Med1 controls thymic T-cell migration into lymph node through enhancer-based Foxo1-Klf2 transcription program.

The migration is the key step for thymic T cells to enter circulation and then lymph nodes (LNs), essential for future immune surveillance. Although promoter-based transcriptional regulation through Foxo1, Klf2, Ccr7, and Sell regulates T-cell migration, it remains largely unexplored whether and how enhancers are involved in this process. Here we found that the conditional deletion of Med1, a component of the mediator complex and a mediator between enhancers and RNA polymerase II, caused a reduction of both CD4+ and CD8+ T cells in LNs, as well as a decrease of CD8+ T cells in the spleen. Importantly, Med1 deletion hindered the migration of thymic αßT cells into the circulation and then into LNs, accompanied by the downregulation of KLF2, CCR7, and CD62L. Mechanistically, Med1 promotes Klf2 transcription by facilitating Foxo1 binding to the Klf2 enhancer. Furthermore, forced expression of Klf2 rescued Ccr7 and Sell expression, as well as αßT-cell migration into LNs. Collectively, our study unveils a crucial role for Med1 in regulating the enhancer-based Foxo1-Klf2 transcriptional program and the migration of αßT cells into LNs, providing valuable insights into the molecular mechanisms underlying T-cell migration.

T-cell selection in the thymus: New routes toward the identification of the self-peptide ligandome presented by thymic epithelial cells.

Within the thymus, thymic epithelial cells (TECs) provide a dedicated niche for the selection of functional T cells expressing a highly variable and self-tolerant T-cell receptor (TCR) repertoire. In this minireview, we start by summarizing recent studies that have improved our understanding on the composition of cortical TEC and medullary TEC microenvironments. Next, we focus on the molecular processes that control the function of TECs in T-cell selection. In particular, we discuss the role of cortical TECs in positive selection and the pathways employed by these cells to generate and present selecting self-peptides:MHC II complexes. Several studies have underscored the role of the ß5t-containing thymoproteasome in the production of unique MHC I-bound peptides critical for CD8 T-cell selection. Contrarily, the identity of the molecular determinants that regulate the generation of MHC II-bound self-peptides capable of positive selecting CD4 T cells is far more uncertain. We highlight recent advances that interconnect the autophagy-lysosomal pathway, the presentation of specific sets of self-peptide:MHC II complexes, and the diversification of CD4 TCR repertoire. Lastly, we discuss how these findings may open up new avenues for deciphering the identity of the MHC I and MHC II ligandome in the thymus.

Regulatory T cell-derived interleukin-15 promotes the diversity of immunological memory.

While the immunosuppressive function of regulatory T (Treg) cells has been extensively studied, their immune-supportive roles have been less well investigated. Using a lymphocytic choriomeningitis virus (LCMV) Armstrong infection mouse model, we found that Treg cell-derived interleukin (IL)-15 is required for long-term maintenance of the KLRG1+ IL-7Rα- CD62L- terminal effector memory CD8+ T (tTEM) cell subset, but dispensable for the suppressive function of Treg cells themselves. In contrast, deletion of Il15 from other sources, including myeloid cells and muscles, did not affect the composition of the memory CD8+ T cell pool. Our findings identify Treg cells as an essential IL-15 source maintaining tTEM cells and suggest that Treg cells promote the diversity of immunological memory.

Clonally expanded PD-1-expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. The disease etiology remains largely unknown; however, a key role in JIA pathogenesis is surely mediated by T cells. T-lymphocytes activity is controlled via signals, known as immune checkpoints. Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of immune checkpoints in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at the single-cell level the feature of T cells in JIA chronic inflammation, both at the transcriptome level via single-cell RNA sequencing and at the protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4+ and CD8+ T cells, those characterized by PD-1 expression were clonally expanded tissue-resident memory (Trm)-like cells and displayed the highest proinflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD-1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T cells regardless of their cytokine production profile.

FURIN regulates cytotoxic T-lymphocyte effector function and memory cell transition in mice.

