Crnic Institute study reveals immune dysregulation in Down Syndrome and potential therapeutic strategy.

The lack of easily measurable biomarkers remains a challenge in executing clinical trials for diabetic neuropathy (DN). Plasma Neurofilament light chain (NFL) concentration is a promising biomarker in immune-mediated neuropathies. Longitudinal studies evaluating NFL in DN have not been performed.

In the Dp16 mouse model, the Crnic Institute recently showed that normalization of copy number of the Ifnr cluster prevented heart malformations, but the mechanisms by which hyperactive IFN signaling may disrupt normal heart development await elucidation.

New research from the Crnic Institute suggests several Down Syndrome features may be linked to a hyperactive antiviral immune response.

The Crnic Institute reports an analysis of the impact of cell differentiation on the p53 transcriptional network using computational studies of large-scale datasets from hundreds of normal tissues and cancer cell types, and an isogenic system consisting of human iPSCs and two differentiated lineages. The results demonstrate that cell differentiation strongly modifies the p53 transcriptional program in a lineage-specific fashion through two major mechanisms: gene silencing by epigenetic regulatory complexes and constitutive transactivation by lineage-specific transcription factors. In differentiated cell types, hundreds of potential p53 target genes become refractory to p53 action either by silencing or constitutive induction. Altogether, the results reveal the vast impact of cell differentiation on the p53 transcriptional program, supporting the notion that p53 may exert its anti-tumoral effects by different mechanisms in diverse cellular contexts.

The authors use human trisomy and tetrasomy 21 cell lines and a mouse model to examine the effects of an additional copy of Pericentrin (PCNT) on cell biology, with a focus on ciliation and ciliary Hedgehog signaling. They demonstrate that modestly increased PCNT levels can attenuate ciliogenesis and may result in trisomy 21-associated phenotypes such as cerebellar growth defects. This work advances our understanding of the trafficking defects caused by increased PCNT and has important implications for our understanding of the cellular basis of trisomy 21, a major hereditary human disorder.

A new study by the Crnic Institute links growth factor deficiency to neurological impairment in Down Syndrome.

The team compared ciliated and unciliated RPE-1 cells with modified HSA21 dosage to show elevated levels of PCNT, an HSA21 resident gene up-regulated in Down syndrome, increases the number of enlarged ectopic PCNT foci peripheral to the centrosome (Figure 4M). These foci disrupt the formation of primary cilia by associating with MTs away from the centrosome, by generating MT dead ends, and by preventing the normal distribution of the centriolar satellites required for efficient ciliogenesis by acting as roadblocks along MTs. They suggest that this disrupts the movement of trafficking events from the cytoplasm to the centrosome by blocking cargo recruitment to mother centriole appendages and the cilium. Further studies will uncover the trafficking dynamics and molecules responsible for ciliary formation and signaling defects. Resetting MT distributions via depolymerization or reducing the number of enlarged PCNT foci allows for normal trafficking and for primary cilia formation. Future work will explore which components are waylaid in the pericentrosomal crowd and their dynamics during trafficking. Moreover, they envision that dysregulated MTs and trafficking could also impact cell types like pancreatic β cells that rely on massive changes to the interphase MT array for signaling and secretion

Individuals with Down Syndrome experience numerous changes in early brain development, including the proliferation and differentiation of neural progenitor cells (NPCs) and the formation and maintenance of myelin in the brain. To study how early neural precursors are affected by trisomy 21, the team differentiated two isogenic lines of induced pluripotent stem cells derived from people with Down syndrome into brain-like and spinal cord-like NPCs and promoted a transition towards oligodendroglial fate by activating the Sonic hedgehog (SHH) pathway.

Response to JAK inhibition suggests that interferon hyperactivation underlies psoriatic arthritis in Down Syndrome.

A Crnic Institute discovery may explain high risk of leukemia in children with Down Syndrome. This groundbreaking identification of precocious clonal hematopoiesis has unlocked new lines of research and discovery for our scientists.

This “Perspective” outlines why individuals with Down Syndrome should be considered an at-risk population for severe COVID-19. Specifically, the immune dysregulation caused by trisomy 21 may result in an exacerbated cytokine release syndrome relative to that observed in the typical euploid population, thus justifying additional monitoring and specialized care for this vulnerable population.

This study used mass cytometry to create a scientific ‘map’ of the immune system. Then, scientists compared the immune system maps of people with Down syndrome to those without and found that, on average, people with Down syndrome have dysregulation in every detected branch of their immune system…..

This project took a deep dive into the T cell biology of people with Down syndrome. T cells are an important cell in the immune system. There are numerous types and subtypes of T cells, each with specific functions in the immune response. For example, “cytotoxic T cells” kill dangerous cells infected by virus or from tumors…..

In this study, our scientists measured 91 metabolites using mass spectrometry and compared the levels of each metabolite in people with Down syndrome to those without. They found 29 metabolites whose levels were significantly altered in people with Down syndrome. The metabolite that was most significantly elevated was quinolinic acid…..

Individuals with Down syndrome have widespread immune dysregulation, including an increased risk of autoimmune and autoinflammatory skin conditions, like alopecia areata. The triplication of chromosome 21 causes activation of a branch of the immune system called interferon, known to contribute to autoimmunity…..

After observing that Down syndrome and various ciliopathies have many clinical overlaps, including cardiovascular, musculoskeletal, and neurological abnormalities, our scientists decided to investigate cilia function in Down syndrome. They found that trisomy 21 deregulates the expression of numerous ciliary genes…..

Red blood cells are the most common cell type in the body, and their contents mirrors systemic metabolic processes. Here our scientists provide the first mass spectrometry–based relative and absolute quantitative metabolomic description of red blood cells from people with Down syndrome. Their results show that red blood cell metabolism is widely deregulated by trisomy 21…..

People with Down syndrome have a different disease spectrum compared to the typical population, but exactly why this is remains unclear. To begin addressing this, our scientists analyzed blood samples from individuals with Down syndrome. They found dozens of proteins that are consistently deregulated by trisomy 21, including many proteins involved in immune control, the complement cascade, and growth factor signaling…..

MORC3 is a chromosome 21 encoded gene linked to inflammatory muscle diseases and cancer; however, its role in normal cell physiology and disease is poorly understood. Here, scientists evaluate the expression of MORC3 in trisomy 21 cells and human samples, and perform detailed genetic, biochemical, and structural analyses of MORC3…..