Follicular helper- and peripheral helper-like T cells drive autoimmune disease in human immune system mice.

Human immune system (HIS) mice constructed in various ways are widely used for investigations of human immune responses to pathogens, transplants and immunotherapies. In HIS mice that generate T cells de novo from hematopoietic progenitors, T cell-dependent multisystem autoimmune disease occurs, most rapidly when the human T cells develop in the native NOD.Cg- Prkdc scid Il2rg tm1Wjl (NSG) mouse thymus, where negative selection is abnormal. Disease develops very late when human T cells develop in human fetal thymus grafts, where robust negative selection is observed. We demonstrate here that PD-1 + CD4 + peripheral (Tph) helper-like and follicular (Tfh) helper-like T cells developing in HIS mice can induce autoimmune disease. Tfh-like cells were more prominent in HIS mice with a mouse thymus, in which the highest levels of IgG were detected in plasma, compared to those with a human thymus. While circulating IgG and IgM antibodies were autoreactive to multiple mouse antigens, in vivo depletion of B cells and antibodies did not delay the development of autoimmune disease. Conversely, adoptive transfer of enriched Tfh- or Tph-like cells induced disease and autoimmunity-associated B cell phenotypes in recipient mice containing autologous human APCs without T cells. T cells from mice with a human thymus expanded and induced disease more rapidly than those originating in a murine thymus, implicating HLA-restricted T cell-APC interactions in this process. Since Tfh, Tph, autoantibodies and LIP have all been implicated in various forms of human autoimmune disease, the observations here provide a platform for the further dissection of human autoimmune disease mechanisms and therapies.

Long-Term Effects and Prognosis Following Suction Blister Epidermal Grafting in Vitiligo Patients.

BACKGROUND: Suction blister epidermal grafting (SBEG) is currently one of the most prevalent surgical methods for stable vitiligo. OBJECTIVE: To investigate the long-term outcomes of vitiligo patients who underwent SBEG and to explore risk factors associated with postoperative relapse. METHODS: A retrospective cohort study was conducted in patients who underwent SBEG in our department between January 2016 and December 2022. Treatment outcomes, including repigmentation rate, adverse events, and postoperative relapse, were surveyed via telephone interview or out-=patient visit. Multivariate logistic regression models were used to assess the potential risk factors for postoperative relapse. Statistical significance was assumed at P < .05. RESULTS: A total of 253 patients were included with a repigmentation rate of 96% (243/253) after grafting. Common adverse events included cobblestone-like appearance (73.1%, 185/253) in the donor site, perigraft halo (46.2%, 117/253), and cobblestone-like appearance (26.1%, 66/253) in the recipient site. Postoperative relapse occurred in 20.1% of patients over a mean time of 29.7 months after grafting. Nonsegmental type of vitiligo and coexistence of autoimmune diseases were risk factors for postoperative relapse. CONCLUSION: SBEG is an effective surgical treatment for vitiligo with high repigmentation rate and good safety profile. Nonsegmental vitiligo and comorbid autoimmune diseases may increase the risk of postoperative relapse.

Impact of COVID-19 Vaccine and COVID-19 Infection on Vitiligo Activity and Progression.

Background: Coronavirus disease 2019 (COVID-19) has given rise to several new onset or exacerbated dermatologic disorders including vitiligo. However, the relationship between COVID-19 infection or its associated vaccines and vitiligo progression is unclear. Aim: We investigate the impact of COVID-19 infection and its associated vaccines on vitiligo progression. Methods: A cross-sectional study was performed among patients who visited Department of Dermatology, Peking University People's Hospital between 2022.1 and 2023.6. Detailed information including demographic characteristics, vitiligo clinical features, information on COVID-19 infection and vaccination and disease progression was collected by an electronic questionnaire. Results: Overall, 314 patients with vitiligo completed the questionnaire. 47.5% were males, with an average age of 25.5±15.9 years. 266 (84.7%) patients had received COVID-19 vaccination, and 70.3% of the patients reported progression of vitiligo after vaccination, mostly within 3 months. 55.6% of the patients had disease progression after the second dose of vaccine. 270 patients experienced COVID-19 infection, and 30.7% of these patients had progression of vitiligo after infection, most of the progression occurred within 1-2 months. 184 patients (68.2%) interrupted treatment. Analysis results indicated patients in active stage had a higher risk for vitiligo progression after COVID-19 infection and vaccination.

