Pulmonary interstitial lesions in pemphigus mouse model: Verifying pemphigus may not be only limited to skin and mucosa.

Interstitial lung disease (ILD) has been identified as a prevalent complication and significant contributor to mortality in individuals with pemphigus. In this study, a murine model of pemphigus was developed through the subcutaneous administration of serum IgG obtained from pemphigus patients, allowing for an investigation into the association between pemphigus and ILD. Pulmonary interstitial lesions were identified in the lungs of a pemphigus mouse model through histopathology, RT-qPCR and Sircol assay analyses. The severity of these lesions was found to be positively associated with the concentration of IgG in the injected serum. Additionally, DIF staining revealed the deposition of serum IgG in the lung tissue of pemphigus mice, indicating that the subcutaneous administration of human IgG directly impacted the lung tissue of the mice, resulting in damage. This study confirms the presence of pulmonary interstitial lesions in the pemphigus mouse model and establishes a link between pemphigus and ILD.

Efficacy and Safety of Hydrogen Therapy in Patients with Early-Stage Interstitial Lung Disease: A Single-Center, Randomized, Parallel-Group Controlled Trial.

Purpose: Several in vivo experiments have shown that molecular hydrogen is a promising therapeutic agent for interstitial lung diseases (ILD). In this study, hydrogen therapy was investigated to determine whether it is superior to N-Acetylcysteine (NAC) for the treatment of patients with early-stage ILD. Patients and Methods: A prospective, single-center, randomized, controlled clinical trial was conducted in 87 patients with early-stage ILD. Hydrogen or NAC therapy was randomly assigned (1:1 ratio) to the eligible patients. The primary endpoint was the change in the high-resolution computed tomography (HRCT) and composite physiologic index (CPI) scores from baseline to week 48. Pulmonary function was evaluated as a secondary endpoint, and adverse events were recorded for safety analysis. Results: The rate of HRCT image improvement from the baseline in the HW group (63.6%) was higher than that in the NAC group (39.5%). A significant decrease in CPI and improvement in DLCO-sb were observed in the hydrogen group compared with those in the control group. Changes in other pulmonary function parameters, including FVC, FEV1, FEV1/FVC%, and TLC, were not significantly different between the two groups. Adverse events were reported in 7 (15.9%) patients in the HW group and 10 (23.3%) patients in the NAC group, but the difference was not significant (P=0.706). Conclusion: Hydrogen therapy exhibits superior efficacy and acceptable safety compared with NAC therapy in patients with early-stage ILD.

Key processes required for the different stages of fungal carnivory by a nematode-trapping fungus.

Nutritional deprivation triggers a switch from a saprotrophic to predatory lifestyle in soil-dwelling nematode-trapping fungi (NTF). In particular, the NTF Arthrobotrys oligospora secretes food and sex cues to lure nematodes to its mycelium and is triggered to develop specialized trapping devices. Captured nematodes are then invaded and digested by the fungus, thus serving as a food source. In this study, we examined the transcriptomic response of A. oligospora across the stages of sensing, trap development, and digestion upon exposure to the model nematode Caenorhabditis elegans. A. oligospora enacts a dynamic transcriptomic response, especially of protein secretion-related genes, in the presence of prey. Two-thirds of the predicted secretome of A. oligospora was up-regulated in the presence of C. elegans at all time points examined, and among these secreted proteins, 38.5% are predicted to be effector proteins. Furthermore, functional studies disrupting the t-SNARE protein Sso2 resulted in impaired ability to capture nematodes. Additionally, genes of the DUF3129 family, which are expanded in the genomes of several NTF, were highly up-regulated upon nematode exposure. We observed the accumulation of highly expressed DUF3129 proteins in trap cells, leading us to name members of this gene family as Trap Enriched Proteins (TEPs). Gene deletion of the most highly expressed TEP gene, TEP1, impairs the function of traps and prevents the fungus from capturing prey efficiently. In late stages of predation, we observed up-regulation of a variety of proteases, including metalloproteases. Following penetration of nematodes, these metalloproteases facilitate hyphal growth required for colonization of prey. These findings provide insights into the biology of the predatory lifestyle switch in a carnivorous fungus and provide frameworks for other fungal-nematode predator-prey systems.

An association study of HLA with levofloxacin-induced severe cutaneous adverse drug reactions in Han Chinese.

