NIAMS Scientific Advances

Homeobox domain transcription factors are proteins that have a region with a specific structure that binds a specific DNA sequence within a gene. These transcriptions factors play a known role in development. More specifically, the POU family of homeobox domain transcription factors play important roles in the development of multiple tissue types including sensory tissues. Mutations in the POU4F3 gene are known to cause a dominant form of hereditary hearing loss in humans. Researchers used whole transcriptome profiling to discover that POU4F3 and POU4F1 are selectively expressed in Merkel cells (MCs), which are specialized touch sensors, from both neonatal and adult mouse skin. Using genetically engineered knockout mice, they determined that POU4F3 is critical for MC development, while POU4F1 is expressed in MCs but not necessary for their development.

The metabolic enzyme PKM2 accumulates in the nucleus in various cancer cells. In this study, researchers found that PKM2 binds to structures called G-quadruplexes (rG4) forming on precursor mRNAs. The balance of folded and unfolded rG4s controls the transcriptional output of rG4-containing RNAs (rG4ome). The rG4ome encodes components related to epithelial-to-mesenchymal transition (e.g., a process that allows tumors to grow and spread) and higher rG4 levels, which are associated with poorer patient survival outcomes in different cancer types. Further, removing PKM2 from the nucleus reduces tumor growth and metastasis.

This study examines how a specific metabolic pathway, called the Aconitate Decarboxylase 1/Itaconate pathway, affects the immune system in people with systemic lupus erythematosus (SLE). The researchers found that this pathway is involved in the immune system dysfunction in animal models of lupus and is also linked to markers that indicate heart disease risk and lupus disease activity levels in people with SLE.

Neutrophil depletion and deregulation are directly linked to development of diabetic foot ulcers (DFU). Scientists used a streptozotocin-treated hyperglycemic (high blood glucose/sugar) mouse model to study how overexpression of SOX2 in the skin affects wound healing. The researchers found that the combination of SOX2 upregulation and hyperglycemia in skin cells called keratinocytes triggers a pro-healing signature and increased neutrophil migration. The results highlight SOX2-mediated gene expression as a potential means of addressing neutrophil depletion in DFU.

Genes are expressed through tightly controlled processes. The first step of gene expression is transcription, a cellular process by which a gene's DNA sequence is copied into RNA. Transcriptional bursting is a fundamental property of genes that allows large amounts of RNA to be produced in a short period of time. This process has been observed in diverse organisms, from bacteria to mammals. In this study, the researchers applied mathematical modeling to single-cell RNA sequencing data—information on the transcriptional activity of individual cells—to infer transcriptional bursting dynamics under multiple conditions. The researchers found that Mediator complex subunit 26 (MED26) had the most profound impact on the entire gene regulatory network, acting downstream of chromatin spatial architecture without affecting TATA box-binding protein recruitment, a key step that helps recruits transcription machinery to the gene. These findings suggest that later steps in the initiation of transcriptional bursts are primary nodes for integrating gene networks in single cells.

Familial hemophagocytic lymphohistiocytosis (HLH) is a life-threatening cytokine storm syndrome caused by recessive, loss of function variants of genes in the pathway that controls the processing of cytolytic granule processing pathway genes. Heterozygous variants in these genes contribute to a secondary form of HLH (macrophage activation syndrome, MAS) that frequently develops in children with systemic juvenile idiopathic arthritis (sJIA). To evaluate the relationship between HLH gene variation and sJIA without MAS, HLH genes were sequenced and compared between 524 patients with sJIA and 2,924 control patients.

In this report, researchers described a deep neural generative framework, the dynamic batching adversarial autoencoder (DB-AAE), which excels at denoising scRNA-seq datasets. DB-AAE directly captures optimal features from input data and enhances feature preservation, including cell type-specific gene expression patterns.

A team of researchers in the Dermatology Consultation Service analyzed tissue samples from 60 of 112 study participants who were referred to the NIH Clinical Center in Bethesda, MD, for suspected VEXAS syndrome. The most reported findings included inflammation of the small blood vessels of the skin, known as leukocystoclastic vasculitis, fever and a painful rash known as neutrophilic dermatosis, and inflammation of the skin around the blood vessels, known as perivascular dermatitis.

