Review and phylogeny of the New Zealand hagfishes (Myxiniformes: Myxinidae), with a description of three new species

Hagfishes from New Zealand are reviewed and a phylogeny proposed using morphological and genetic data (DNA sequences of cytochrome c oxidase subunit I gene, COI, and the small subunit RNA, 16S). E ptatretus cryptus sp. nov. was previously confused with Eptatretus cirrhatus (Forster in Bloch & Schneider, 1801) because of their similar morphology, and is found from the Three Kings Islands to Stewart Island and in the eastern part of the Chatham Rise (at depths of 96–922 m). E ptatretus poicilus sp. nov. is endemic to the Three Kings Islands, where it is common and associated with soft sediment and deep‐sea coral‐sponge habitats (114–842 m). N eomyxine caesiovitta sp. nov. is a slender hagfish found along the east coast of the North Island south to the Chatham Rise (430–1083 m). A neotype is erected for E. cirrhatus (type locality: Breaksea Sound, Fiordland), occurring widely in New Zealand coastal, shelf, and slope waters (1–922 m), but not at the Three Kings Islands. Eptatetrus goliath Mincarone & Stewart, 2006, Neomyxine biniplicata (Richardson & Jowett, 1951), and Nemamyxine elongata Richardson, 1958 are further described using additional material. Rubicundus eos (Fernholm, 1991) is still only known from the holotype (type locality: Challenger Plateau). Genetic results showed that the New Zealand Eptatretus species form a monophyletic group within the subfamily Eptatretinae, indicating likely speciation from a single common ancestor within the area. E ptatretus poicilus sp. nov. is the sister species of E. cirrhatus, and E . cryptus sp. nov. is closely associated with the clade formed by these two species. Eptatretus goliath is most closely associated with Eptatretus minor Fernholm & Hubbs, 1981 (Gulf of Mexico), these two species basally diverging within New Zealand hagfishes. The endemic genus Neomyxine forms a well‐supported monophyletic group of as yet uncertain position within the phylogenetic tree. A key to the New Zealand hagfishes, fresh colour photographs, distribution maps, and in situ video recordings are presented. © 2015 The Linnean Society of London     

Regulatory T Cells in Early Life: Comparative Study of CD4+CD25high T Cells from Foals and Adult Horses

The immune system of mammals is subject to continuous development during the postnatal phase of life. Studies following the longitudinal development of the immune system in healthy children are limited both by ethical considerations and sample volumes. Horses represent a particular valuable large animal model for T regulatory (Treg) cells and allergy research. We have recently characterised Treg cells from horses, demonstrated their regulatory capability and showed both their expansion and induction in vitro. Insect bite hypersensitivity (IBH) is a common allergy in horses resembling atopic dermatitis and studies have shown that first exposure to allergens in adult life results in an increased incidence of IBH. The aim of the present study was to characterize circulating CD4⁺CD25^highFoxP3⁺cells in foals, evaluate their suppressive capability and their in vitro induction compared to adult horses. 19 foals (age range, 1–5 months), their adult mothers and six one-year-old horses (yearlings) were included in the study. The proportion of FoxP3⁺ cells within the circulating CD4⁺CD25^high population was significantly higher in foals (47%) compared to their mothers (18%) and to yearlings (26%). Treg cells from foals also displayed a higher suppressive capability. Furthermore, CD4⁺CD25^high cells in foals could be induced in vitro from CD4⁺CD25⁻ cells in a significantly higher proportion compared to mares. These cells also displayed a significantly enhanced suppressive capability. In summary these findings support the notion that exposure of horses to allergens during maturation of the immune system assists the establishment of induced (i)Treg driven tolerance.     