The proprotein convertase subtilisin/kexins (PCSKs) regulate biological actions by cleaving immature substrate proteins. The archetype PCSK, FURIN, promotes the pathogenicity of viruses by proteolytically processing viral proteins. FURIN has also important regulatory functions in both innate and adaptive immune responses but its role in the CD8+ CTLs remains enigmatic. We used a T-cell-specific FURIN deletion in vivo to demonstrate that FURIN promotes host response against the CTL-dependent lymphocytic choriomeningitis virus by virtue of restricting viral burden and augmenting interferon gamma (IFNG) production. We also characterized Furin KO CD8+ T cells ex vivo, including after their activation with FURIN regulating cytokines IL12 or TGFB1. Furin KO CD8+ T cells show an inherently activated phenotype characterized by the upregulation of effector genes and increased frequencies of CD44+ , TNF+ , and IFNG+ cells. In the activated CTLs, FURIN regulates the productions of IL2, TNF, and GZMB and the genes associated with the TGFBR-signaling pathway. FURIN also controls the expression of Eomes, Foxo1, and Bcl6 and the levels of ITGAE and CD62L, which implies a role in the development of CTL memory. Collectively, our data suggest that the T-cell expressed FURIN is important for host responses in viral infections, CTL homeostasis/activation, and memory development.

CD3 downregulation identifies high-avidity human CD8 T cells.

CD8 T cells recognize infected and cancerous cells via their T-cell receptor (TCR), which binds peptide-MHC complexes on the target cell. The affinity of the interaction between the TCR and peptide-MHC contributes to the antigen sensitivity, or functional avidity, of the CD8 T cell. In response to peptide-MHC stimulation, the TCR-CD3 complex and CD8 co-receptor are downmodulated. We quantified CD3 and CD8 downmodulation following stimulation of human CD8 T cells with CMV, EBV, and HIV peptides spanning eight MHC restrictions, observing a strong correlation between the levels of CD3 and CD8 downmodulation and functional avidity, regardless of peptide viral origin. In TCR-transduced T cells targeting a tumor-associated antigen, changes in TCR-peptide affinity were sufficient to modify CD3 and CD8 downmodulation. Correlation analysis and generalized linear modeling indicated that CD3 downmodulation was the stronger correlate of avidity. CD3 downmodulation, simply measured using flow cytometry, can be used to identify high-avidity CD8 T cells in a clinical context.

Dysregulated lipid metabolism networks modulate T-cell function in people with relapsing-remitting multiple sclerosis.

Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing-remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4 + T cells are pathogenic in RRMS, and defective T-cell function could be mediated in part by liver X receptors (LXRs)-nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4 + T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T-cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4 + T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T-cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalized membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4 + T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.

The interaction effect between BMI, diabetes and age at diabetes onset on the risk of thyroid cancer: A population-based cohort study in Shanghai, China.

AIM: To determine the association of the presence of diabetes and, among persons with diabetes, the age at type 2 diabetes mellitus (T2DM) onset, BMI and the interactive effect with the subsequent thyroid cancer risk. MATERIALS AND METHODS: We conducted a population register-based longitudinal cohort study in Shanghai, including 428 568 persons with new-onset T2DM matched with the general population. The risk of thyroid cancer among subgroups was calculated based on standardized incidence ratio (SIR), hazard ratio (HR) and Cox proportional hazards models. RESULTS: In total, 1142 thyroid cancer cases were identified during 8 years of follow-up, with an incidence rate of 59.01/100 000 person-years and a higher risk (SIR = 1.21) compared with the general population. The earlier age at T2DM onset and higher BMI were associated with an increasing risk of thyroid cancer independently (onset age <50, SIR: 1.46; BMI ≥30.0 kg/m2, SIR: 1.93), with the highest risk in patients with both BMI ≥30.0 kg/m2 and onset age <50 years (SIR = 3.91, HR = 3.04). Among patients with T2DM onset age <60 years, SIR increased with higher BMI, while there were no trends when onset age ≥60 years. Among patients with BMI ≥25.0 kg/m2, SIR increased with an earlier onset age, whereas no trends were shown in the BMI <24.9 kg/m2 groups. Obese (BMI ≥30.0 kg/m2) patients had a significantly higher HR of thyroid cancer only when T2DM onset age <60 years. CONCLUSIONS: Both earlier age of T2DM onset (<50 years) and higher BMI (≥30 kg/m2) contributed to the higher risk of thyroid cancer. Patients with young-onset T2DM and obesity are considered more vulnerable to thyroid cancer development.

The CD177 c.1291A Allele Leads to a Loss of Membrane Expression and Mimics a CD177-Null Phenotype.

CD177 is a glycosyl phosphatidyl inositol (GPI)-linked, neutrophil-specific glycoprotein that in 3-5% of normal individuals is absent from all neutrophils. The molecular mechanism behind the absence of CD177 has not been unravelled completely. Here, we analyse the impact of the recently described CD177 c.1291G>A variant on CD177 expression. Recombinant CD177 c.1291G>A was expressed in HEK293F cells and its expression on the cell surface, inside the cell, and in the culture supernatant was investigated. The CD177 c.1291G>A protein was characterised serologically and its interaction with proteinase 3 (PR3) was demonstrated by confocal laser scanning microscopy. Our experiments show that CD177 c.1291G>A does not interfere with CD177 protein biosynthesis but affects the membrane expression of CD177, leading to very low copy numbers of the protein on the cellular surface. The mutation does not interfere with the ability of the protein to bind PR3 or human polyclonal antibodies against wild-type CD177. Carriers of the c.1291G>A allele are supposed to be phenotyped as CD177-negative, but the protein is present in soluble form. The presence of CD177 c.1291A leads to the production of an unstable CD177 protein and an apparent "CD177-null" phenotype.

Direct Population of Triplet States for Efficient Organic Afterglow through the Intra/Intermolecular Heavy-Atom Effect.

Organic afterglow is a fascinating phenomenon with exceptional applications. However, it encounters challenges such as low intensity and efficiency, and typically requires UV-light excitation and facile intersystem crossing (ISC) due to its spin-forbidden nature. Here, we develop a novel strategy that bypasses the conventional ISC pathway by promoting singlet-triplet transition through the synergistic effects of the intra/intermolecular heavy-atom effect in aromatic crystals, enabling the direct population of triplet excited states from the ground state. The resulting materials exhibit a bright organic afterglow with a remarkably enhanced quantum efficiency of up to 5.81%, and a significantly increased organic afterglow lifetime of up to 157 microseconds under visible light. Moreover, given the high-efficiency visible-light excitable organic afterglow emission, the potential application is demonstrated in lifetime-resolved, color-encoded, and excitation wavelength-dependent pattern encryption. This work demonstrates the importance of the direct population method in enhancing the organic afterglow performance and red-shifting the excitation wavelength, and provides crucial insights for advancing organic optoelectronic technologies that involve triplet states.

Peripheral T-cell lymphoma with a T follicular-helper phenotype: A different entity? Results of the Spanish Real-T study.

Nodal peripheral T-cell lymphoma (PTCL) with a T follicular helper phenotype (PTCL-TFH) is a new type of PTCL. We aimed to define its clinical characteristics and prognosis compared to PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). This retrospective observational study included 175 patients diagnosed with PTCL between 2008 and 2013 in 13 Spanish sites. Patient diagnosis was centrally reviewed, and patients were reclassified according to the World Health Organization (WHO) 2016 criteria: 21 patients as PTCL-NOS, 55 as AITL and 23 as PTCL-TFH. Median follow-up was 56.07 months (95% CI 38.7-73.4). Progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with PTCL-TFH than in those with PTCL-NOS and AITL (PFS, 24.6 months vs. 4.6 and 7.8 months, respectively, p = 0.002; OS, 52.6 months vs. 10.0 and 19.3 months, respectively, p < 0.001). Histological diagnosis maintained an independent influence on both PFS (hazard ratio [HR] 4.1 vs. PTCL-NOS, p = 0.008; HR 2.6 vs. AITL, p = 0.047) and OS (HR 5.7 vs. PTCL-NOS, p = 0.004; HR 2.6 vs. AITL, p = 0.096), regardless of the International Prognostic Index. These results suggest that PTCL-TFH could have more favourable features and prognosis than the other PTCL subtypes, although larger series are needed to corroborate these findings.

Role of interferons (IFNs) in the differentiation of T peripheral helper (Tph) cells.