A Prospective Study of Dermoscopic and Ultrastructural Features of Vitiligo-Associated Leukotrichia.

Background: Dermoscopic and ultrastructural features of vitiligo-associated leukotrichia (VAL) have not been well studied. This study is aimed at the dermoscopic and ultrastructural features of VAL. Methods: We present a cross-sectional study of VAL-related dermoscopic signs and their relationship with disease stages and duration of leukotrichia. Characteristics of hair surface and finer details including melanosomes, macrofibrils, and remnant nucleus were observed under Electron Microscopy (EM). Results: One hundred and forty samples on distinct sites from 100 patients were collected. Among 75 VAL from the scalp, the prevalence of diameter diversity of leukotrichia (52.6% vs 8.1%), Pohl-Pinkus constrictions (34.2% vs 0), and depigmented hair roots signs (34.2% vs 8.1%) in patients with progressive vitiligo was much higher than that in patients with stable vitiligo (all P<0.05). The EM result of VAL showed that melanosomes were smaller with vesicles formation, reduced counts, and incomplete shape, and macrofibrils were irregularly arranged with widened spaces and vesicles formation. Limitations: No conclusions about the histopathologic characteristics or dermoscopic-histopathologic correlation of the VAL. Conclusion: The dermoscopic signs of diameter diversity of leukotrichia, Pohl-Pinkus constrictions, and depigmented hair roots are related to progressive vitiligo. The process of melanin synthesis and formation of VAL are impaired at the early stage of VAL under Electron microscopy.

Poisson-based image editing for semi-supervised vitiligo lesion segmentation with limited annotations.

Vitiligo lesion segmentation is crucial for the assessment and treatment of vitiligo. There are two significant challenges in this problem, namely, the availability of dense segmentation annotations and the collection of large amounts of vitiligo images, which are also major challenges in medical image analysis (MIA). However, most existing methods often heavily rely on the availability of large-scale labeled datasets and high-quality annotations. Consequently, the performance of these models may not be easily reproducible or transferable to those domains with limited data availability. As a result, there is a need to develop alternative approaches that can leverage unlabeled datasets for segmentation with a small-scale training set. In this paper, we propose a data augmentation strategy based on image editing, which can synthesize a large number of samples using a small number of annotated data. The synthesized examples are of high visual quality and enforce the segmentation performance without any cost. Besides, we also adapt the Mean-Teacher framework for reliable predictions mining from unlabeled samples to alleviate the demands of densely annotated segmentations. We obtain pseudo-labels for unlabeled samples by utilizing highly confident pixels. On the other hand, we proposed a new Bimodal Vitiligo Lesions Segmentation (BVLS) dataset containing fine-grain segmentation masks and bimodal images usually used for vitiligo diagnosis to mitigate the lack of a vitiligo segmentation dataset. Extensive experiments conducted on the BLVS dataset demonstrate that our approach can achieve significant improvements (+17.27%) compared with previous data augmentation methods on the UNet backbone. Furthermore, the semi-supervised framework can reach an IoU of 49.71% with only 10% annotated images. Our code and dataset are availabel at https://github.com/JcWang20/BLVS.

Origin, phenotype and autoimmune potential of T cells in human immune system mice receiving neonatal human thymus tissue.

Robust human immune system (HIS) mice are created using human fetal thymus tissue and hematopoietic stem cells (HSCs). A HIS mouse model using neonatal human thymus tissue and umbilical cord blood (CB) HSCs (NeoHu) was recently described. We improved the model by removing the native murine thymus, which can also generate human T cells, and demonstrated definitively the capacity of human T cells to develop in a grafted neonatal human thymus. Human T cells derived from the neonatal thymus tissue appeared in peripheral blood early post-transplantation and CB-derived T cells appeared later. Naïve T cells were demonstrated in peripheral blood but effector memory and T peripheral helper phenotypes predominated later, in association with development of autoimmunity in some animals. Treatment of thymus grafts with 2-deoxyglucose (2-DG) increased the proportion of stem cells derived from injected HSCs, delayed onset of autoimmune disease, reduced early T cell reconstitution, and reduced effector/memory T cell conversion. Younger neonatal human thymus tissue was associated with improved T cell reconstitution. While the NeoHu model bypasses the need for fetal tissue, it has yet to demonstrate equivalent reconstitution to fetal tissue, though 2-DG can improve results by removing native thymocytes prior to transplantation.

