Neurofilament light (NfL) protein is a marker of neuro-axonal damage and can be measured not only in cerebrospinal fluid but also in serum, which allows for repeated assessments. There is still ...limited knowledge regarding the association of serum NfL (sNfL) with age and subclinical morphologic brain changes and their dynamics in the normal population. We measured sNfL by a single molecule array (Simoa) assay in 335 individuals participating in a population-based cohort study and after a mean follow-up time of 5.9 years (n = 103). Detailed clinical examination, cognitive testing and 3T brain MRI were performed to assess subclinical brain damage. We show that rising and more variable sNfL in individuals >60 years indicate an acceleration of neuronal injury at higher age, which may be driven by subclinical comorbid pathologies. This is supported by a close association of sNfL with brain volume changes in a cross-sectional and especially longitudinal manner.
The consequences of PI3Kδ deficiency have been extensively characterized in mice, providing much of our knowledge on the biological role of PI3Kδ, such as its involvement in early development of B ...cells and regulation of adaptive immune responses.2 Heterozygous gain-of-function mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ gene (PIK3CD; the gene encoding p110δ) cause a primary immunodeficiency disorder characterized by both immunodeficiency and immune dysregulation (activated PI3Kδ syndrome). At the age of 8 years, he had recurrent diarrhea caused by inflammatory colitis, which was diagnosed as Crohn disease and successfully treated with mesalazine for approximately 2 years. Since the age of 12 years, he had recurrent respiratory tract infections, including 2 cases of severe pneumonia that required hospitalization and administration of intravenous antibiotics. Sorted cells were cultured in RPMI 1640 medium/10% FCS for 30 minutes in the presence of IC87114 (Merck, Whitehouse Station, NJ) or an equal amount of dimethyl sulfoxide and were subsequently stimulated with anti-CD3 antibody for 10 minutes, as described previously.E2 Cells were then permeabilized and prepared for staining with the Transcription Factor Phospho Buffer Set (BD Biosciences), according to the manufacturer's protocol; stained with an Alexa Fluor 647–conjugated mAb against phospho-AKT (Ser473; Cell Signaling, Danvers, Mass); and analyzed with a FACSCalibur flow cytometer (Becton Dickinson). Deceased patient Living patient Year of birth 1994 1995 Sex Male Male Infections Recurrent sinopulmonary infections since infancy, including 1 case of pneumonia accompanied by Streptococcus pneumoniae sepsis, chronic diarrhea (diagnosed as postenteritis syndrome) Osteomyelitis at age of 8 months, recurrent sinopulmonary infections since the 12th year of life, including 2 cases of severe pneumonia Other clinical manifestations Chronic diarrhea (diagnosed as postenteritis syndrome) Diagnosis of Crohn disease at age 12 years, diagnosis of psoriasis at age 18 years Serum immunoglobulin concentration IgG (g/L) 2.83 (5-13)∗ 2.7 (7-16) IgA (g/L) 0.16 (0.4-1.8) 0.3 (0.7-4) IgM (g/L) <0.15 (0.4-1.8) 0.53 (0.4-2.3) Complement Total complement activity CH50 (%) >165 (90-150) >165 (90-150) C3c (g/L) 1.55 (0.9-1.8) 1.22 (0.9-1.8) C4 (g/L) 0.38 (0.1-0.4) 0.26 (0.1-0.4) Lymphocyte subset analysis Lymphocyte count (cells/μL) 4,560 (1,700-6,900) 2,204 (1,000-2,800) CD3+ (relative %) 72% (43% to 76%) 80% (55% to 83%) CD3+CD4+ (relative %) 37% (23% to 48%) 37.3% (28% to 57%) CD3+CD8+ (relative %) 30% (14% to 33%) 40.1% (10% to 39%) CD3−CD16+CD56+ (relative %) 10.2% (4% to 23%) 8.4% (7% to 31%) CD19+ (relative %) 0.6% (14% to 44%) 1.3% (6% to 19%) Lymphocyte proliferation assay PHA (cells/μL) 45,567 (34,797) 34,298 (32,100) Concanavalin A (cells/μL) 22,032 (21,560) 8,208 (6,234) Pokeweed mitogen (cells/μL) NM 9,644 (11,001) IL-2 (cells/μL) 5,743 (4,734) 3,340 (4,011) Anti-CD3 antibody (cells/μL) 21,440 (20,674) 22,012 (25,325) Granulocyte phenotyping CD16 (%) NM 93 (96) CD32 (%) NM 100 (100) CD64 (%) NM 13 (1) CD18 (%) NM 100 (100) CD11b (%) NM 100 (100) CD15 (%) NM 94 (99) Granulocyte function tests Phagocytosis of Escherichia coli (%) 96 (100) 98 (99) Oxidative burst induction N-formyl-methionyl-leucyl-phenylalanine (%) NM 35 (8) E coli (%) 94 (96) 98 (100) Phorbol 12-myristate 13-acetate (%) 100 (99) 100 (100) NK cell activity Natural cytotoxicity (1:30) 5 (27) 4 (30) ADCC (1:30) 9 (42) 11 (58) Table I Characteristics of patients with PI3Kδ deficiency Lymphocytes 2204 cells/μL (38% of leukocytes) CD19+ B cells 1.3% CD27−IgM+IgD+ naive B cells 1% CD27+IgM+IgD+ memory B cells 0.1% CD27+IgM−IgD− switched memory B cells 0% CD38++IgM++ transitional B cells 0.1% CD38+++IgM−/+ plasma cells 0.1% CD21lowCD38low B cells 0% CD16+CD56+CD3− NK cells 8.4% CD3+ T cells 80% CD3+CD4+ helper cells 37.3 % CD3+CD8+ cytotoxic T cells 40.1% CD3+TCR2+ α/β T cells 65.8% CD4/CD8 double-negative TCR2+ cells 0.6% CD4+CD45RO+ CD4 memory cells 14.7% Circulating CXCR5+CD4+ T cells 1.8% CD4+CD25+CD127low regulatory T cells 3.1% CD4+CD45RA+ naive CD4 T cells 20% CD4+CD45RA+CD31+ recent thymic emigrant T cells 14.7% CD8+CD27−CD28− late CD8 effector cells 15.2% CD8+CD27+CD28− effector cells 3% Table E1 Peripheral B- and T-lymphocyte subsets in a patient aged 16 years with PI3Kδ deficiency