Levofloxacin-induced severe cutaneous adverse drug reactions (LEV-SCARs) remain unexplored. An association study of human leukocyte antigen (HLA) alleles with LEV-SCARs among 12 patients, 806 healthy subjects, and 100 levofloxacin-tolerant individuals was performed. The carrier frequencies of HLA-B∗13:01 (odds ratio [OR]: 4.50; 95% confidence interval [CI]: 1.15-17.65; p = 0.043), HLA-B∗13:02 (OR: 6.14; 95% CI: 1.73-21.76; p = 0.0072), and serotype B13 (OR: 17.73; 95% CI: 3.61-86.95; p = 4.85 × 10-5) in patients with LEV-SCARs were significantly higher than those of levofloxacin-tolerant individuals. Molecular docking analysis suggested that levofloxacin formed more stable binding models with HLA-B∗13:01 and HLA-B∗13:02 than with non-risk HLA-B∗46:01. Mass spectrometry revealed that nonapeptides bound to HLA-B∗13:02 shifted at several positions after exposure to levofloxacin. Prospective screening for serotype B13 (sensitivity: 83%, specificity: 78%) and alternative drug treatment for carriers may significantly decrease the incidence of LEV-SCARs.

The cAMP-PKA pathway regulates prey sensing and trap morphogenesis in the nematode-trapping fungus Arthrobotrys oligospora.

Sensing environmental factors and responding swiftly to them is essential for all living organisms. For instance, predators must act rapidly once prey is sensed. Nematode-trapping fungi (NTF) are predators that use "traps" differentiated from vegetative hyphae to capture, kill, and consume nematodes. These traps undergo drastic and rapid morphological changes upon nematode induction. Multiple signaling hubs have been shown to regulate this remarkable process. Here, we demonstrate that the conserved cAMP-PKA signaling pathway exerts a crucial role in trap morphogenesis of the nematode-trapping fungi Arthrobotrys oligospora. A gene deletion mutant of the PKA catalytic subunit TPK2 proved insensitive toward nematode presence. Moreover, we show that the G protein alpha subunit GPA2 acts upstream of adenylate cyclase, with GPA2 deletion resulting in substantially reduced trap formation, whereas exogenous provision of cAMP rescued the prey-sensing and trap morphogenesis defects of a gpa2 mutant. Thus, we show that cAMP production triggered by G protein signaling and downstream PKA activity are vital for prey-sensing and trap development in A. oligospora, demonstrating that this highly conserved signaling pathway is critical for nematode-trapping fungi and nematode predator-prey interactions.

Dupilumab combined with low-dose systemic steroid therapy improves efficacy and safety for bullous pemphigoid.

Routine systemic therapy for bullous pemphigoid (BP) has been challenged due to the inevitably adverse effects. According to the successful applications of dupilumab in BP cases reported, therefore, we investigate the real-life efficacy and safety of dupilumab combined with low-dose oral steroid for BP. A cohort of BP patients who received either dupilumab plus low-dose methylprednisolone (dupilumab group) or merely methylprednisolone (control group) was retrospectively reviewed. The time to disease control was investigated. Additionally, the control dose and cumulative dosage of steroids, Bullous Pemphigoid Disease Area Index (BPDAI) scores, pruritus scores, and adverse events were assessed. A total of 40 patients, with 20 in each group, were retrospectively studied. The time to disease control was shorter in the dupilumab group than the control group (14 days vs. 19 days, p = 0.043). When the disease was controlled, the control dose and cumulative dosage of methylprednisolone in the dupilumab group were substantially lower than those of the control (24.6 mg vs. 48.8 mg, 376.8 mg vs. 985.6 mg, both p < 0.01). Compared with the control, the percentage change from baseline in BPDAI scores and pruritus scores were both significantly reduced, and the adverse events were also less frequent in the dupilumab group. The combination therapy of dupilumab plus low-dose methylprednisolone exhibits superior efficacy and safety in comparison with the current first-line systemic therapy for BP.

Prey sensing and response in a nematode-trapping fungus is governed by the MAPK pheromone response pathway.

Detection of surrounding organisms in the environment plays a major role in the evolution of interspecies interactions, such as predator-prey relationships. Nematode-trapping fungi (NTF) are predators that develop specialized trap structures to capture, kill, and consume nematodes when food sources are limited. Despite the identification of various factors that induce trap morphogenesis, the mechanisms underlying the differentiation process have remained largely unclear. Here, we demonstrate that the highly conserved pheromone-response MAPK pathway is essential for sensing ascarosides, a conserved molecular signature of nemaotdes, and is required for the predatory lifestyle switch in the NTF Arthrobotrys oligospora. Gene deletion of STE7 (MAPKK) and FUS3 (MAPK) abolished nematode-induced trap morphogenesis and conidiation and impaired the growth of hyphae. The conserved transcription factor Ste12 acting downstream of the pheromone-response pathway also plays a vital role in the predation of A. oligospora. Transcriptional profiling of a ste12 mutant identified a small subset of genes with diverse functions that are Ste12 dependent and could trigger trap differentiation. Our work has revealed that A. oligospora perceives and interprets the ascarosides produced by nematodes via the conserved pheromone signaling pathway in fungi, providing molecular insights into the mechanisms of communication between a fungal predator and its nematode prey.

