Upshaw-Schulman syndrome (USS) is an extremely rare hereditary deficiency of ADAMTS13 activity, termed congenital TTP. The clinical signs are usually mild during childhood, often with isolated ...thrombocytopenia. But their symptoms become more evident when patients have infections or get pregnant. We identified 43 USS-patients in Japan, who ranged in age from early childhood to 79 years of age. Analysing the natural history of these USS patients based on ADAMTS13 gene mutations may help characterise their clinical phenotypes. Severe neonatal jaundice that requires exchange blood transfusion, a hallmark of USS, was found in 18 of 43 patients (42%). During childhood, 25 of 43 patients were correctly diagnosed with USS without gender disparity. These 25 patients were categorised as having 'the early-onset phenotype'. Between 15 and 45 years of age, 15 were correctly diagnosed, and, interestingly, they were all female. The remaining three patients were male and were diagnosed when they were older than 45 years of age, suggesting that they were 'the late-onset phenotype'. Two of these three males developed sudden overt TTP when they were 55 and 63 years old, respectively. These two men had two different homozygous ADAMTS13 gene mutations, p.R193W/p.R193W and p.C1024R/p.C1024R, respectively. Both of which were not discovered in the US or Western countries. In vitro expression studies showed that these two proteins were consistently secreted into the culture medium but to a lesser extent and with reduced activity compared to the wild-type protein. Our results indicate that 'the late-onset phenotype' of USS is formed with ethnic specificity.
IgG4-related skin disease Tokura, Y.; Yagi, H.; Yanaguchi, H. ...
British journal of dermatology (1951),
November 2014, Letnik:
171, Številka:
5
Journal Article
Recenzirano
Summary
IgG4‐related disease (IgG4‐RD) is a recently established clinical entity characterized by high levels of circulating IgG4, and tissue infiltration of IgG4+ plasma cells. IgG4‐RD exhibits a ...distinctive fibroinflammatory change involving multiple organs, such as the pancreas and salivary and lacrimal glands. The skin lesions of IgG4‐RD have been poorly characterized and may stem not only from direct infiltration of plasma cells but also from IgG4‐mediated inflammation. Based on the documented cases together with ours, we categorized the skin lesions into seven subtypes: (1) cutaneous plasmacytosis (multiple papulonodules or indurations on the trunk and proximal part of the limbs), (2) pseudolymphoma and angiolymphoid hyperplasia with eosinophilia (plaques and papulonodules mainly on the periauricular, cheek and mandible regions), (3) Mikulicz disease (palpebral swelling, sicca syndrome and exophthalmos), (4) psoriasis‐like eruption (strikingly mimicking psoriasis vulgaris), (5) unspecified maculopapular or erythematous eruptions, (6) hypergammaglobulinaemic purpura (bilateral asymmetrical palpable purpuric lesions on the lower extremities) and urticarial vasculitis (prolonged urticarial lesions occasionally with purpura) and (7) ischaemic digit (Raynaud phenomenon and digital gangrene). It is considered that subtypes 1–3 are induced by direct infiltration of IgG4+ plasma cells, while the other types (4–7) are caused by secondary mechanisms. IgG4‐related skin disease is defined as IgG4+ plasma‐cell‐infiltrating skin lesions that form plaques, nodules or tumours (types 1–3), but may manifest secondary lesions caused by IgG4+ plasma cells and/or IgG4 (types 4–7).
What is already known about this topic?
IgG4‐related disease (IgG4‐RD) is a recently established clinical entity characterized by fibroinflammatory lesions, high levels of circulating IgG4 and tissue infiltration of IgG4+ plasma cells.
What does this study add?
We comprehensively categorized the skin lesions of IgG4‐RD into primary lesions with direct infiltration of IgG4+ plasma cells (three subtypes) and secondary nonspecific inflammatory lesions where the role of IgG4 remains to be elucidated (four subtypes).
Our study clarifies IgG4‐related skin disease and its differential diagnoses.
Pulmonary arterial hypertension (PAH) is a progressive disorder characterised by raised pulmonary artery pressures with pathological changes in small pulmonary arteries. Previous studies have shown ...that approximately 70% of familial PAH and also 11-40% of idiopathic PAH (IPAH) cases have mutations in the bone morphogenetic protein receptor type II (BMPR2) gene. In addition, mutations in the activin receptor-like kinase 1 (ALK1) gene have been reported in PAH patients. Since both the BMPR2 and ALK1 belonging to the transforming growth factor (TGF)-beta superfamily are known to predispose to PAH, mutations in other genes of the TGF-beta/BMP signalling pathways may also predispose to PAH.
We screened for mutations in ENDOGLIN(ENG), SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6 and SMAD8 genes, which are involved in the TGF-beta/BMP signallings, in 23 patients with IPAH who had no mutations in BMPR2 or ALK1.
A nonsense mutation in SMAD8 designated c.606 C>A, p.C202X was identified in one patient. The father of this patient was also identified as having the same mutation. Functional analysis showed the truncated form of the SMAD8 C202X protein was not phosphorylated by constitutively active ALK3 and ALK1. The SMAD8 mutant was also unable to interact with SMAD4. The response to BMP was analysed using promoter-reporter activities with SMAD4 and/or ca-ALK3. The transcriptional activation of the SMAD8 mutant was inefficient compared with the SMAD8 wild type.