Excellent Repigmentation of Generalized Vitiligo with Oral Baricitinib Combined with NB-UVB Phototherapy.

Vitiligo is an acquired autoimmune skin disorder, clinically characterized by distinct white macules and patches resulting from progressive melanocyte destruction. JAK-STAT pathway plays an important role in the loss of epidermal melanocytes. Baricitinib can block the JAK-STAT pathway and the downstream chemokines as a new JAK1/2 inhibitor. In this report, we describe the successful treatment of 2 patients with oral baricitinib combined with NB-UVB phototherapy, which provides a good alternative and supplementary to treat refractory vitiligo.

Ultrathin Skin Grafting Versus Suction Blister Epidermal Grafting in the Treatment of Resistant Stable Vitiligo: A Self-Controlled Comparative Study.

BACKGROUND: Surgical therapies are effective methods to treat resistant stable vitiligo, with each method having advantages and disadvantages. OBJECTIVE: This study aimed to compare the efficacy and safety of ultrathin skin grafting (UTSG) and suction blister epidermal grafting (SBEG) to treat stable vitiligo. METHODS: A total of 15 patients with 45 vitiligo patches were recruited. Each vitiligo patch was divided in half; 1 half was treated by UTSG, whereas the other half was treated by SBEG. The patients were followed up monthly for 3 months to assess the repigmentation rate, relative melanin index (RMI), and relative erythema index (REI) at different timepoints. RESULTS: Excellent repigmentation was observed in 97.8% of patches that underwent UTSG and 93.3% that underwent SBEG. The RMI and REI at 1, 2, and 3 months after the grafting procedure did not significantly differ between the 2 methods. At the recipient site, incomplete fall-off of the graft occurred in 4.4% of patches that underwent UTSG, whereas a "cobblestone appearance" was observed in 66.7% of patches that underwent SEBG. UTSG caused fewer complications at the donor site than SBEG. CONCLUSION: Compared with SBEG, UTSG is faster and achieves better cosmetic outcomes at the recipient and donor sites.

T1D patient-derived hematopoietic stem cells are programmed to generate Tph, Tfh, and autoimmunity-associated B cell subsets in human immune system mice.

Interactions between B cells and CD4+ T cells play a central role in the development of Type 1 Diabetes (T1D). Two helper cell subsets, follicular (Tfh) and peripheral (Tph) helper T cells, are increased in patients with T1D but their role in driving B cell autoimmunity is undefined. We used a personalized immune (PI) mouse model to generate human immune systems de novo from hematopoietic stem cells (HSCs) of patients with T1D or from healthy controls (HCs). Both groups developed Tfh and Tph-like cells, and those with T1D-derived immune systems demonstrated increased numbers of Tph-like and Tfh cells compared to HC-derived PI mice. T1D-derived immune systems included increased proportions of unconventional memory CD27-IgD- B cells and reduced proportions of naïve B cells compared to HC PI mice, resembling changes reported for patients with systemic lupus erythematosus. Our findings suggest that T1D HSCs are genetically programmed to produce increased proportions of T cells that promote the development of unconventional, possibly autoreactive memory B cells. PI mice provide an avenue for further understanding of the immune abnormalities that drive autoantibody pathogenesis and T1D.

Sensitive silica-alumina modified capacitive non-Faradaic glucose sensor for gestational diabetes.

A highly sensitive silica-alumina (Si-Al)-modified capacitive non-Faradaic glucose biosensor was introduced to monitor gestational diabetes. Glucose oxidase (GOx) was attached to the Si-Al electrode surface as the probe through amine-modification followed by glutaraldehyde premixed GOx as aldehyde-amine chemistry. This Si-Al (∼50 nm) modified electrode surface has increased the current flow upon binding of GOx with glucose. Capacitance values were increased by increasing the glucose concentrations. A mean capacitance value was plotted and the detection limit was found as 0.03 mg/mL with the regression coefficient value, R² = 0.9782 [y = 0.8391x + 1.338] on the linear range between 0.03 and 1 mg/mL. Further, a biofouling experiment with fructose and galactose did not increase the capacitance, indicating the specific glucose detection. This Si-Al-modified capacitance sensor detects a lower level of glucose presence and helps in monitoring gestational diabetes.

scRNA-seq of human vitiligo reveals complex networks of subclinical immune activation and a role for CCR5 in Treg function.