Extensive cutaneous iatrogenic Kaposi's sarcoma after bullous pemphigoid treatment with oral methylprednisolone: a rare Chinese case report.

Bullous pemphigoid (BP) is an autoimmune disease that requires immunosuppressive therapy. Systemic corticosteroids are considered the standard treatment for moderate-to-severe BP. Kaposi's sarcoma (KS) is a rare multifocal endothelial tumour that affects the skin, mucosa and viscera. As an angioproliferative disease of obscure aetiopathogenesis and histogenesis, KS is associated with human herpesvirus 8 (HHV-8). This current case report describes a rare occurrence of extensive cutaneous KS in a 60-year-old Chinese male patient after oral methylprednisolone treatment for BP with an emphasis on its pathological characterization. A total of more than 40 nodules were found on his trunk and lower limbs covering more than 20% of his body surface area. Immunohistochemical staining of biopsy samples from the lesion showed the patient was positive for HHV-8, CD31, CD34, XIIIa, ERG and Ki-67. The Epstein-Barr virus test showed the patient tested negative for immunoglobulin (Ig)A and IgM, but was positive for IgG. Immunosuppression associated with the treatment for BP may activate a latent HHV-8 infection and induce the development of KS.

The High Osmolarity Glycerol (HOG) Pathway Functions in Osmosensing, Trap Morphogenesis and Conidiation of the Nematode-Trapping Fungus Arthrobotrys oligospora.

Hog1, a mitogen-activated protein kinase (MAPK), has been identified in diverse fungal species, and it regulates various cellular processes, such as osmoadaptation, nutrient-sensing, and pathogenesis. However, the roles that Hog1 plays in nematode-trapping fungi were previously unclear. Here, we characterized orthologs of Saccharomyces cerevisiae Hog1 and membrane mucin Msb2 in the nematode-trapping fungus Arthrobotrys oligospora. We generated gene deletion mutants of HOG1 and MSB2 in A. oligospora, and characterized their roles in osmosensing, growth, and trap morphogenesis. We found that both hog1 and msb2 mutants were highly sensitive to high osmolarity. Predation analyses further revealed that hog1 and msb2 deletion caused a reduction in trap formation and predation efficiency. Furthermore, HOG1 is required for conidiation in A. oligospora, demonstrating its critical role in this developmental pathway. In summary, this study demonstrated that the conserved Hog1 and Msb2 govern physiology, growth and development in the nematode-trapping fungus A. oligospora.

Natural diversity in the predatory behavior facilitates the establishment of a robust model strain for nematode-trapping fungi.

Nematode-trapping fungi (NTF) are a group of specialized microbial predators that consume nematodes when food sources are limited. Predation is initiated when conserved nematode ascaroside pheromones are sensed, followed by the development of complex trapping devices. To gain insights into the coevolution of this interkingdom predator-prey relationship, we investigated natural populations of nematodes and NTF that we found to be ubiquitous in soils. Arthrobotrys species were sympatric with various nematode species and behaved as generalist predators. The ability to sense prey among wild isolates of Arthrobotrys oligospora varied greatly, as determined by the number of traps after exposure to Caenorhabditis elegans While some strains were highly sensitive to C. elegans and the nematode pheromone ascarosides, others responded only weakly. Furthermore, strains that were highly sensitive to the nematode prey also developed traps faster. The polymorphic nature of trap formation correlated with competency in prey killing, as well as with the phylogeny of A. oligospora natural strains, calculated after assembly and annotation of the genomes of 20 isolates. A chromosome-level genome assembly and annotation were established for one of the most sensitive wild isolates, and deletion of the only G-protein ß-subunit-encoding gene of A. oligospora nearly abolished trap formation. In summary, our study establishes a highly responsive A. oligospora wild isolate as a model strain for the study of fungus-nematode interactions and demonstrates that trap formation is a fitness character in generalist predators of the nematode-trapping fungus family.

Clinical profile of cutaneous adverse drug reactions: a retrospective study of 1883 hospitalized patients from 2007 to 2016 in Shanghai, China.

