Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes.

β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells

The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions

Abstract Activated myeloid cells and astrocytes are the predominant cell types in active multiple sclerosis (MS) lesions. Both cell types can adopt diverse functional states that play critical roles in lesion formation and resolution. In order to identify phenotypic subsets of myeloid cells and astrocytes, we profiled two active MS lesions with thirteen glial activation markers using imaging mass cytometry (IMC), a method for multiplexed labeling of histological sections. In the acutely demyelinating lesion, we found multiple distinct myeloid and astrocyte phenotypes that populated separate lesion zones. In the post-demyelinating lesion, phenotypes were less distinct and more uniformly distributed. In both lesions cell-to-cell interactions were not random, but occurred between specific glial subpopulations and lymphocytes. Finally, we demonstrated that myeloid, but not astrocyte phenotypes were activated along a lesion rim-to-center gradient, and that marker expression in glial cells at the lesion rim was driven more by cell-extrinsic factors than in cells at the center. This proof-of-concept study demonstrates that highly multiplexed tissue imaging, combined with the appropriate computational tools, is a powerful approach to study heterogeneity, spatial distribution and cellular interactions in the context of MS lesions. Identifying glial phenotypes and their interactions at different lesion stages may provide novel therapeutic targets for inhibiting acute demyelination and low-grade, chronic inflammation.https://deepblue.lib.umich.edu/bitstream/2027.42/152171/1/40478_2019_Article_779.pd

Severe complications from COVID-19 in U.S. children and adolescents with sickle cell disease

BACKGROUND: Sickle Cell Disease (SCD) is the most common inherited blood disorder in the United States, causing red blood cells to take on a rigid “sickle” shape, leading to chronic hemolytic anemia and occlusion of blood vessels. SCD results in repeated vascular injury and inflammation, reduced immune functioning, and causes acute complications such as pain crises and Acute Chest Syndrome, as well as progressive damage to every organ system of the body. Given the tendency of hypoxia and other stressors to trigger sickling and SCD complications, it is likely that young individuals with SCD are at increased risk during COVID-19 illness. OBJECTIVES: To characterize complications of SARS-CoV-2 infection in children and adolescents with Sickle Cell Disease, and to determine if children with SCD have worse clinical outcomes than other Black and African American patients without SCD. METHODS: Surveillance for COVID-19 related complications was conducted across the United States from March 15, 2020 to January 31, 2021 as part of the CDC’s Overcoming COVID-19 public health registry. Hospitalized patients < 21 years of age, with positive SARS-CoV-2 test (reverse-transcriptase polymerase chain reaction ([RT-PCR]) and/or antibody test) or recent exposure without an alternate diagnosis were included in the registry. Clinicians reported data on patient demographics, baseline health status, clinical course, and outcomes in a standardized report form. A case series of patients with Sickle Cell Disease was identified in the registry, and illness and outcomes of Black and African American children and adolescents with and without SCD were analyzed in order to characterize disease course, complications, and outcomes in this population. RESULTS: Of 1,996 patients from 62 sites, 585 were Black or African American (54% male, median age 9.6 years), and 47 patients were reported with an underlying diagnosis of Sickle Cell Disease (45% male, median age 14.2 years). 43 (91%) of these patients were Black or African American, which was much higher than expected from the CDC’s estimate that 1 in 365 African American children have SCD. SCD patients came from 22 hospitals in 17 states, and were admitted between March 30 and December 8, 2020. Median hospital stay was 5 days (IQR 2.5-8), whereas for non-SCD Black patients it was 6 days (3-10). Overall, 65% (28/43) of Black SCD patients had at least one additional underlying condition, the most common of which was asthma (n=17, 40%). In comparison, 48% (262/542) of Black patients without SCD reported no underlying conditions, and 45% (n=245) reported two or more, of which obesity was the most common (n=99, 24%). The majority of patients with SCD had acute COVID-19, and only 19% (n=8) of patients with SCD were diagnosed with multisystem inflammatory syndrome in children (MIS-C), which is presumed to be a post-infectious complication, whereas 54% (n=285) of the comparison group had MIS-C. Overall, 35% (n=15) of the SCD patients were admitted to the ICU, compared to 67% (n=362) of patients without SCD. Median length of ICU stay was 4 days (2-7) in both the SCD and non-SCD groups. There were no deaths reported in patients with SCD, although one patient was transferred to a different hospital for a lung transplant, and death was rare in Black patients without SCD (n=9, 1.7%) w. Additionally, 30 patients (64%) presented with an SCD-related complication, including Acute Chest Syndrome (n=15, 32%) and vaso-occlusive pain crises (n=19, 40%). CONCLUSIONS: As a whole, Black children and adolescents with SCD did not display clinical outcomes more severe than Black children without SCD, however they were hospitalized at approximately 27 times the expected rate, suggesting that SCD may be a risk factor for hospitalization with COVID-19. COVID-19 may trigger SCD Complications, and some very severe cases show that SCD may be a risk factor for COVID-19 complications as well.2023-11-22T00:00:00

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions

Abstract Background Inflammation in chronic active lesions occurs behind a closed blood–brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. Objective To characterize the histopathological correlates of different QSM hyperintensity patterns in MS lesions. Methods MS brain slabs were imaged with MRI and QSM, and processed for histology. Immunolabeled cells were quantified in the lesion rim, center, and adjacent normal‐appearing white matter (NAWM). Iron+ myeloid cell densities at the rims were correlated with susceptibilities. Human‐induced pluripotent stem cell (iPSC)‐derived microglia were used to determine the effect of iron on the production of reactive oxygen species (ROS) and pro‐inflammatory cytokines. Results QSM hyperintensity at the lesion perimeter correlated with activated iron+ myeloid cells in the rim and NAWM. Lesions with high punctate or homogenous QSM signal contained no or minimally activated iron− myeloid cells. In vitro, iron accumulation was highest in M1‐polarized human iPSC‐derived microglia, but it did not enhance ROS or cytokine production. Conclusion A high QSM signal outlining the lesion rim but not punctate signal in the center is a biomarker for chronic inflammation in white matter lesions