A beryllium-10 chronology of late-glacial moraines in the upper Rakaia valley, Southern Alps, New Zealand supports Southern- Hemisphere warming during the Younger Dryas

Interhemispheric differences in the timing of pauses or reversals in the temperature rise at the end of the last ice age can help to clarify the mechanisms that influence glacial terminations. Our beryllium-10 (10Be) surface-exposure chronology for the moraines of the upper Rakaia valley of New Zealand's Southern Alps, combined with glaciological modeling, show that late-glacial temperature change in the atmosphere over the Southern Alps exhibited an Antarctic-like pattern. During the Antarctic Cold Reversal, the upper Rakaia glacier built two well-defined, closely-spaced moraines on Reischek knob at 13,900 ± 120 [1σ; ± 310 yrs when including a 2.1% production-rate (PR) uncertainty] and 13,140 ± 250 (±370) yrs ago, in positions consistent with mean annual temperature approximately 2 °C cooler than modern values. The formation of distinct, widely-spaced moraines at 12,140 ± 200 (±320) and 11,620 ± 160 (±290) yrs ago on Meins Knob, 2 km up-valley from the Reischek knob moraines, indicates that the glacier thinned by ∼250 m during Heinrich Stadial 0 (HS 0, coeval with the Younger Dryas 12,900 to 11,600 yrs ago). The glacier-inferred temperature rise in the upper Rakaia valley during HS 0 was about 1 °C. Because a similar pattern is documented by well-dated glacial geomorphologic records from the Andes of South America, the implication is that this late-glacial atmospheric climate signal extended from 79°S north to at least 36°S, and thus was a major feature of Southern Hemisphere paleoclimate during the last glacial termination

GWAS for Systemic Sclerosis Identifies Multiple Risk Loci and Highlights Fibrotic and Vasculopathy Pathways

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.Funding: This work was supported by Spanish Ministry of Economy and Competitiveness (grant ref. SAF2015-66761-P), Consejeria de Innovacion, Ciencia y Tecnologia, Junta de Andalucía (P12-BIO-1395), Ministerio de Educación, Cultura y Deporte through the program FPU, Juan de la Cierva fellowship (FJCI-2015-24028), Red de Investigación en Inflamación y Enfermadades Reumaticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013), and Scleroderma Research Foundation and NIH P50-HG007735 (to H.Y.C.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. PopGen 2.0 is supported by a grant from the German Ministry for Education and Research (01EY1103). M.D.M and S.A. are supported by grant DoD W81XWH-18-1-0423 and DoD W81XWH-16-1-0296, respectively

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

Roles of stromal cells in the immune system

Stromal cells were typically defined as passive organizers of an organ, producing extracellular matrix and basement membrane proteins. While stromal cells do provide important structural support for most organs, their role in coordinating the local microenvironment in the steady state and during inflammation is becoming increasingly better known. In this article we will review the many roles of stromal cells in regulating immune responses in their local tissue environment, including both lymphoid tissue and inflammatory lesions

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells

Fibroblastic reticular cells (FRCs), through their expression of CC chemokine ligand (CCL)19 and CCL21, attract and retain T cells in lymph nodes (LNs), but whether this function applies to both resting and activated T cells has not been examined. Here we describe a model for conditionally depleting FRCs from LNs based on their expression of the diphtheria toxin receptor (DTR) directed by the gene encoding fibroblast activation protein-α (FAP). As expected, depleting FAP+ FRCs causes the loss of naïve T cells, B cells, and dendritic cells from LNs, and this loss decreases the magnitude of the B- and T-cell responses to a subsequent infection with influenza A virus. In contrast, depleting FAP+ FRCs during an ongoing influenza infection does not diminish the number or continued response of activated T and B cells in the draining LNs, despite still resulting in the loss of naïve T cells. Therefore, different rules govern the LN trafficking of resting and activated T cells; once a T cell is engaged in antigen-specific clonal expansion, its retention no longer depends on FRCs or their chemokines, CCL19 and CCL21. Our findings suggest that activated T cells remain in the LN because they down-regulate the expression of the sphingosine-1 phosphate receptor-1, which mediates the exit of lymphocytes from secondary lymphoid organs. Therefore, LN retention of naïve lymphocytes and the initiation of an immune response depend on FRCs, but is an FRC independent and possibly cell-autonomous response of activated T cells, which allows the magnitude of clonal expansion to determine LN egress