High SYK Expression Drives Constitutive Activation of CD21low B Cells

International audienceHuman CD21low B cells present with an activated phenotype and accumulate in distinct disorders connected with chronic immune stimulation. Signaling studies had revealed an increased basal phosphorylation of spleen tyrosine kinase (SYK) and phospholipase Cγ2. Additional BCR stimulation of these constitutively active cells, however, led to reduced activation of these signaling molecules and subsequently NF-\kappaB and Ca2+ activation. In this article, we demonstrate that high SYK expression is a common feature of CD21low B cells independent of the underlying disorder, and that this high expression is sufficient to drive constitutive phosphorylation of SYK and its immediate targets Bruton's tyrosine kinase and phospholipase Cγ2. Inhibition of SYK activity eliminated features of the constitutive activation in these cells and partly restored BCR signaling. High SYK expression is especially induced by CpG or CD40L in combination with IL-21, but not BCR stimulation, suggesting the importance of the immune-stimulatory context for the induction of this B cell phenotype. In summary, high SYK expression is a common feature of human CD21low B cells and presumably results from chronic activation in inflammatory environments present in a subgroup of patients with heterogeneous disorders like chronic infection, autoimmunity, and immunodeficiency. High SYK expression by itself drives the constitutive activation observed in these B cells, which in turn may contribute to the hyporesponsiveness upon BCR stimulation. Given the high prevalence of autoreactive clones among CD21low B cells in autoimmune disorders, the dominant role of SYK in CD21low B cells may provide a new option for therapeutic interventions in patients with expanded CD21low B cells and humoral autoimmunity

Disturbed canonical NF-kB signaling in B cells of CVID patients

Background: Most patients with common variable immunodeficiency(CVID) present with severely reduced switched memory B cells and some display an increase of CD21low B cells (CVID 21low) while others don't (CVID 21norm). Altered B-cell receptor (BCR) signaling may contribute to the defective memory formation observed in CVID. Objective: To investigate canonical NF-kB signaling in CVID patients' B cells as a central pathway in B-cell differentiation. Methods: Degradation of IkBa and p65 phosphorylation, nuclear translocation of p65 and the regulation of target genes and cell function were investigated after different modes of B-cell stimulation. Results: BCR-mediated canonical NF-kB signaling was impaired in all mature naïve CVID-derived B cells. This impairment was more profound in naïve B cells of CVID 21low than of 21norm patients and most pronounced in CD21low B cells. The signaling defect translated into reduced induction of Bcl-xL and IkBa, two bona-fide target genes of the canonical NF-kB pathway. CD40L- and TLR9-mediated signaling was less strongly altered. Signaling in CD21low B cells but not CD21pos B cells of HIV patients was similarly affected. Conclusion: Combined with the previous description of disturbed Ca2+ signaling the discovery of NF-kB signaling defects especially in CVID 21low patients suggests a broad underlying signaling defect affecting especially BCR-derived signals. Given the immune phenotype of monogenic defects affecting Ca2+ and NF-kB signaling the latter is more likely to contribute to the humoral deficiency. The strongly disturbed BCR signaling of CD21low B cells is characteristic for this cell type and independent of the underlying disease

The T1 phenotype of follicular helper T cells indicates an IFN-γ-associated immune dysregulation in patients with CD21low common variable immunodeficiency.

BACKGROUND A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology. OBJECTIVES On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients. METHODS We quantified T1/T2/T17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation. RESULTS Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3CCR6 T1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet) B cells in lymph nodes, and an accumulation of T-betCD21 B cells in peripheral blood of affected patients. CONCLUSION Identification of excessive IFN-γ production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21 B cells might serve as a marker of this IFN-γ-associated dysregulation

Melatonin and Pancreatic Islets: Interrelationships between Melatonin, Insulin and Glucagon

The pineal hormone melatonin exerts its influence in the periphery through activation of two specific trans-membrane receptors: MT1 and MT2. Both isoforms are expressed in the islet of Langerhans and are involved in the modulation of insulin secretion from β-cells and in glucagon secretion from α-cells. De-synchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genome-wide association studies identifying particularly the MT2 as a risk factor for this rapidly spreading metabolic disturbance. Since melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. This factor has hitherto been underestimated; the disruption of diurnal signaling within the islet may be one of the most important mechanisms leading to metabolic disturbances. The study of melatonin–insulin interactions in diabetic rat models has revealed an inverse relationship: an increase in melatonin levels leads to a down-regulation of insulin secretion and vice versa. Elucidation of the possible inverse interrelationship in man may open new avenues in the therapy of diabetes

Structural, Surface, and Catalytic Properties of Aluminas

The published data concerning the structural, surface, and catalytic properties of aluminas are reviewed, and these properties are related to the preparation procedures. The experimental and computational investigations of the structural characteristics of the polymorphs most useful for applications in catalysis, which are \u3b3-, \u3b7-, \u3b4-, and \u3b8-Al2O3, are critically analyzed. The thermodynamics of the various polymorphs and the kinetics of the phase transitions are considered. The available information on Br\uf8nsted sites (i.e., hydroxyl groups), Lewis acid sites, and acid\u2013base pairs othe surface of aluminas is discussed. Data regarding the application of aluminas as a catalyst and as a catalyst support are summarized. Suggestions for future research are proposed

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo