Epidermolysis Bullosa in Chinese Patients: Genetic Analysis and Mutation Landscape in 57 Pedigrees and Sporadic Cases.

Epidermolysis bullosa encompasses a group of inherited blistering skin disorders. The pathogenic mutations in 10-25% of patients with epidermolysis bullosa have not been identified by Sanger sequencing. The aims of this study were to identify the pathogenic sequence alterations in a large cohort of Chinese patients with epidermolysis bullosa and to clarify the relationship between clinical phenotypes and genotypes. Whole-exome sequencing was performed on 44 pedigrees and 13 sporadic cases. The results were further confirmed by Sanger sequencing. In total, 52 mutations, comprising 19 novel and 33 previously reported mutations, were identified in 5 genes, with a mutation detection rate of 100%. A relationship between subtypes and pathogenic genes was established: 12 cases of epidermolysis bullosa simplex were associated with mutations in KRT5/14 and PLEC; one case of junctional epidermolysis bullosa carried mutations in ITGB4; and 44 cases of dystrophic epidermolysis bullosa were caused by mutations in COL7A1. The results of this study support whole-exome sequencing as a promising tool in the genetic diagnosis of epidermolysis bullosa.

Massively Parallel Sequencingof the Filaggrin Gene Reveals an Association Between FLG Loss-of-function Mutations and Leprosy.

Filaggrin, encoded by the FLG gene, plays a crucial role in the barrier function of epidermis, but the association between FLG loss-of-function mutations and infectious skin diseases has not been systematically studied. FLG coding sequences from 945 patients with leprosy and 916 healthy controls were captured and enriched using an array-based high-throughput system, and subjected to next-generation sequencing. The loss-of-function mutations found were further validated by Sanger sequencing. A total of 21 loss-of-function mutations were found in 945 patients with leprosy, with a carrier rate of 17.53%, while the prevalence of these mutations in 916 healthy controls was 14.77%, which was significantly lower than in patients. Two individual FLG loss-of-function mutations (K4022X and Q1790X) were found to be significantly associated with leprosy. These results suggest a possible role for filaggrin in defending against leprosy pathogens.

A case of generalized eosinophilic pustular folliculitis: treatment with JAK inhibitor.

AIM: This case study aims to report the efficacy and safety of a Janus kinase (JAK) inhibitor in the treatment of generalized eosinophilic pustular folliculitis (EPF). METHODS: We present a case of a 16-year-old Chinese patient who had been suffering from EPF for two years and had shown no response to both topical and systemic glucocorticoids. The patient was subsequently treated with oral tofacitinib at a dosage of 5mg daily. RESULTS: Significant remission of eruption and pruritus was observed in the patient upon treatment with tofacitinib. However, a relapse occurred upon dose reduction. Subsequent switch to the highly selective JAK1 inhibitor upadacitinib resulted in complete recovery, with the patient achieving a symptom-free status after six months. CONCLUSIONS: JAK inhibitors show promise as a potential treatment option for EPF patients who do not respond to traditional therapies.

Single-cell sequencing analysis reveals development and differentiation trajectory of Schwann cells manipulated by M. leprae.

BACKGROUND: M. leprae preferentially infects Schwann cells (SCs) in the peripheral nerves leading to nerve damage and irreversible disability. Knowledge of how M. leprae infects and interacts with host SCs is essential for understanding mechanisms of nerve damage and revealing potential new therapeutic strategies. METHODOLOGY/PRINCIPAL FINDINGS: We performed a time-course single-cell sequencing analysis of SCs infected with M. leprae at different time points, further analyzed the heterogeneity of SCs, subpopulations associated with M. leprae infection, developmental trajectory of SCs and validated by Western blot or flow cytometry. Different subpopulations of SCs exhibiting distinct genetic features and functional enrichments were present. We observed two subpopulations associated with M. leprae infection, a stem cell-like cell subpopulation increased significantly at 24 h but declined by 72 h after M. leprae infection, and an adipocyte-like cell subpopulation, emerged at 72 h post-infection. The results were validated and confirmed that a stem cell-like cell subpopulation was in the early stage of differentiation and could differentiate into an adipocyte-like cell subpopulation. CONCLUSIONS/SIGNIFICANCE: Our results present a systematic time-course analysis of SC heterogeneity after infection by M. leprae at single-cell resolution, provide valuable information to understand the critical biological processes underlying reprogramming and lipid metabolism during M. leprae infection of SCs, and increase understanding of the disease-causing mechanisms at play in leprosy patients as well as revealing potential new therapeutic strategies.

The immune-suppressive landscape in lepromatous leprosy revealed by single-cell RNA sequencing.

Lepromatous leprosy (L-LEP), caused by the massive proliferation of Mycobacterium leprae primarily in macrophages, is an ideal disease model for investigating the molecular mechanism of intracellular bacteria evading or modulating host immune response. Here, we performed single-cell RNA sequencing of both skin biopsies and peripheral blood mononuclear cells (PBMCs) of L-LEP patients and healthy controls. In L-LEP lesions, we revealed remarkable upregulation of APOE expression that showed a negative correlation with the major histocompatibility complex II gene HLA-DQB2 and MIF, which encodes a pro-inflammatory and anti-microbial cytokine, in the subset of macrophages exhibiting a high expression level of LIPA. The exhaustion of CD8+ T cells featured by the high expression of TIGIT and LAG3 in L-LEP lesions was demonstrated. Moreover, remarkable enhancement of inhibitory immune receptors mediated crosstalk between skin immune cells was observed in L-LEP lesions. For PBMCs, a high expression level of APOE in the HLA-DRhighFBP1high monocyte subset and the expansion of regulatory T cells were found to be associated with L-LEP. These findings revealed the primary suppressive landscape in the L-LEP patients, providing potential targets for the intervention of intracellular bacteria caused persistent infections.