We describe the first mutation in SMAD8 in a patient with IPAH. Our findings suggest the involvement of SMAD8 in the pathogenesis of PAH.
G-protein-coupled receptors (GPCRs) and their ligands function in the progression of human malignancies. Gα12 and Gα13, encoded by GNA12 and GNA13, respectively, are referred to as the GEP oncogene ...and are implicated in tumor progression. However, the molecular mechanisms by which Gα12/13 activation promotes cancer progression are not fully elucidated. Here, we demonstrate elevated expression of Gα12/13 in human ovarian cancer tissues. Gα12/13 activation did not promote cellular migration in the ovarian cancer cell lines examined. Rather, Gα12/13 activation promoted cell growth. We used a synthetic biology approach using chimeric G proteins and GPCRs activated solely by artificial ligands to selectively trigger signaling pathways downstream of specific G proteins. We found that Gα12/13 promotes proliferation of ovarian cancer cells by activating the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway. Furthermore, we reveal that inhibition of YAP by short hairpin RNA or a specific inhibitor prevented the growth of ovarian cancer cells. Therefore, YAP may be a suitable therapeutic target in ovarian cancer.
To better understand long-term temperature changes in urban streams, we investigated stream temperatures in the central Tokyo area and its suburbs from 1978 through 1998. Stream temperature data were ...analyzed together with data on thermal effluents of urban wastewater and air temperature for the same period. Statistical analyses indicated that the stream temperature in winter and early spring increased at a rate of 0.11–0.21
°C/year in segments that had a considerable increase in wastewater heat input over the same period. These segments showed an appreciable change in the relationship between air temperature and stream temperature, which suggests that the increase in anthropogenic heat input from wastewater was the main cause of the long-term increase in stream temperature. Other possible factors such as increasing air temperature and heat exchange with seawater were found to have comparatively minor influences.
Naturally occurring CD25+CD4+ regulatory T cells are engaged in the maintenance of immunological self-tolerance and down-regulation of various immune responses. Recent studies with mice showed that ...Foxp3, which encodes the transcription factor Scurfin, is a master regulatory gene for the development and function of CD25+CD4+ regulatory T cells. Here we examined the role of FOXP3 in human CD25+CD4+ regulatory T cells. The FOXP3 gene and its protein product were preferentially expressed in peripheral CD25+CD4+ T cells, in particular CD25+CD45RO+CD4+ T cells in normal individuals and, interestingly, in some human T cell leukemia virus type 1-infected T cell lines, which constitutively express CD25. TCR stimulation of CD25−CD45RO−CD4+ naive T cells failed to elicit FOXP3 expression at the gene or protein level. Ex vivo retroviral gene transfer of FOXP3, on the other hand, converted peripheral CD25−CD45RO−CD4+ naive T cells into a regulatory T cell phenotype similar to CD25+CD4+ regulatory T cells. For example, FOXP3-transduced T cells exhibited impaired proliferation and production of cytokines including IL-2 and IL-10 upon TCR stimulation, up-regulated the expression of regulatory T cell-associated molecules such as CD25 and CTL-associated antigen-4 and suppressed in vitro proliferation of other T cells in a cell–cell contact-dependent manner. Thus, human FOXP3 is a crucial regulatory gene for the development and function of CD25+CD4+ regulatory T cells, and can be used as their reliable marker. Furthermore, regulatory T cells de novo produced from normal naive T cells by FOXP3 transduction can be instrumental for treatment of autoimmune/inflammatory diseases and negative control of various immune responses.
Background
In drug‐induced hypersensitivity syndrome (DIHS), latent human herpesvirus (HHV)‐6 is frequently reactivated in association with flaring of symptoms such as fever and hepatitis. We ...recently demonstrated an emergence of monomyeloid precursors expressing HHV‐6 antigen in the circulation during this clinical course.
Methods
To clarify the mechanism of HHV‐6 reactivation, we immunologically investigated peripheral blood mononuclear cells (PBMCs), skin‐infiltrating cells, and lymphocytes expanded from skin lesions of patients with DIHS.
Results
The circulating monomyeloid precursors in the patients with DIHS were mostly CD11b+CD13+CD14−CD16high and showed substantial expression of skin‐associated molecules, such as CCR4. CD13+CD14− cells were also found in the DIHS skin lesions, suggesting skin recruitment of this cell population. We detected high levels of high‐mobility group box (HMGB)‐1 in blood and skin lesions in the active phase of patients with DIHS and showed that recombinant HMGB‐1 had functional chemoattractant activity for monocytes/monomyeloid precursors in vitro. HHV‐6 infection of the skin‐resident CD4+ T cells was confirmed by the presence of its genome and antigen. This infection was likely to be mediated by monomyeloid precursors recruited to the skin, because normal CD4+ T cells gained HHV‐6 antigen after in vitro coculture with highly virus‐loaded monomyeloid precursors from the patients.
Conclusions
Our results suggest that monomyeloid precursors harboring HHV‐6 are navigated by HMGB‐1 released from damaged skin and probably cause HHV‐6 transmission to skin‐infiltrating CD4+ T cells, which is an indispensable event for HHV‐6 replication. These findings implicate the skin as a cryptic and primary site for initiating HHV‐6 reactivation.
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