Interleukin (IL)-21-producing T peripheral helper (Tph) cells are thought to contribute to extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. In this study, we investigated the relationship between Tph cells and interferons (IFNs) in several autoimmune diseases because our previous study demonstrated that type I IFNs promote the differentiation of IL-21-producing Tph-like cells. The frequency of Tph cells in the blood as well as serum IFN-α2a and IFN-λ1 were markedly elevated in patients with active systemic lupus erythematosus (SLE) compared to other autoimmune diseases or healthy controls. Notably, the frequency of Tph cells was positively correlated with the SLE disease activity index, serum IFN-α and serum IFN-λ1 in SLE patients. Additionally, we found that type III IFNs (IFN-λ1, IFN-λ2 and IFN-λ3) promote the differentiation of programmed cell death-1 (PD-1)+ CXCR5 -CD4+ T cells and enhance the secretion of IL-21, IFN-γ and CXCL13. IFN-λ1, like IFN-α, up-regulated the mRNA expression of IL21, IFNG, CXCL13, CD244, SLAMF7, GZMB, PRF1, CCR5 and PRDM1, whereas it down-regulated that of CXCR5 and BCL6, reflecting a Tph-related gene expression pattern. IFN-α in combination with IFN-λ1, IFN-λ2 or IFN-λ3 significantly increased the differentiation of PD-1+CXCR5- Tph-like cells and the secretion of Tph-related cytokines as compared with each IFN alone, suggesting a cooperative interaction. From these findings, it is highly probable that type III IFNs in addition to type I IFNs play a key role in the differentiation of Tph cells and that high levels of IFN-α and IFN-λ1 trigger the differentiation and expansion of Tph cells in SLE.

A variety of 'exhausted' T cells in the tumor microenvironment.

In T-cell biology, 'exhaustion' was initially described as a hyporesponsive state in CD8+ T cells during chronic infections. Recently, exhaustion has been recognized as a T-cell dysfunctional state in the tumor microenvironment (TME). The term 'exhaustion' is used mainly to refer to effector T cells with a reduced capacity to secrete cytokines and an increased expression of inhibitory receptors. The up-regulation of exhaustion-related inhibitory receptors, including programmed cell death protein 1 (PD-1), in such T cells has been associated with the development of tumors, prompting the development of immune checkpoint inhibitors. In addition to CD8+ T cells, CD4+ T cells, including the regulatory T (Treg) cell subset, perform a wide variety of functions within the adaptive immune system. Up-regulation of the same inhibitory receptors that are associated with CD8+ T-cell exhaustion has also been identified in CD4+ T cells in chronic infections and cancers, suggesting a similar CD4+ T-cell exhaustion phenotype. For instance, high expression of PD-1 has been observed in Treg cells in the TME, and such Treg cells can play an important role in the resistance to PD-1 blockade therapies. Furthermore, recent progress in single-cell RNA sequencing has shown that CD4+ T cells with cytotoxic activity are also vulnerable to exhaustion. In this review, we will discuss novel insights into various exhausted T-cell subsets, which could reveal novel therapeutic targets and strategies to induce a robust anti-tumor immune response.

Linking lesions in sensorimotor cortex to contralateral hand function in multiple sclerosis: a 7†T MRI study.

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectional area and higher infratentorial lesion volume were associated with reduced contralateral motor hand function. Cortical lesions in the primary sensorimotor hand area, spinal cord cross-sectional area and normalized brain volume were also associated with smaller maximal motor-evoked potential amplitude and longer corticomotor conduction times. The effect of cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates. Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function, intracortical lesions on reduced motor-evoked potential amplitude and leucocortical lesions on delayed corticomotor conduction. Together, this comprehensive multilevel assessment of sensorimotor brain damage shows that the presence of a cortical lesion in the primary sensorimotor hand area is associated with impaired corticomotor function of the hand, after accounting for damage at the subcortical level. The results also provide preliminary evidence that cortical lesion types may affect the various facets of corticomotor function differentially.

Identification of Two Novel Pathogenic Variants of the ATM Gene in the Iranian-Azeri Turkish Ethnic Group by Applying Whole Exome Sequencing.

