MAPKAP kinase 2 (MK2)-dependent and independent models of blister formation in pemphigus vulgaris

Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by autoantibodies to the keratinocyte adhesion protein desmoglein (Dsg) 3. Previous studies suggest that PV pathogenesis involves p38 mitogen activated protein kinase-dependent and -independent pathways. However, p38 is a difficult protein to study and therapeutically target because it has four isoforms and multiple downstream effectors. In the current study, we identify MAPKAP kinase 2 (MK2) as a downstream effector of p38 signaling in PV and describe MK2-dependent and -independent mechanisms of blister formation using passive transfer of human anti-Dsg IgG4 mAbs to neonatal mice. In human keratinocytes, PV mAbs activate MK2 in a dose-dependent manner. MK2 is also activated in human pemphigus skin blisters, causing translocation of MK2 from the nucleus to the cytosol. Small molecule inhibition of MK2 and silencing of MK2 expression block PV mAb-induced Dsg3 endocytosis in human keratinocytes. Additionally, small molecule inhibition and genetic deletion of p38α and MK2 inhibit spontaneous, but not induced, suprabasal blisters by PV mAbs in mouse passive transfer models. Collectively, these data suggest that MK2 is a key downstream effector of p38 that can modulate PV autoantibody pathogenicity. MK2 inhibition may be a valuable adjunctive therapy for control of pemphigus blistering

Pemphigus Associated with Psoriasis Vulgaris: A Retrospective Study of Seven Patients and a Review of the Literature

The aim of this study was to analyze the characteristics and the treatment for patients with psoriasis who presented with subsequent pemphigus after their treatment. A retrospective study of seven patients with psoriasis associated with pemphigus was performed, including the clinical assessment and treatments. The patients with a median age of 74 (range from 54 to 85) were significantly older than those in previously reported cases, where the median age was 58 (range from 15 to 77) (P&lt;0.05). Six out of seven patients were male, which represents a higher ratio than that reported in literature (10/20). The duration between the diagnosis of psoriasis and onset of pemphigus ranged from 4 to 30 years, and previous studies reported a much wider range that, from a few months to 52 years. Patients developed pemphigus after the treatments for psoriasis with ultraviolet light, steroids, or immunosuppressant. Our study represents a distinct subset of patients with psoriasis accompanied with pemphigus who share typical clinical characteristics. Among these patients, most are elderly men and the dominant subtype is pemphigus foliaceus. Our data suggests that no treatment for psoriasis specifically correlated with the development of pemphigus. The combination treatment of steroids with immunosuppressant lead to an improvement of the disease. </p

Genomic insights into local adaptation and future climate-induced vulnerability of a keystone forest tree in East Asia

Assessment of population vulnerability and adaptive capacity under climate change is crucial for informing conservation strategies. Sang et al. assemble a reference genome for Populus koreana and combine population genomics and modelling to predict spatiotemporal responses to climate change.Rapid global climate change is posing a substantial threat to biodiversity. The assessment of population vulnerability and adaptive capacity under climate change is crucial for informing conservation and mitigation strategies. Here we generate a chromosome-scale genome assembly and re-sequence genomes of 230 individuals collected from 24 populations for Populus koreana, a pioneer and keystone tree species in temperate forests of East Asia. We integrate population genomics and environmental variables to reveal a set of climate-associated single-nucleotide polymorphisms, insertion/deletions and structural variations, especially numerous adaptive non-coding variants distributed across the genome. We incorporate these variants into an environmental modeling scheme to predict a highly spatiotemporal shift of this species in response to future climate change. We further identify the most vulnerable populations that need conservation priority and many candidate genes and variants that may be useful for forest tree breeding with special aims. Our findings highlight the importance of integrating genomic and environmental data to predict adaptive capacity of a key forest to rapid climate change in the future

Anti-BP180 Autoantibodies Are Present in Stroke and Recognize Human Cutaneous BP180 and BP180-NC16A