CD27-IgD- memory B cells are modulated by in vivo interleukin-6 receptor (IL-6R) blockade in rheumatoid arthritis

IntroductionEnhanced B cell activity, particularly memory B cells have gained interest in evaluating response during therapies with biologics. CD27-IgD- double-negative (DN) B cells lacking the conventional memory marker CD27 are reported to be part of the memory compartment, however, only scarce data is available for rheumatoid arthritis (RA). We therefore focused on DN B cells in RA, studied their isotypes and modulation during interleukin-6 receptor (IL-6R) inhibition by tocilizumab (TCZ).MethodsDN B cells were phenotypically analyzed from 40 RA patients during TCZ at baseline week 12, week 24 and 1 year. A single B cell polymerase chain reaction (PCR) approach was used to study Ig receptors, V_H gene rearrangements and specific isotypes.ResultsPhenotypic analysis showed a significantly expanded population of DN B cells in RA which contain a heterogeneous mixture of IgG-, IgA- and IgM-expressing cells with a clear dominance of IgG+ cells. DN B cells carry rearranged heavy chain gene sequences with a diversified mutational pattern consistent with memory B cells. In contrast to tumor necrosis factor alpha (TNF-α) inhibition, a significant reduction in mutational frequency of BCR gene rearrangements at week 12, 24 and 1 year (P <0.0001) was observed by in vivo IL-6R inhibition. These changes were observed for all BCR isotypes IgG, IgA and IgM at week 12, 24 and 1 year (P <0.0001). IgA-RF, IgA serum level and IgA+ DN B cells decreased significantly (P <0.05) at week 12 and week 24 during TCZ. Patients with a good European League Against Rheumatism (EULAR) response to TCZ had less DN B cells at baseline as compared to moderate responders (P = 0.006). Univariate logistic regression analysis revealed that the frequency of DN B cells at baseline is inversely correlated to a subsequent good EULAR response (P = 0.024) with an odds ratio of 1.48 (95% confidence interval as 1.05 to 2.06).ConclusionsIn RA, the heterogeneous DN B cell compartment is expanded and dominated by IgG isotype. TCZ can modulate the mutational status of DN Ig isotype receptors over 1 year. Interestingly, the frequency of DN B cells in RA may serve as a baseline predictor of subsequent EULAR response to TCZ.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0580-y) contains supplementary material, which is available to authorized users.     

Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial

IntroductionTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). During the clinical development programme, increases in mean serum creatinine (SCr) of approximately 0.07 mg/dL and 0.08 mg/dL were observed which plateaued early. This study assessed changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to placebo in patients with active RA.MethodsThis was a randomised, placebo-controlled, Phase 1 study ({"type":"clinical-trial","attrs":{"text":"NCT01484561","term_id":"NCT01484561"}}NCT01484561). Patients were aged ≥18 years with active RA. Patients were randomised 2:1 to oral tofacitinib 10 mg twice daily (BID) in Period 1 then placebo BID in Period 2 (tofacitinib → placebo); or oral placebo BID in both Periods (placebo → placebo). Change in mGFR was evaluated by iohexol serum clearance at four time points (run-in, pre-dose in Period 1, Period 1 end, and Period 2 end). The primary endpoint was the change in mGFR from baseline to Period 1 end. Secondary endpoints included: change in mGFR at other time points; change in estimated GFR (eGFR; Cockcroft–Gault equation) and SCr; efficacy; and safety.Results148 patients were randomised to tofacitinib → placebo (N = 97) or placebo → placebo (N = 51). Baseline characteristics were similar between groups. A reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in adjusted geometric mean mGFR was observed during tofacitinib treatment in Period 1 vs placebo. During Period 2, mean mGFR returned towards baseline during placebo treatment, and there was no difference between the two treatment groups at the end of the study – ratio (tofacitinib → placebo/placebo → placebo) of adjusted geometric mean fold change of mGFR was 1.04 (90% CI: 0.97, 1.11). Post-hoc analyses, focussed on mGFR variability in placebo → placebo patients, were consistent with this conclusion. At study end, similar results were observed for eGFR and SCr. Clinical efficacy and safety were consistent with prior studies.ConclusionIncreases in mean SCr and decreases in eGFR in tofacitinib-treated patients with RA may occur in parallel with decreases in mean mGFR; mGFR returned towards baseline after tofacitinib discontinuation, with no significant difference vs placebo, even after post-hoc analyses. Safety monitoring will continue in ongoing and future clinical studies and routine pharmacovigilance.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01484561","term_id":"NCT01484561"}}NCT01484561. Registered 30 November 2011.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0612-7) contains supplementary material, which is available to authorized users.