Vitiligo is an autoimmune skin disease characterized by the targeted destruction of melanocytes by T cells. Cytokine signaling between keratinocytes and T cells results in CD8+ T cell infiltration of vitiligo lesions, but the full scope of signals required to coordinate autoimmune responses is not completely understood. We performed single-cell RNA sequencing on affected and unaffected skin from patients with vitiligo, as well as healthy controls, to define the role of each cell type in coordinating autoimmunity during disease progression. We confirmed that type 1 cytokine signaling occupied a central role in disease, but we also found that this pathway was used by regulatory T cells (Tregs) to restrain disease progression in nonlesional skin. We determined that CCL5-CCR5 signaling served as a chemokine circuit between effector CD8+ T cells and Tregs, and mechanistic studies in a mouse model of vitiligo revealed that CCR5 expression on Tregs was required to suppress disease in vivo but not in vitro. CCR5 was not required for Treg recruitment to skin but appeared to facilitate Treg function by properly positioning these cells within the skin. Our data provide critical insights into the pathogenesis of vitiligo and uncover potential opportunities for therapeutic interventions.

Aristolochic acid I promoted clonal expansion but did not induce hepatocellular carcinoma in adult rats.

Aristolochic acid I (AAI) is a well-known nephrotoxic carcinogen, which is currently reported to be also associated with hepatocellular carcinoma (HCC). Whether AAI is a direct hepatocarcinogen remains controversial. In this study we investigated the association between AAI exposure and HCC in adult rats using a sensitive rat liver bioassay with several cofactors. Formation of glutathione S-transferase placental form-positive (GST-P+) foci was used as the marker for preneoplastic lesions/clonal expansion. We first conducted a medium-term (8 weeks) study to investigate whether AAI had any tumor-initiating or -promoting activity. Then a long-term (52 weeks) study was conducted to determine whether AAI can directly induce HCC. We showed that oral administration of single dose of AAI (20, 50, or 100 mg/kg) in combination with partial hepatectomy (PH) to stimulate liver proliferation did not induce typical GST-P+ foci in liver. In the 8-week study, only high dose of AAI (10 mg · kg-1 · d-1, 5 days a week for 6 weeks) in combination with PH significantly increased the number and area of GST-P+ foci initiated by diethylnitrosamine (DEN) in liver. Similarly, only high dose of AAI (10 mg· kg-1· d-1, 5 days a week for 52 weeks) in combination with PH significantly increased the number and area of hepatic GST-P+ foci in the 52-week study. No any nodules or HCC were observed in liver of any AAI-treated groups. In contrast, long-term administration of AAI (0.1, 1, 10 mg· kg-1· d-1) time- and dose-dependently caused death due to the occurrence of cancers in the forestomach, intestine, and/or kidney. Besides, AAI-DNA adducts accumulated in the forestomach, kidney, and liver in a time- and dose-dependent manner. Taken together, AAI promotes clonal expansion only in the high-dose group but did not induce any nodules or HCC in liver of adult rats till their deaths caused by cancers developed in the forestomach, intestine, and/or kidney. Findings from our animal studies will pave the way for further large-scale epidemiological investigation of the associations between AA and HCC.

Role of the thymus in spontaneous development of a multi-organ autoimmune disease in human immune system mice.

We evaluated the role of the thymus in development of multi-organ autoimmunity in human immune system (HIS) mice. T cells were essential for disease development and the same T cell clones with varying phenotypes infiltrated multiple tissues. De novo-generated hematopoietic stem cell (HSC)-derived T cells were the major disease drivers, though thymocytes pre-existing in grafted human thymi contributed if not first depleted. HIS mice with a native mouse thymus developed disease earlier than thymectomized mice with a thymocyte-depleted human thymus graft. Defective structure in the native mouse thymus was associated with impaired negative selection of thymocytes expressing a transgenic TCR recognizing a self-antigen. Disease developed without direct recognition of antigens on recipient mouse MHC. While human thymus grafts had normal structure and negative selection, failure to tolerize human T cells recognizing mouse antigens presented on HLA molecules may explain eventual disease development. These new insights have implications for human autoimmunity and suggest methods of avoiding autoimmunity in next-generation HIS mice.