Background: The ATM gene encodes a multifunctional kinase involved in important cellular functions, such as checkpoint signaling and apoptosis, in response to DNA damage. Bi-allelic pathogenic variants in this gene cause Ataxia Telangiectasia (AT), while carriers of ATM pathogenic variants are at increased risk of cancer depending on the pathogenicity of the variant they carry. Identifying pathogenic variants can aid in the management of the disease in carriers. Methods: Whole-exome sequencing (WES) was performed on three unrelated patients from the Iranian-Azeri Turkish ethnic group referred to a genetic center for analysis. WES was also conducted on 400 individuals from the same ethnic group to determine the frequencies of all ATM variants. Blood samples were collected from the patients and their family members for DNA extraction, and PCR-Sanger sequencing was performed to confirm the WES results. Results: The first proband with AT disease had two novel compound heterozygote variants (c.2639-2A>T, c.8708delC) in the ATM gene revealed by WES analysis, which was potentially/likely pathogenic. The second proband with bi-lateral breast cancer had a homozygous pathogenic variant (c.6067G>A) in the ATM gene identified by WES analysis. The third case with a family history of cancer had a heterozygous synonymous pathogenic variant (c.7788G>A) in the ATM gene found by WES analysis. Sanger sequencing confirmed the WES results, and bioinformatics analysis of the mutated ATM RNA and protein structure added evidence for the potential pathogenicity of the novel variants. WES analysis of the cohort revealed 38 different variants, including a variant (rs1800057, ATM:c.3161C>G, p.P1054R) associated with prostate cancer that had a higher frequency in our cohort. Conclusion: Genetic analysis of three unrelated families with ATM-related disorders discovered two novel pathogenic variants. A homozygous missense pathogenic variant was identified in a woman with bi-lateral breast cancer, and a synonymous but pathogenic variant was found in a family with a history of different cancers.

Three-dimensional vessel wall imaging with 1.5-T MRI to visualize invisible occluded cerebral artery.

BACKGROUND: Endovascular thrombectomy (EVT) is performed for acute ischemic stroke (AIS) caused by large vessel occlusion; therefore, preoperative visualization of the occluded invisible vessel course reduces complications and ensures success. Three-dimensional (3D) proton density-weighted (PDW) vessel wall imaging (VWI) using variable refocusing flip angle pulse-turbo spin-echo sequences (VRFA-TSE) with 3.0-T magnetic resonance imaging (MRI) can provide this information. PURPOSE: To assess the effectiveness of 3D PDW-VWI using 1.5-T MRI without VRFA function. MATERIAL AND METHODS: Five consecutive patients with AIS caused by large vessel occlusion underwent EVT in our institute. VWI with 1.5-T MRI using 3D PDW-fast spin echo (FSE) technique was added to conventional brain imaging. RESULTS: PDW-FSE was successfully performed in all cases. 3D PDW-FSE was useful to visualize both the anterior and posterior circulations by clearly revealing invisible vessels but could not demonstrate the length and size of the clot in all five cases. CONCLUSION: 3D PDW-FSE with 1.5-T MRI without VRFA could clearly depict the course of the invisible occluded artery and might support favorable outcomes after EVT in patients with AIS.

Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy.

INTRODUCTION: To examine the extent to which positron emission tomography (PET)-, cerebrospinal fluid (CSF)-, and plasma-related amyloid-ß/tau/neurodegeneration (A/T/N) biomarkers are associated with Alzheimer's disease (AD) neuropathology at autopsy. METHODS: A total of 100 participants who respectively underwent antemortem biomarker measurements and postmortem neuropathology were included in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We examined the associations of PET-, CSF-, and plasma-related A/T/N biomarkers in combinations or alone with AD neuropathological changes (ADNC). RESULTS: PET- and CSF-related A/T/N biomarkers in combination showed high concordance with the ADNC stage and alone showed high accuracy in discriminating autopsy-confirmed AD. However, the plasma-related A/T/N biomarkers alone showed better discriminative performance only when combined with apolipoprotein E (APO)E ε4 genotype. DISCUSSION: This study supports that PET- and CSF-related A/T/N profiles can be used to predict accurately the stages of AD neuropathology. For diagnostic settings, PET-, CSF-, and plasma-related A/T/N biomarkers are all useful diagnostic tools to detect the presence of AD neuropathology. HIGHLIGHTS: PET- and CSF-related A/T/N biomarkers in combination can accurately predict the specific stages of AD neuropathology. PET- and CSF-related A/T/N biomarkers alone may serve as a precise diagnostic tool for detecting AD neuropathology at autopsy. Plasma-related A/T/N biomarkers may need combined risk factors when used as a diagnostic tool. Aß PET and CSF p-tau181/Aß42 were most consistent with Aß pathology, while tau PET and CSF p-tau181/Aß42 were most consistent with tau pathology.