Mucosal-associated invariant T (MAIT) cells are characterized by the combined expression of the semi-invariant T cell receptor (TCR) Vα7.2, the lectin receptor CD161, as well as IL-18R, and play an ...important role in antibacterial host defense of the gut. The current study characterized CD161(+) MAIT and CD161-TCRVα7.2(+) T cell subsets within a large cohort of HIV patients with emphasis on patients with slow disease progression and elite controllers. Mononuclear cells from blood and lymph node samples as well as plasma from 63 patients and 26 healthy donors were analyzed by multicolor flow cytometry and ELISA for IL-18, sCD14 and sCD163. Additionally, MAIT cells were analyzed after in vitro stimulation with different cytokines and/or fixed E.coli. Reduced numbers of CD161(+) MAIT cells during HIV infection were detectable in the blood and lymph nodes of all patient groups, including elite controllers. CD161+ MAIT cell numbers did not recover even after successful antiretroviral treatment. The loss of CD161(+) MAIT cells was correlated with higher levels of MAIT cell activation; an increased frequency of the CD161-TCRVα7.2(+)T cell subset in HIV infection was observed. In vitro stimulation of MAIT cells with IL-18 and IL-12, IL-7 and fixed E.coli also resulted in a rapid and additive reduction of the MAIT cell frequency defined by CD161, IL-18R and CCR6. In summary, the irreversible reduction of the CD161(+) MAIT cell subset seems to be an early event in HIV infection that is independent of later stages of the disease. This loss appears to be at least partially due to the distinctive vulnerability of MAIT cells to the pronounced stimulation by microbial products and cytokines during HIV-infection.
Knowledge about the longitudinal change of cerebral small-vessel disease–related magnetic resonance imaging abnormalities increases our pathophysiologic understanding of cerebral microangiopathy. The ...change of specific lesion types may also serve as secondary surrogate endpoint in clinical trials. A surrogate endpoint needs to progress fast enough to allow monitoring of treatment effects within a reasonable time period, and change of the brain abnormality needs to be correlated with clinical change. Confluent white matter lesions show fast progression and correlations with cognitive decline. Thus, the change of confluent white matter lesions may be used as a surrogate marker in proof-of-concept trials with small patient numbers needed to show treatment effects on lesion progression. Nonetheless if the expected change in cognitive performance resulting from treatment effects on lesion progression is used as outcome, the sample size needed to show small to moderate treatment effects becomes very large. Lacunes may also fulfill the prerequisites of a surrogate marker, but in the general population the incidence of lacunes over short observational periods is small. For other small-vessel disease–related brain abnormalities including microbleeds and microstructural changes in normal-appearing white matter longitudinal change and correlations with clinical decline is not yet fully determined.
Microbes or danger signals trigger inflammasome sensors, which induce polymerization of the adaptor ASC and the assembly of ASC specks. ASC specks recruit and activate caspase-1, which induces ...maturation of the cytokine interleukin 1β (IL-1β) and pyroptotic cell death. Here we found that after pyroptosis, ASC specks accumulated in the extracellular space, where they promoted further maturation of IL-1β. In addition, phagocytosis of ASC specks by macrophages induced lysosomal damage and nucleation of soluble ASC, as well as activation of IL-1β in recipient cells. ASC specks appeared in bodily fluids from inflamed tissues, and autoantibodies to ASC specks developed in patients and mice with autoimmune pathologies. Together these findings reveal extracellular functions of ASC specks and a previously unknown form of cell-to-cell communication.
General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT ...consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10
) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Background and Purpose- Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple ...types of small vessel disease-related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods- Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network-based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results- The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi (
<0.001 for global cognitive function, processing speed, executive functions, and memory and
<0.001 for poor functional outcome). Volumes of lacunes, enlarged perivascular spaces, and cortical infarcts were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of white matter hyperintensities, lacunes, gray matter, and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on
scores strongly predicted cognitive and functional outcomes (
<0.001) even above the contribution of the individual brain changes. Conclusions- Global burden of small vessel disease-related brain changes as quantified by an image segmentation tool is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of white matter hyperintensities, lacunar, gray matter, and hippocampal volumes could be used as an imaging marker associated with vascular cognitive impairment.
The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five ...individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.
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