smokers and smokers : implications for autoimmunity in rheumatoid arthritis

Introduction: Smoking is a well-established risk factor for rheumatoid arthritis (RA), and it has been proposed that smoking-induced citrullination renders autoantigens immunogenic. To investigate this mechanism, we examined human lung tissue from 40 subjects with defined smoking status, with or without chronic obstructive pulmonary disease (COPD), and control tissues from other organs for citrullinated proteins and the deiminating enzymes peptidylarginine deiminase type-2 (PAD2) and -4 (PAD4). Methods: Lung tissue samples, dissected from lobectomy specimens from 10 never smokers, 10 smokers without airflow limitation, 13 COPD smokers and eight COPD ex-smokers, and control tissue samples (spleen, skeletal muscle, liver, ovary, lymph node, kidney and heart), were analysed for citrullinated proteins, PAD2 and PAD4 by immunoblotting. Citrulline and homocitrulline residues in enolase and vimentin were analysed by partial purification by gel electrophoresis followed by mass spectrometry in 12 of the lung samples and one from each control tissues. Band intensities were scored semi-quantitatively and analysed by two-tailed Mann-Whitney T-test. Results: Within the lung tissue samples, citrullinated proteins, PAD2 and PAD4 were found in all samples, with an increase in citrullination in COPD (P = 0.039), but minimal difference between smokers and non-smokers (P = 0.77). Citrullination was also detected at lower levels in the tissues from other organs, principally in lymph node, kidney and skeletal muscle. Mass spectrometry of the lung samples showed that vimentin was citrullinated at positions 71, 304, 346, 410 and 450 in non-smokers and smokers both with and without COPD. A homocitrulline at position 104 was found in four out of six COPD samples and one out of six non-COPD. Citrulline-450 was also found in three of the control tissues. There were no citrulline or homocitrulline residues demonstrated in a-enolase. Conclusions: We have shown evidence of citrullination of vimentin, a major autoantigen in RA, in both non-smokers and smokers. The increase in citrullinated proteins in COPD suggests that citrullination in the lungs of smokers is mainly due to inflammation. The ubiquity of citrullination of vimentin in the lungs and other tissues suggests that the relationship between smoking and autoimmunity in RA may be more complex than previously thought

Identification of citrullinated α-enolase as a candidate autoantigen in rheumatoid arthritis

Antibodies against citrullinated proteins are highly specific for rheumatoid arthritis (RA), but little is understood about their citrullinated target antigens. We have detected a candidate citrullinated protein by immunoblotting lysates of monocytic and granulocytic HL-60 cells treated with peptidylarginine deiminase. In an initial screen of serum samples from four patients with RA and one control, a protein of molecular mass 47 kDa from monocytic HL-60s reacted with sera from the patients, but not with the serum from the control. Only the citrullinated form of the protein was recognised. The antigen was identified by tandem mass spectrometry as α-enolase, and the positions of nine citrulline residues in the sequence were determined. Serum samples from 52 patients with RA and 40 healthy controls were tested for presence of antibodies against citrullinated and non-citrullinated α-enolase by immunoblotting of the purified antigens. Twenty-four sera from patients with RA (46%) reacted with citrullinated α-enolase, of which seven (13%) also recognised the non-citrullinated protein. Six samples from the controls (15%) reacted with both forms. α-Enolase was detected in the RA joint, where it co-localised with citrullinated proteins. The presence of antibody together with expression of antigen within the joint implicates citrullinated α-enolase as a candidate autoantigen that could drive the chronic inflammatory response in RA

The Triarchic Psychopathy Measure (TriPM): alternative to the PCL-R?

Psychopathic personality disorder is the subject of many research papers and in particular in the context of forensic settings, where its link to risk of future violence has been established. This topic is well examined but there is still considerable debate about the nature of the construct and how psychopathy is measured. Contemporary models such as the triarchic theory (Patrick, Fowles & Krueger, 2009) have been put forward yet the research into psychopathy tends to rely on one assessment tool, the Psychopathy Checklist-Revised (PCL-R; Hare, 2003) that is argued not to capture elements of psychopathy such as boldness. The Triarchic Psychopathy Measure (TriPM; Patrick, 2010) is a measure that is based on the triarchic theory, and it places an equal focus on boldness when measuring psychopathy. It is however a self-report instrument, and this approach has many limitations. This paper aims to review the scientific support for the TriPM and to discuss its potential application to clinical practice. It concludes that the TriPM may not yet be a contender for the PCL-R throne as the sole tool of choice for psychopathy measurement, but the research into the application of the TriPM is expanding our understanding of psychopathy as a construct

Inter-decadal variability of phytoplankton biomass along the coastal West Antarctic Peninsula

