B cell homeostasis is disturbed by immunosuppressive therapies in patients with ANCA-associated vasculitides

Abstract

B-lymphocytes play a pivotal role in ANCA-associated vasculitides (AAV). The homeostasis of peripheral human B-lymphocyte subpopulations is tightly regulated, but may be disturbed in autoimmune disease or following immunosuppressive therapies. To elucidate the effect of immunosuppression and the relevance of B-lymphocyte disturbances, the B-lymphocyte compartment was analysed in 61 AAV patients. After immunosuppressive treatment a general B-lymphocytopenia developed in AAV patients. Within the B-lymphocyte subpopulations transitional B cells are the first maturation stage found in the peripheral blood. Transitional B-lymphocytes were significantly lower in AAV patients after immunosuppressive therapy compared to healthy controls. Furthermore, marginal zone B cells – a B-lymphocyte population protecting against encapsulated bacteria -- were markedly lowered after immunosuppressive therapy in AAV patients. AAV patients treated with immunosuppressants had lower numbers of naïve and memory B-lymphocytes. Numbers of marginal zone B cells, memory B cells and plasmablasts correlated with concentrations of immunoglobulins. We evaluated plasmablasts for a potential correlation with disease activity. Different from what has been reported for e.g. large vessel vasculitis, absolute numbers of plasmablasts were not increased in patients with AAV and showed no correlation to disease activity. As low transitional B cells after treatment with immunosuppressants indicated an impaired early B-lymphocyte development, seven patients treated with the B cell depleting agent rituximab (RTX) because of relapsing disease activity were analysed for their B cell repopulation kinetics. In the majority of these patients repopulation of the peripheral B cell compartment by newly formed transitional B cells after RTX treatment was constricted and delayed.     

Flow Cytometric Measurements of Somatic Cell Mutations in Thorotrast Patients

Exposure to ionizing radiation has long been well-recognized as a risk factor for cancer development. Since ionizing radiation can induce mutations, an accurate way of measuring somatic mutation frequencies could be a useful tool for evaluating cancer risks. In the present study, we have examined in vivo somatic mutation frequencies at the erythrocyte glycophorin A (GPA) and T-cell receptor (TCR) loci in 18 Thorotrast patients who have been continuously irradiated with alpha-particles emitted from the internal deposition of thorium dioxide and who thus have increased risks of certain malignant tumors. When compared with controls, the results showed a significantly higher frequency of mutants at the lymphocyte TCR loci but not at the erythrocyte GPA loci in the Thorotrast patients. The discrepancy between the results of the two assays is discussed.     

An Adaptive Approach to Family-Centered Intervention in Schools: Linking Intervention Engagement to Academic Outcomes in Middle and High School

This study examined the impact of an adaptive approach to family intervention in public schools on academic outcomes from age 11 to 17. Students were randomly assigned to the three-session Family Check-Up (FCU), which is designed to motivate change in parenting practices by using an assessment-driven approach and strengths-based feedback. All services were voluntary, and approximately 25% of the families engaged in the FCU. Compared with matched controls, adolescents whose parents received the FCU maintained a satisfactory GPA into high school, and intervention engagement was associated with improved attendance. The highest-risk families were the most likely to engage in the family-centered intervention, suggesting the efficacy of integrating supportive services to families in the context of other schoolwide approaches to promote the success and achievement of vulnerable students.     

Into the pressure cooker: Student stress in college preparatory high schools

PurposeThe goals of this study were to (1) measure psychological, physiological, and behavioral indicators of stress, (2) assess the relationship between stress and student attitudes, and (3) explore coping behaviors in response to stress, among a sample of students in two academically high-achieving environments.MethodThree hundred thirty-three students in grades 9 through 12 from two college-preparatory high schools completed a cross-sectional online survey that included the Students' Life Satisfaction Scale, School Attitude Assessment Questionnaire-Revised, and assessments for stress-related indicators, including eating, sleeping and exercise, and strategies they utilized for coping with stress.ResultsStudents reported a high prevalence of physical and psychological correlates of stress, and related unhealthy behaviors such as widespread and chronic sleep deprivation and rushed meals.ConclusionsThe results suggest areas to focus attention for identifying and addressing maladaptive responses to stress among high-achieving student populations.     

Th17 and Treg lymphocytes as cellular biomarkers of disease activity in Granulomatosis with Polyangiitis

Granulomatosis with Polyangiitis (GPA) (formerly known as Wegener's granulomatosis) is a vasculitis of unknown etiology affecting predominantly small‐ to medium‐sized vessels, usually involving the upper and lower respiratory tract and kidneys. Anti‐neutrophil cytoplasmic autoantibodies are probably the initial cause of the inflammatory process that leads to the typical necrotizing lesions. In this issue of the European Journal of Immunology, Szczeklik et al. [Eur. J. Immunol. 2017. 47: 724–733] report some interesting findings on the possible involvement of T‐cell subsets in the pathogenesis of the disease. This prospective study, performed on a large cohort of patients, identifies Th17 lymphocytes as the possible pathogenic subset of GPA, and Treg cells as the possible suppressors of the inflammatory process. These two subsets in peripheral blood could be used as cellular biomarkers of disease activity, and this would result particularly useful in the follow‐up of patients once the immunosuppressive treatment has been initiated.     

Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome

Objective

Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap.

Granulomatosis with polyangiitis (Wegener’s) complicated by splenic rupture and severe acute respiratory distress syndrome: A case report

Even in the absence of disease‐specific radiological signs of granulomatosis with polyangiitis (GPA), severe intrapulmonary GPA may be present. Rapidly establishing the diagnosis with a confirmatory biopsy is key to initiate lifesaving therapy.     

The creatine transporter mediates the uptake of creatine by brain tissue, but not the uptake of two creatine-derived compounds

Hereditary creatine transporter deficiency causes brain damage, despite the brain having the enzymes to synthesize creatine. Such damage occurring despite an endogenous synthesis is not easily explained. This condition is incurable, because creatine may not be delivered to the brain without its transporter. Creatine-derived compounds that crossed the blood-brain barrier in a transporter-independent fashion would be useful in the therapy of hereditary creatine transporter deficiency, and possibly also in neuroprotection against brain anoxia or ischemia. We tested the double hypothesis that: (1) the creatine carrier is needed to make creatine cross the plasma membrane of brain cells and (2) creatine-derived molecules may cross this plasma membrane independently of the creatine carrier. In in vitro mouse hippocampal slices, incubation with creatine increased creatine and phosphocreatine content of the tissue. Inhibition of the creatine transporter with 3-guanidinopropionic acid (GPA) dose-dependently prevented this increase. Incubation with creatine benzyl ester (CrOBzl) or phosphocreatine-Mg-complex acetate (PCr-Mg-CPLX) increased tissue creatine content, not phosphocreatine. This increase was not prevented by GPA. Thus, the creatine transporter is required for creatine uptake through the plasma membrane. Since there is a strong indication that creatine in the brain is mainly synthesized by glial cells and transferred to neurons, this might explain why hereditary transporter deficiency is attended by severe brain damage despite the possibility of an endogenous synthesis. CrOBzl and PCr-Mg-CPLX cross the plasma membrane in a transporter-independent way, and might be useful in the therapy of hereditary creatine transporter deficiency. They may also prove useful in the therapy of brain anoxia or ischemia.