Objective: Current evidence has revealed a significant association between bullous pemphigoid (BP) and neurological diseases (ND), including stroke, but the incidence of BP autoantibodies in patients with stroke has not previously been investigated. Our study aimed to assess BP antigen-specific antibodies in stroke patients.Design: One hundred patients with stroke and 100 matched healthy controls were randomly selected for measurement of anti-BP180/BP230 IgG autoantibodies by enzyme-linked immunosorbent assay (ELISA), salt-split indirect immunofluorescence (IIF), and immunoblotting against human cutaneous BP180 and BP180-NC16A.Results: Anti-BP180 autoantibodies were found in 14 (14.0%) patients with stroke and 5 (5.0%) of controls by ELISA (p &lt; 0.05). Sera from 13 (13.0%) patients with stroke and 3 (3.0%) controls reacted with 180-kDa proteins from human epidermal extract (p &lt; 0.05). 11 (11.0%) of stroke and 2 (2.0%) of control sera recognized the human recombinant full length BP180 and NC16A (p &lt; 0.05). The anti-BP180-positive patients were significantly younger than the negative patients at the time of stroke (p &lt; 0.001).Conclusion: Development of anti-BP180 autoantibodies occurs at a higher frequency after stroke, suggesting BP180 as a relatively common autoantigen after stroke and providing novel insights into BP pathogenesis in aging

Pathogenicity and Epitope Characteristics Do Not Differ in IgG Subclass-Switched Anti-Desmoglein 3 IgG1 and IgG4 Autoantibodies in Pemphigus Vulgaris

Pemphigus vulgaris (PV) is characterized by IgG1 and IgG4 autoantibodies to desmoglein (Dsg) 3, causing suprabasal blistering of skin and mucous membranes. IgG4 is the dominant autoantibody subclass in PV and correlates with disease activity, whereas IgG1 can be associated with remittent disease. It is unknown if switching the same variable region between IgG4 and IgG1 directly impacts pathogenicity. Here, we tested whether three pathogenic PV monoclonal antibodies (mAbs) from three different patients demonstrate differences in antigen affinity, epitope specificity, or pathogenicity when expressed as IgG1 or IgG4. F706 anti-Dsg3 IgG4 and F779 anti-Dsg3 IgG1, previously isolated as heterohybridomas, and Px43, a monovalent anti-Dsg3/Dsg1 IgG antibody isolated by phage display, were subcloned to obtain paired sets of IgG1 and IgG4 mAbs. Using ELISA and cell surface staining assays, F706 and F779 demonstrated similar antigen binding affinities of IgG1 and IgG4, whereas Px43 showed 3- to 8-fold higher affinity of IgG4 versus IgG1 by ELISA, but identical binding affinities to human skin, perhaps due to targeting of a quaternary epitope best displayed in tissues. All 3 mAb pairs targeted the same extracellular cadherin (EC) domain on Dsg3, caused Dsg3 internalization in primary human keratinocytes, and caused suprabasal blisters in human skin at comparable doses. We conclude that switching IgG1 and IgG4 subclasses of pathogenic PV mAbs does not directly affect their antigen binding or pathogenic properties

Low-mass dark matter search results from full exposure of PandaX-I experiment

We report the results of a weakly-interacting massive particle (WIMP) dark matter search using the full 80.1\;live-day exposure of the first stage of the PandaX experiment (PandaX-I) located in the China Jin-Ping Underground Laboratory. The PandaX-I detector has been optimized for detecting low-mass WIMPs, achieving a photon detection efficiency of 9.6\%. With a fiducial liquid xenon target mass of 54.0\,kg, no significant excess event were found above the expected background. A profile likelihood analysis confirms our earlier finding that the PandaX-I data disfavor all positive low-mass WIMP signals reported in the literature under standard assumptions. A stringent bound on the low mass WIMP is set at WIMP mass below 10\,GeV/c$^2$, demonstrating that liquid xenon detectors can be competitive for low-mass WIMP searches.Comment: v3 as accepted by PRD. Minor update in the text in response to referee comments. Separating Fig. 11(a) and (b) into Fig. 11 and Fig. 12. Legend tweak in Fig. 9(b) and 9(c) as suggested by referee, as well as a missing legend for CRESST-II legend in Fig. 12 (now Fig. 13). Same version as submitted to PR