A self-controlled comparative study of mini punch graft versus suction blister epidermal graft in the treatment of stable vitiligo.

BACKGROUND: Mini punch graft (MPG) and suction blister epidermal graft (SBEG) are both effective for stable vitiligo, but there is a lack of self-controlled comparison between these two procedures. OBJECTIVE: To compare the efficacy and safety of MPG and SBEG in stable vitiligo. MATERIALS AND METHODS: Twenty-three patients were enrolled in this study. A single white patch from each patient was divided into two halves, one half was treated by MPG, while the other half was treated by SBEG (blister or dermabrasion for recipient site), followed by narrow-band UVB irradiation twice a week for 3 months. The repigmentation rate, relative melanin index (RMI), and relative erythema index (REI) were measured at different time points. RESULTS: The repigmentation rate of grafts was 98.7% (312/316) in MPG, 98% (49/50) in SBEG (blister for recipient site) and 99.3% (272/274) in SBEG (dermabrasion for recipient site). The RMI and REI at different time points had no statistical difference between MPG and SBEG. Cobblestone appearance was the predominant complication in SBEG. For MPG, superficial scar occurred in two cases in recipient sites and no obvious side effects in donor sites. CONCLUSIONS: MPG is much easier, faster with less side effects in donor site.

Evaluation of the potential interference of camouflage on the treatment of vitiligo: An observer-blinded self-controlled study.

Camouflage improves the quality of life in vitiligo patients. However, whether the use of camouflage interferes the efficacy of the treatment of vitiligo remains controversial. To evaluate the impact and safety of dihydroxyacetone (DHA)-containing camouflage on the treatment of vitiligo. Thirty patients were enrolled. Comparable vitiliginous patches in each patient were randomly divided into camouflage group or blank group. The therapeutic modalities including topical corticosteroids with or without NB-UVB phototherapy were applied to both groups of lesions. The outcomes were assessed at baseline and then every 4 weeks for up to 12 weeks, including types of repigmentation patterns, percentage of repigmentation, trans epidermal water loss (TEWL), and adverse events. Twenty-eight patients completed the study. There were no differences in repigmentation types and percentage of repigmentation at the endpoint of study between two groups. No difference in TEWL was found at the end of the study between the two groups. Temporary skin irritation (itching and tingling) occurred in one patient in camouflage group after phototherapy between 8 and 12 weeks' treatment. DHA-containing camouflage is a safe make-up for vitiligo. It has little impact on the efficacy of the treatment of vitiligo or on the function of skin barrier.

Ablation of DJ-1 Enhances Oxidative Stress by Disturbing the Function of Mitochondria in Epidermal Melanocytes.

BACKGROUND: Oxidative stress is implicated in the pathogenesis of vitiligo. The function of DJ-1 in oxidative damage of melanocytes is still elusive. AIMS: The aim of this study was to investigate the role of DJ-1 in oxidative damage of melanocytes. MATERIAL AND METHODS: The expression of DJ-1 in melanocytes was studied by reverse transcription-quantitative polymerase chain reaction and Western blot. Short-interfering RNAs (siRNA) were employed to downregulate DJ-1. The cells were pooled into three groups: mock group (cells with transfection reagent), negative control (NC) group (negative siRNA control), and siRNA group. After H2O2 treatment for 24 h, the morphological changes, cell viability, apoptosis, intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), and mitochondrial respiration were measured in different groups. RESULTS: DJ-1 was highly expressed in PIG1 melanocytes. DJ-1 knockdown rendered PIG1 melanocytes more susceptible to oxidative stress. Loss of DJ-1 led to apoptosis of PIG1 cells by impairing the function of mitochondria, including morphological abnormalities, ROS accumulation, depolarization of MMP, less adenosine-triphosphate (ATP) production, and less proton leak. CONCLUSIONS: DJ-1 plays a role in maintaining the antioxidative capacity in epidermal melanocytes.