BACKGROUND: Cutaneous adverse drug reactions (CADRs) are drug-induced skin reactions with or without systemic involvement, ranging from mild maculopapular exanthema (MPE) to life-threatening severe CADRs (S-CADRs). Due to their unpredictability and severity, early recognition of suspected causative drugs is highly recommended. However, the profile of CADRs remains unknown in China. OBJECTIVES: To assess the clinical profile, predominant causative drugs, and cost associated with CADRs in Shanghai, China. MATERIALS AND METHODS: Clinical records of inpatients admitted with a diagnosis of CADRs to the dermatology ward of Huashan Hospital from January 2007 to December 2016 were retrospectively studied. RESULTS: A total of 1,883 patients (1,231 female and 652 male), admitted with a diagnosis of CADR, were investigated. S-CADRs made up 21.99% of all cases (n=414), and urticaria (27.19%) was the most frequent reaction. Of the patients, 53.43% suffered from multiple drug-induced drug eruptions and the rest (45.83%) from single drug-induced drug eruptions. Overall, antimicrobials (28.85%) was the main drug group involved, and for S-CADRs, this was antiepileptic drugs (36.15%). The total cost for CADRs was RMB23,718,788.83 ($3,588,319.04). Both age and sex were related to admission cost (p=0.005 and p=7.84E-8, respectively). Antimicrobials were the most common treatment causing CADRs. CONCLUSION: The management of CADRs requires considerable medical cost. CADRs are not only a health problem but also a significant financial burden for affected individuals.

HLA-A*24:02 is associated with metronidazole-induced cutaneous adverse drug reactions in Han Chinese individuals: A pilot case-control study with both HLA gene and T cell receptor repertoire analysis.

Metronidazole, a widely used drug for the treatment of infections with anaerobic and facultative anaerobic bacteria and protozoa, can frequently cause metronidazole-induced cutaneous adverse reactions (McADRs). The aim of the present study was to investigate the association between human leucocyte antigen (HLA) alleles and McADRs in a Chinese Han population. The frequency of HLA-B*24:02 carriers among the McADR patients was 73.3%, which was significantly higher than that of the population controls (32.16%, OR = 5.80, 95% CI = [1.80-18.72], Pc = 0.004) and of the metronidazole-tolerant patients (26.67%, OR = 7.56, 95% CI = [2.02-28.35], Pc = 0.004). Molecular docking showed that metronidazole and one of its major metabolites had the potential to bind in the HLA groove and that there was a relatively stable binding state of the HLA-B*24:02-metronidazole/the metabolite complex. The CDR3 repertoires of both T cell receptor (TCR)Vα and Vß of the patients showed a significantly skewed or an oligoclonal distribution. The TCRVß CDR3 of the patients shared a similar motif, "CASSxxxxxxQxF." The current study demonstrated that both the HLA-A*24:02 allele and TCR are involved in the pathogenesis of McADRs.

HLA-A*02:01 allele is associated with tanshinone-induced cutaneous drug reactions in Chinese population.

Tanshinone, a widely used Chinese patent medicine, has been confirmed to have various kinds of pharmacological effects although frequently causing cutaneous adverse drug reactions (cADRs). We aim to identify whether human leukocyte antigen (HLA) class I alleles are associated with tanshinone-induced cADRs in Han Chinese. The association study including 18 patients with tanshinone-induced cADRs, 67 tanshinone-tolerant volunteers, and two general population databases consisted of 10,689 and 169,995 healthy subjects was performed. The frequency of tanshinone-induced cADRs patients carrying HLA-A*02:01 was significantly higher when compared with the general control groups (OR = 6.25, Pc = 7.20 × 10-5; OR = 7.14, Pc = 8.00 × 10-6), and with the tolerant group (OR = 5.09, Pc = 0.024). The molecular docking assay confirmed high affinity of the ingredients of tanshinone towards HLA-A*02:01 (≤-7.5 kcal/mol). The result suggested HLA-A*02:01 may work as a promisingly predictive marker for tanshinone personalized therapy in Han Chinese.

Skin ulcers infected with conditional pathogenic strains treated with local hydrogen water packing in two pemphigus vulgaris patients: Case reports with follow-up for 2 months.

We are the first to report on a new, safe, and effective treatment of infections induced by conditional pathogenic strains with local wet packing with hydrogen water. The new treatment method may also shed light on the therapy of chronic, inflammatory skin ulcers.

Comprehensive assessment of T cell receptor ß repertoire in Stevens-Johnson syndrome/toxic epidermal necrolysis patients using high-throughput sequencing.

Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions characterized by widespread epidermal necrosis. Recent studies have indicated that SJS/TEN is a specific immune reaction regulated by T cells. Certain drug serves as foreign antigens that are presented by major histocompatibility complex (MHC) and recognized by T cell receptors (TCRs), inducing adaptive immune responses. However, few studies have performed detailed characterization of TCR repertoire in SJS/TEN, and it remains unclear whether the particular types of TCRs expanded clonally are drug-specific, which would provide a potential underlying mechanism of SJS/TEN. In this study, using high-throughput sequencing, we comprehensively assessed the diversity, composition and molecular characteristics of the TCRß repertoires in 17 SJS/TEN patients associated with three different causative drugs including methazolamide (MZ), carbamazepine (CBZ) and allopurinol (ALP). Systematic analysis of the TCRß sequences revealed that SJS/TEN patients had more highly expanded clones and less TCR repertoire diversity, and the TCR repertoire diversity of these patients showed certain associations with the clinical severity of disease. Similar predominant clonotypes, shared-usage TRBV/TRBJ subtypes and combinations thereof were observed among different subjects with the same causative agent. Our observations provide enhanced understanding of the role of T lymphocytes in the pathogenesis of SJS/TEN and enumerate potential therapeutic targets.

HLA-C*12:02 is strongly associated with Xuesaitong-induced cutaneous adverse drug reactions.

Xuesaitong (XST) is mainly used to treat cardiovascular and cerebrovascular diseases, sometimes causing cutaneous adverse drug reactions (cADRs) with unknown mechanisms of pathogenicity or risk factors. We aimed to verify whether human leukocyte antigen (HLA) alleles are associated with XST-related cADRs in Han Chinese population. We carried out an association study including 12 subjects with XST-induced cADRs, 283 controls, and 28 XST-tolerant subjects. Five out of 12 patients with XST-induced cADRs carried HLA-C*12:02, and all of them received XST via intravenous drip. The carrier frequency of HLA-C*12:02 was significantly high compare to that of the control population (Pc = 4.4 × 10-4, odds ratio (OR) = 21.75, 95% CI = 5.78-81.88). Compared with that of the XST-tolerant group, the patients who received XST through intravenous drip presented a higher OR of cADRs (Pc = 0.011, OR = 27.00, 95% CI = 2.58-282.98). The results suggest that HLA-C*12:02 is a potentially predictive marker of XST-induced cADRs in Han Chinese, especially when XST is administered via intravenous drip.

Association Study and Fine-Mapping Major Histocompatibility Complex Analysis of Pemphigus Vulgaris in a Han Chinese Population.

To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study of 240 PV patients and 1,031 control individuals, and we selected the top single nucleotide polymorphisms for replication in independent samples, with 252 patient samples and 1,852 control samples. We identified rs11218708 (P = 3.1 × 10-8, odds ratio = 1.54) at chromosome locus 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the major histocompatibility complex region showed three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10-38, odds ratio = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10-12, odds ratio = 3.25), and rs1051336 at the HLA-DRA gene (P = 3.06 × 10-6, odds ratio = 0.33). A systematic evaluation using gene- and pathway-based analyses showed a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlights the involvement of immune-mediated processes in the pathophysiology of PV and illustrates the value of imputation to identify variants in the major histocompatibility complex region.

Overexpression of cytotoxic proteins correlates with liver function impairment in patients with drug reaction with eosinophilia and systemic symptoms (DRESS).

Drug reaction with eosinophilia and systemic symptoms (DRESS) is characterised by skin rash and multivisceral involvement. The liver is the organ most frequently affected and the degree of liver function impairment often correlates with the mortality rate of DRESS. We aimed to examine the expression of cytotoxic proteins, including soluble Fas ligand (sFasL), TNF-α, granulysin, perforin, and granzyme B in the sera and skin lesions of patients with DRESS and evaluate their clinical significance. Our cohort consisted of 21 patients with DRESS and control groups including 39 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis, 21 patients with maculopapular eruption, and 29 normal controls. Concentrations of cytotoxic proteins in the sera were measured using enzyme-linked immunosorbent assays. Tissue samples were also obtained from typical skin lesions, and immunohistochemical staining was conducted to assess the local expression of cytotoxic proteins. We found that sFasL and granzyme B were significantly overexpressed in the sera of DRESS patients compared to normal controls. Furthermore, the levels of sFasL, perforin, and granzyme B significantly correlated with the serum level of liver enzymes in DRESS patients. Immunohistochemical examination also showed overexpressed cytotoxic proteins in cutaneous DRESS lesions. Cytotoxic proteins may play a vital role in the pathogenesis of DRESS, and serum sFasL, perforin, and granzyme B may also be involved in liver function impairment in DRESS patients.