Spondyloarthritis (SpA) is an inflammatory disease that affects the gastrointestinal tract, skeleton, and eyes. HLA-B27 is a major risk gene for SpA, but the underlying mechanisms are unclear. One hypothesis is that HLA-B27 promotes SpA through misfolding-induced endoplasmic reticulum (ER) stress that in turn upregulates IL-23 expression via the transcription factor CHOP. In this study, the researchers knocked out CHOP expression in an animal model of HLA-B27-associated SpA. Despite reduced IL-23 production, gut inflammation did not improve, indicating that the gut disease did not occur as a result of ER stress-induced IL-23 production.

Scientists at NIAMS and the National Cancer Institute have identified a new clue to the diagnosis of BAP1 TPDS through a study at the NIH Clinical Center in Bethesda, Maryland. Individuals with known mutations in the BAP1gene were enrolled in the study and evaluated for nail abnormalities.

Clonal hematopoiesis is a term to describe a process where healthy individuals acquire genetic mutations in their blood cells later in life. Cells that carry these mutations promote inflammation, which increases risk of death due to cardiovascular disease.

Merkel cell carcinoma is an aggressive skin cancer that occurs when nerve-like cells that produce hormones (called neuroendocrine cells) grow out of control. The disease is rare in people under age 50. Genetic screenings of people with early onset Merkel cell carcinoma show that 19 percent had well-described variants in genes associated with an increased likelihood of cancer development.

Testing for MAA may be clinically useful in children with myositis. Given the association between MAA and severe disease, children with myositis who have one or more MAA types may need to receive more aggressive treatment than those without these autoantibodies.

Neutrophils are essential first responders in the immune system, playing a significant role in various diseases. This method will be helpful in neutrophil-targeted drug development by offering real-time, high-throughput screening.

This case report is the first description of topical ruxolitinib—a JAK inhibitor—improving skin rash in two patients with JDM or DM who did not improve with other treatments.

Findings from this study provide additional knowledge about the different species and subspecies of staphylococci that live on the human skin and how these different types of bacteria have adapted to varied skin areas.

New research from NIAMS and NIAID indicates that preventive medicine and musculoskeletal interventions have important economic benefits. Using decades of data on health and income, researchers showed that faster walking speeds and mobility are strongly associated with higher income.

RNA binding proteins (RBPs) are a large and diverse class of proteins. They are encoded by more than 1,500 genes in humans. RBPs control every aspect of RNA metabolism and posttranscriptionally regulate gene expression. However, identifying RBPs is challenging because many of them lack clearly identifiable features and are involved in processes not necessarily thought to be RNA related, such as metabolism (all the chemical changes that occur in a cell to break down a molecule).

During the intestinal inflammatory response STAT4 regulates transcriptional activity in ILC1 and NK cells.

The study reports genotypic and phenotypic associations with functional variation in PLCG2.

The study characterizes the colonization of eukaryotic RNA viruses in RAG-deficient patient population and also demonstrates the importance of these patients as potential reservoirs of viral persistence and evolution.

Neutrophil Extracellular Traps (NETs) cause bone destruction in periodontitis lesions by triggering the IL-17/Th17 response.

Modifying the activity of VEGF (a known stimulator of osteoblastogenesis) could be a promising treatment pathway for rare bone diseases.

This study suggests that bone health is improving in later generations due to reduced smoking rates and increased activity levels.

Early diagnosis and interventions have improved the quality of life for STAT3DN patients.

The modified clinical algorithm allows for faster diagnosis and treatment of children with APECED syndrome.

The study reports the use of urine as a biomarker source for JDM.

According to the study, new therapeutic interventions for GCA could be possible by targeting key drivers of mitochondrial extrusion and/or clearance.

A physician should be aware of the ophthalmological effects of autoinflammatory diseases, particularly this new entity called the VEXAS syndrome.

According to the report, mutations of UBA1 in hematopoietic stem cells appear to cause abnormal inflammation and myeloid predominance in VEXAS syndrome.

Recombinant amphiregulin could be a potential therapeutic agent for cutaneous I/R injury.

The study identifies several novel SLE susceptibility genes in an ancestrally diverse childhood-onset lupus cohort.

CD271 could be a promising pharmaceutical target for the treatment of cutaneous squamous cell carcinoma.

Hypodermal macrophages play an important role in infection outcomes in the skin.  

An epigenomic map of epidermal differentiation during skin development.

The study identified 3 new types of myositis in cancer patients receiving immune checkpoint inhibitors (ICIs) treatment.

Dermatomyositis (DM) Patients with anti-Mi2 autoantibodies against a transcriptional repressor protein (CHD4/NuRD complex) showed severe muscle disease than other DM patients.

Disparities in skin cancer presentation between races and ethnicities.

Zilucoplan treatment did not improve immune-mediated necrotizing myopathy (IMNM) symptoms.

Research has found that SARS-CoV-2 spike protein binds to platelet integrin receptors to trigger platelet deformation.

Research has indicated that Neutrophil Extracellular Traps (NETs) play a direct role in the production of autoantigens and the erosion of bone in rheumatoid arthritis.

Spondyloarthritis is a family of inflammatory diseases that affects the spine, pelvic joints, shoulders, and knees. This study demonstrated that altering the expression of ERAP1 protein may protect against arthritis.

Researchers found that fostamatinib reduced the proinflammatory response in severe COVID-19 cases in this study.

IL-2-STAT5 pathway plays an important role in CD4+ T cell metabolism and growth. High STAT5 activity in T cells might be linked to lymphoid malignancies.

The study described how the regulation of residual UBA1b translation is fundamental to VEXAS syndrome pathogenesis and contributes to disease prognosis.

Premenopausal SLE females receiving CYC may benefit from GnRHa treatment to increase their pregnancy chances.

An artificial intelligence (AI) algorithm can count mpox skin lesions in patient photographs with close correlation to manual counts.

Presence of co-existing anti-Sp4 autoantibodies identifies a subgroup of anti-TIF1γ-positive DM patients with lower cancer risk.

NETs were detected in many organs of adult patients who died from COVID-19 complications. Compared with other SARS-CoV-2 strains, the Omicron variant was associated with decreased NET levels.

Molecular and epigenetic mechanisms that lead to the formation of muscle and neuronal cells from embryonic stem cells (ESCs).

Anti-FHL1 autoantibodies in juvenile myositis is associated with V-sign rash on their chest and co-existing anti-Ro52 autoantibodies but not with adverse outcomes.

PGZ induces significant improvements in vascular stiffness and cardiometabolic parameters in SLE. The role of PGZ as a modulator of cardiovascular disease risk in SLE should be further explored.

The FOXM1 pathway is a novel regulator of NET formation during diabetic wound healing and can be used as a therapeutic target to promote healing in DFUs. Expression of TREM1 in neutrophils is less in DFUs.

This study provides some of the first and only available data about the direct relationship between FDG-PET activity and angiographic change in large-vessel vasculitis.

A derivative of itaconic acid, 4-octyl itaconate, inhibits immune dysregulation and organ damage in lupus mice.

The study provides a new view of human neutrophil heterogeneity, with potential implications for neutrophil characterization in health and disease.

The Society for Immunotherapy of Cancer (SITC) published the first clinical practice guideline (CPG) focused on immunotherapy for nonmelanoma skin cancer (NMSC).

The protocol describes in detail the mechanical and enzymatic dissociation of mononucleated cells from whole limb muscles and injured tibialis anterior (TA) muscles to isolate FAPs and MuSCs. Additionally, it describes an optimized method for culturing quiescent and activated FAPs and MuSCs.

Treatment with statins might lead to an increase in statin-associated autoimmune diseases, notably myositis or other related myopathies, in the American Indian population.

Nicotinamide riboside (NR) can be used as a potential adjunct to lupus treatment.

GMR biosensors can serve as a real-time diagnostic tool for clinical management of influenza infection.

Systemic use of antibiotics has long lasting effects on skin microbial communities, leading to the development and persistence of antibiotic resistance.

New medications help many people with inflammatory conditions and may ease severe COVID-19, but they carry risks.

There are striking differences between men and women in their ability to respond to certain infections, predisposition to and prognosis in certain cancers, and risk for developing an autoimmune disease. However, the underlying mechanisms that drive the differences between the male and female immune system remain insufficiently characterized, especially for innate immune system cells like neutrophils.