Abatacept decreases disease activity in a absence of CD4+ T cells in a collagen-induced arthritis model

IntroductionAbatacept is a fusion protein of human cytotoxic T-lymphocyte–associated protein (CTLA)-4 and the Fc portion of human immunoglobulin G1 (IgG1). It is believed to be effective in the treatment of rheumatoid arthritis by inhibiting costimulation of T cells via blocking CD28–B7 interactions as CTLA-4 binds to both B7.1 (CD80) and B7.2 (CD86). However, the interaction of CD28 with B7 molecules is crucial for activation of naive cells, whereas it is unclear whether the action of already activated CD4⁺ T cells, which are readily present in established disease, also depends on this interaction. The aim of this study was to determine whether the mode of action of abatacept depends solely on its ability to halt T cell activation in established disease.MethodsArthritis was induced in thymectomized male DBA/1 mice by immunisation with bovine collagen type II. The mice were subsequently depleted for CD4⁺ T cells. Abatacept or control treatment was started when 80 % of the mice showed signs of arthritis. Arthritis severity was monitored by clinical scoring of the paws, and anti-collagen antibody levels over time were determined by enzyme-linked immunosorbent assay.ResultsTreatment with abatacept in the absence of CD4⁺ T cells resulted in lower disease activity. This was associated with decreasing levels of collagen-specific IgG1 and IgG2a antibodies, whereas the antibody levels in control or CD4⁺ T cell–depleted mice increased over time.ConclusionsThese results show that abatacept decreased disease activity in the absence of CD4⁺ T cells, indicating that the mode of action of abatacept in established arthritis does not depend entirely on its effects on CD4⁺ T cell activation.     

Premature refutation of a human-mediated marine species introduction: the case history of the marine snail <Emphasis Type="Italic">Littorina littorea</Emphasis> in the northwestern Atlantic

The European periwinkle snail, Littorina littorea was discovered in Pictou, NS, Canada in 1840. This snail’s subsequent rapid, conspicuous spread south from Pictou along the Canadian maritime coast and then along the New England and mid-Atlantic coast to New Jersey, its virtual absence in pre-European contact deposits, and its close association with human mechanisms of transport from Europe are among the clearest evidence for a human-mediated introduction. However, molecular genetic data have been proposed as evidence that L. littorea’s occurrence in North America was not the result of a human introduction by Wares et al. (Ecol Lett 5:577–584, 2002). Reexamination of these genetic data and reexamination of all other data available reveal that a human-mediated introduction of L. littorea is the simplest explanation of its occurrence in North America. The refutation of the human-mediated introduction of L. littorea was premature.     

Rotifers from the Balearic archipelago

Ecological and historical factors of the Balearic archipelago (Western Mediterranean Sea) result is some peculiarities to its rotifer fauna. A group of warm-stenothermous species are frequent seasonally in the islands. Among them the occurrence of Keratella procurva (Thorpe, 1912), a pantropical species, is remarkable, and this is found more or less abundantly on each island. We briefly describe the different habitat categories of the archipelago. Clustering the collected species we relate each community type to its habitat; in this sense we distinguish 4 community type in the islands corresponding to different environments. This work also summarizes all the obtainable data on the rotifer fauna of the Balearic archipelago, adding the results of the investigations done in the last survey (spring, 1989); a checklist, including 100 species from the archipelago, is shown (69 Majorca, 72 Minorca, 24 Ibiza, 25 Formentera). Some examples of pantropical distribution are given, and the biotic and abiotic factors which determine the colonization of the islands by these species are discussed.     

Isoform-specific Binding of Selenoprotein P to the β-Propeller Domain of Apolipoprotein E Receptor 2 Mediates Selenium Supply

Sepp1 supplies selenium to tissues via receptor-mediated endocytosis. Mice, rats, and humans have 10 selenocysteines in Sepp1, which are incorporated via recoding of the stop codon, UGA. Four isoforms of rat Sepp1 have been identified, including full-length Sepp1 and three others, which terminate at the second, third, and seventh UGA codons. Previous studies have shown that the longer Sepp1 isoforms bind to the low density lipoprotein receptor apoER2, but the mechanism remains unclear. To identify the essential residues for apoER2 binding, an in vitro Sepp1 binding assay was developed using different Sec to Cys substituted variants of Sepp1 produced in HEK293T cells. ApoER2 was found to bind the two longest isoforms. These results suggest that Sepp1 isoforms with six or more selenocysteines are taken up by apoER2. Furthermore, the C-terminal domain of Sepp1 alone can bind to apoER2. These results indicate that apoER2 binds to the Sepp1 C-terminal domain and does not require the heparin-binding site, which is located in the N-terminal domain. Site-directed mutagenesis identified three residues of Sepp1 that are necessary for apoER2 binding. Sequential deletion of extracellular domains of apoER2 surprisingly identified the YWTD β-propeller domain as the Sepp1 binding site. Finally, we show that apoER2 missing the ligand-binding repeat region, which can result from cleavage at a furin cleavage site present in some apoER2 isoforms, can act as a receptor for Sepp1. Thus, longer isoforms of Sepp1 with high selenium content interact with a binding site distinct from the ligand-binding domain of apoER2 for selenium delivery.     

Substance P innervation of the rat thymus

Immunohistochemistry for substance P (SP) in the rat thymus revealed fine varicose neural profiles in specific regions of the thymus. Thymic SP innervation was abundant within the capsule and interlobular septa. The majority of SP+ nerve fibers within the septa were free of vascular association, although some fibers were associated with the vasculature deep within the septa. SP+ nerve fibers entered the thymic cortex from the septa and distributed among cortical thymocytes and mast cells. Along the corticomedullary junction, SP+ nerve fibers were found in association with the vasculature. The medullary region of the thymus received only a sparse innervation of SP+ fibers. In addition, SP+ nerve fibers coursed adjacent to OX-8+ cells and mast cells in the extrathymic connective tissue surrounding the thymus. The present study provides evidence that SP is present in nerve fibers in the thymus, and may be available to interact with thymocytes, mast calls, and other cells in the thymus, and affect their development and function.     

Parsimony dictates a human introduction: on the use of genetic and other data to distinguish between the natural and human-mediated invasion of the European snail Littorina littorea in North America

Two centuries of historical, archaeological, paleontological, geological, oceanographical and biological data conclusively indicate that the periwinkle snail Littorina littorea was introduced to North America from Europe either by Norse explorers 1000 years ago or by European colonists after 1840. Available genetic data do not indicate ancient divergence of North American and European L. littorea and thus do not challenge all other evidence that it was introduced from Europe by humans.