The West Antarctic Peninsula (WAP) is a climatically sensitive region where periods of strong warming have caused significant changes in the marine ecosystem and food-web processes. Tight coupling between phytoplankton and higher trophic levels implies that the coastal WAP is a bottom-up controlled system, where changes in phytoplankton dynamics may largely impact other food-web components. Here, we analysed the inter-decadal time series of year-round chlorophyll-a (Chl) collected from three stations along the coastal WAP: Carlini Station at Potter Cove (PC) on King George Island, Palmer Station on Anvers Island and Rothera Station on Adelaide Island. There were trends towards increased phytoplankton biomass at Carlini Station (PC) and Palmer Station, while phytoplankton biomass declined significantly at Rothera Station over the studied period. The impacts of two relevant climate modes to the WAP, the El Niño-Southern Oscillation and the Southern Annular Mode, on winter and spring phytoplankton biomass appear to be different among the three sampling stations, suggesting an important role of local-scale forcing than large-scale forcing on phytoplankton dynamics at each station. The inter-annual variability of seasonal bloom progression derived from considering all three stations together captured ecologically meaningful, seasonally co-occurring bloom patterns which were primarily constrained by water-column stability strength. Our findings highlight a coupled link between phytoplankton and physical and climate dynamics along the coastal WAP, which may improve our understanding of overall WAP food-web responses to climate change and variability

Permanent and reliable inactivation of Huntington's disease mutation via customized CRISPR/SaCas9 gene editing

Allele-specific CRISPR/SaCas9 gene editing therapy targeting the mutated HTT exon-1 would decrease the formation of mHTT aggregates reducing the neuronal dysfunction and striatum atrophy

Summer microbial community composition governed by upper-ocean stratification and nutrient availability in northern Marguerite Bay, Antarctica

The Western Antarctic Peninsula warmed significantly during the second half of the twentieth century, with a concurrent retreat of the majority of its glaciers, and marked changes in the sea-ice field. These changes may affect summertime upper-ocean stratification, and thereby the seasonal dynamics of phytoplankton and bacteria. In the present study, we examined coastal Antarctic microbial community dynamics by pigment analysis and applying molecular tools, and analysed various environmental parameters to identify the most important environmental drivers. Sampling focussed on the austral summer of 2009–2010 at the Rothera oceanographic and biological Time Series (RaTS) site in northern Marguerite bay, Antarctica. The Antarctic summer was characterized by a salinity decrease (measured at 15 m depth) coinciding with increased meteoric water fraction. Maximum Chl-a values of 35 µg l-1 were observed during midsummer and mainly comprised of diatoms. Microbial community fingerprinting revealed four distinct periods in phytoplankton succession during the summer while bacteria showed a delayed response to the phytoplankton community. Non-metric multidimensional scaling analyses showed that phytoplankton community dynamics were mainly directed by temperature, mixed layer depth and wind speed. Both high and low N/P ratios might have influenced phytoplankton biomass accumulation. The bacterioplankton community composition was mainly governed by Chl-a, suggesting a link to phytoplankton community changes. High-throughput 16 S and 18 S rRNA amplicon sequencing revealed stable eukaryotic and bacterial communities with regards to observed species, yet varying temporal relative contributions. Eukaryotic sequences were dominated by pennate diatoms in December followed by polar centric diatoms in January and February. Our results imply that the reduction of mixed layer depth during summer, caused by meltwater-related surface stratification, promotes a succession in diatoms rather than in nanophytoflagellates in northern Marguerite Bay, which may favour higher trophic levels

Erratum to: Smoking, Porphyromonas gingivalis and the immune response to citrullinated autoantigens before the clinical onset of rheumatoid arthritis in a Southern European nested case–control study

No abstract available

Association of distinct fine specificities of anti-citrullinated peptide antibodies with elevated immune responses to Prevotella intermedia in a subgroup of patients with rheumatoid arthritis and periodontitis

Objective In addition to the long-established link with smoking, periodontitis (PD) is also a risk factor for rheumatoid arthritis (RA). To elucidate the mechanism by which PD could induce antibodies to citrullinated peptides (ACPA), we examine the antibody response to a novel citrullinated peptide from cytokeratin type I 13 identified in gingival crevicular fluid (GCF), and compare the response to 4 other citrullinated peptides in patients with RA, well-characterized for PD and smoking. Methods The citrullinomes of GCF and periodontal tissue from people with PD were mapped by mass spectrometry. Antibodies to citrullinated peptides from cytokeratin type I 13 (cCK13), tenascin-C (cTNC5), vimentin (cVIM), enolase (CEP-1) and fibrinogen β (cFIBβ) were examined by ELISA in patients with RA (n=287) and osteoarthritis (OA) (n=330), and cross-reactivity assessed by inhibition assays. Results A novel citrullinated peptide cCK13-1 (444TSNASGR-cit-TSDV-cit-RP458) identified in GCF, exhibited elevated antibody responses in RA patients (24%). Anti-cCK13-1 antibodies correlated with anti-cTNC5 antibodies, and absorption experiments confirmed this was not due to cross-reactivity. Only anti-cCK13-1 and anti-cTNC5 were associated with antibodies to the periodontal pathogen Prevotella intermedia (p=0.05 and p =0.001 respectively), but not with antibodies to Porphyromonas gingivalis arginine gingipains. Antibodies to CEP-1, cFIBβ and cVIM correlated with each other, and with smoking and shared epitope risk factors in RA. Conclusion This study identifies two groups of ACPA fine specificities associated with different RA risk factors; one predominantly linked to smoking and shared epitope, the other linking anti- cTNC5 and cCK13-1 to infection with the periodontal pathogen P. intermedia