Engineering Mice to Study Human Immunity.

Humanized mice, which carry a human hematopoietic and immune system, have greatly advanced our understanding of human immune responses and immunological diseases. These mice are created via the transplantation of human hematopoietic stem and progenitor cells into immunocompromised murine hosts further engineered to support human hematopoiesis and immune cell growth. This article explores genetic modifications in mice that enhance xeno-tolerance, promote human hematopoiesis and immunity, and enable xenotransplantation of human tissues with resident immune cells.

Atgl-Dependent Adipocyte Lipolysis Promotes Lipodystrophy and Restrains Fibrogenic Responses during Skin Fibrosis.

During skin fibrosis, extracellular matrix proteins are overproduced, and resident lipid-filled mature dermal adipocytes are depleted in both human disease and mouse models. However, the mechanisms underlying this reduction in lipid-filled adipocytes during fibrosis are poorly understood. In this study, we found that adipocyte lipolysis through the rate-limiting enzyme Atgl is required for loss of adipose tissue during skin fibrosis in mice.

Genetic and molecular drivers of scleroderma pathogenesis.

Scleroderma is a heterogeneous disease with various clinical findings involving immune dysregulation, vasculopathy, and fibrosis. Biological and genetic studies over recent decades have elucidated molecular mechanisms of scleroderma pathogenesis. Genetic association studies have identified interferon and other immune regulatory genes as strongly linked to scleroderma risk, highlighting the immune system as a fundamental determinant of disease.

Cross-tissue organization of myeloid cells in scleroderma and related fibrotic diseases.

Purpose Of Review: Scleroderma and other fibrotic diseases have been investigated using single-cell RNA sequencing (scRNA-Seq), which has demonstrated enrichment in myeloid cell populations in multiple tissues. However, scRNA-Seq studies are inconsistent in their nomenclature of myeloid cell types, including dendritic cells, monocytes, and macrophages. Using cell type-defining gene signatures, I propose a unified nomenclature through analysis of myeloid cell enrichment across fibrotic tissues.

Gene trajectory inference for single-cell data by optimal transport metrics.

Single-cell RNA sequencing has been widely used to investigate cell state transitions and gene dynamics of biological processes. Current strategies to infer the sequential dynamics of genes in a process typically rely on constructing cell pseudotime through cell trajectory inference. However, the presence of concurrent gene processes in the same group of cells and technical noise can obscure the true progression of the processes studied.

TGF-β1 Drives Integrin-Dependent Pericyte Migration and Microvascular Destabilization in Fibrotic Disease.

Interactions between endothelial cells (ECs) and mural pericytes (PCs) are critical in maintaining the stability and function of the microvascular wall. Abnormal interactions between these two cell types are a hallmark of progressive fibrotic diseases such as systemic sclerosis (also known as scleroderma). However, the role of PCs in signaling microvascular dysfunction remains underexplored.

IL-6 trans-signaling in a humanized mouse model of scleroderma.

Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop an immune system like humans when engrafted with human hematopoietic stem cells (HSCs).

Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis.

Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs.

Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor.

Morphea after -induced facial nerve palsy.

Morphea, also known as localized scleroderma, is characterized by inflammation and fibrosis of the skin. The exact pathogenesis of morphea is unknown, but generally includes genetic predisposition to autoimmunity combined with an environmental insult. Previous cases have been associated with active infection; however, infection as a direct cause of morphea was not generalizable to most patients.

Publisher Correction: HER2 joins AKT to inhibit STING immunity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Microbiome: Ecology of eczema.

Patients with atopic dermatitis have fundamentally different skin microbial populations compared with people with healthy skin. Bacteria associated with atopic dermatitis express genes for survival in dry conditions and for ammonia production, modulating the pH of this distinct environment and driving complex ecological interactions.