Dysfunction of cerebellar microglia in Ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disease caused by mutations in the ATM gene and characterized by cerebellar atrophy, progressive ataxia, immunodeficiency, male and female sterility, radiosensitivity, cancer predisposition, growth retardation, insulin-resistant diabetes, and premature aging. ATM phosphorylates more than 1500 target proteins, which are involved in cell cycle control, DNA repair, apoptosis, modulation of chromatin structure, and other cytoplasmic as well as mitochondrial processes. In our quest to better understand the mechanisms by which ATM deficiency causes cerebellar degeneration, we hypothesized that specific vulnerabilities of cerebellar microglia underlie the etiology of A-T. Our hypothesis is based on the recent finding that dysfunction of glial cells affect a variety of process leading to impaired neuronal functionality (Song et al., 2019). Whereas astrocytes and neurons descend from the neural tube, microglia originate from the hematopoietic system, invade the brain at early embryonic stage, and become the innate immune cells of the central nervous system and important participants in development of synaptic plasticity. Here we demonstrate that microglia derived from Atm-/- mouse cerebellum display accelerated cell migration and are severely impaired in phagocytosis, secretion of neurotrophic factors, and mitochondrial activity, suggestive of apoptotic processes. Interestingly, no microglial impairment was detected in Atm-deficient cerebral cortex, and Atm deficiency had less impact on astroglia than microglia. Collectively, our findings validate the roles of glial cells in cerebellar attrition in A-T.

Genetic Risk Variants for Class Switching Recombination Defects in Ataxia-Telangiectasia Patients.

BACKGROUND: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. A-T patients manifest considerable variability in clinical and immunological features, suggesting the presence of genetic modifying factors. A striking heterogeneity has been observed in class switching recombination (CSR) in A-T patients which cannot be explained by the severity of ATM mutations. METHODS: To investigate the cause of variable CSR in A-T patients, we applied whole-exome sequencing (WES) in 20 A-T patients consisting of 10 cases with CSR defect (CSR-D) and 10 controls with normal CSR (CSR-N). Comparative analyses on modifier variants found in the exomes of these two groups of patients were performed. RESULTS: For the first time, we identified some variants in the exomes of the CSR-D group that were significantly associated with antigen processing and presentation pathway. Moreover, in this group of patients, the variants in four genes involved in DNA double-strand breaks (DSB) repair signaling, in particular, XRCC3 were observed, suggesting an association with CSR defect. CONCLUSION: Additional impact of certain variants, along with ATM mutations, may explain the heterogeneity in CSR defect phenotype among A-T patients. It can be concluded that genetic modulators play an important role in the course of A-T disease and its clinical severity.

Genetic variations in ATM and H2AX loci contribute to risk of hematological abnormalities in individuals exposed to BTEX chemicals.

BACKGROUND: Loci controlling DNA double-strand breaks (DSBs) repair play an important role in defending against the harmful health effects of benzene, toluene, ethylbenzene, and xylene (BTEX), but their gene variants may alter their repair capacity. The aim of the current study was to determine the relationship of functional polymorphisms ATM-rs228589 A>T, WRN-rs1800392 G>T and H2AX-rs7759 A>G in DBS repair loci with the abnormal hematological indices in workers who exposed to BTEXs. METHODS: We included 141 cases with one or more abnormal hematological parameters, who had been occupationally exposed to BTEX chemicals and 152 controls with a similar exposure condition but without any abnormal hematological parameters. Atmospheric concentrations of BTEXs were measured and whole blood samples were taken from the participants to determine hematologic parameters and SNP genotyping. RESULTS: Results showed that T allele of ATM-rs228589 and G allele of H2AX-rs7759 had a higher frequency in cases than controls (p = 0.012 and p = 0.001, respectively). Also, AT and TT genotypes of ATM-rs228589 and AG and GG genotypes of H2AX-rs7759 were higher in cases compared to controls. The AT and TT genotypes of ATM-rs228589 have significant associations with a risk of hematological abnormalities in the codominant (AT vs. AA, p = 0.018), dominant (AT + TT vs. AA, p = 0.010) and overdominant (AT vs. AA + TT, p = 0.037) models. The GG and AG genotypes of H2AX-rs7759 were in relation with increased risk of abnormal hematological indices under codominant (GA vs. AA, p = 0.009 & GG vs. AA, p = 0.005), dominant (AG + GG vs. AA, p = 0.001), and recessive (GG vs. AA + AG, p = 0.025) models. CONCLUSIONS: These observations may help to understand the mechanisms of BTEX hematotoxicity and identify useful biomarkers of risk assessment for workers exposed to BTEX.