Plasma cells are not restricted to the CD27+phenotype: characterization of CD27-CD43+antibody-secreting cells

Circulating antibody-secreting cells are present in the peripheral blood of healthy individuals reflecting the continued activity of the humoral immune system. Antibody-secreting cells typically express CD27. Here we describe and characterize a small population of antibody-secreting class switched CD19+CD43+ B cells that lack expression of CD27 in the peripheral blood of healthy subjects. In this study, we characterized CD27-CD43+ cells. We demonstrate that class-switched CD27-CD43+ B cells possess characteristics of conventional plasmablasts as they spontaneously secrete antibodies, are morphologically similar to antibody-secreting cells, show downregulation of B cell differentiation markers, and have a gene expression profile related to conventional plasmablasts. Despite these similarities, we observed differences in IgA and IgG subclass distribution, expression of homing markers, replication history, frequency of somatic hypermutation, immunoglobulin repertoire, gene expression related to Toll-like receptors, cytokines, and cytokine receptors, and antibody response to vaccination. Their frequency is altered in immune-mediated disorders. Conclusionwe characterized CD27-CD43+ cells as antibody-secreting cells with differences in function and homing potential as compared to conventional CD27+ antibody-secreting cells.Stemcel biology/Regenerative medicine (incl. bloodtransfusion

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Purpose: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. Results: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. Conclusion: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported

An African Ancestry-Specific Allele of CTLA4 Confers Protection against Rheumatoid Arthritis in African Americans

Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is ∼1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462×10−26, Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13–0.26, p = 2.4×10−28, Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations

Table_1_Plasma cells are not restricted to the CD27+ phenotype: characterization of CD27-CD43+ antibody-secreting cells.docx [Dataset]

Circulating antibody-secreting cells are present in the peripheral blood of healthy individuals reflecting the continued activity of the humoral immune system. Antibody-secreting cells typically express CD27. Here we describe and characterize a small population of antibody-secreting class switched CD19+CD43+ B cells that lack expression of CD27 in the peripheral blood of healthy subjects. In this study, we characterized CD27-CD43+ cells. We demonstrate that class-switched CD27-CD43+ B cells possess characteristics of conventional plasmablasts as they spontaneously secrete antibodies, are morphologically similar to antibody-secreting cells, show downregulation of B cell differentiation markers, and have a gene expression profile related to conventional plasmablasts. Despite these similarities, we observed differences in IgA and IgG subclass distribution, expression of homing markers, replication history, frequency of somatic hypermutation, immunoglobulin repertoire, gene expression related to Toll-like receptors, cytokines, and cytokine receptors, and antibody response to vaccination. Their frequency is altered in immune-mediated disorders.Peer reviewe

Waste-to-energy: Coupling Waste Treatment to Highly Efficient CHP

© 2018 Walter de Gruyter GmbH, Berlin/Boston. Municipal Solid Waste Incineration (MSWI) has become the most widespread Best Available Technology (BAT) to treat residual waste streams in a reliable and safe way. As such, MSWI has contributed to achieve the landfill diversion targets in many EU member states. Modern waste incinerators, also referred to as Waste-to-Energy (WtE) plants, have furthermore evolved to producers of electricity, heat and steam for energy-consuming industries, agriculture and residences. However, due to the specific composition and properties of MSW and similar waste, and due to the historical development of MSWI, the exploitation of WtE plants as combined heat and power (CHP) plants is not straightforward. The aims of this paper are to develop a better understanding of these limitations, to point out possibilities for increasing the level of energy recovery and utilization in WtE plants, and to document this approach with data and experiences from selected WtE plants currently integrated in CHP schemes. Finally, some design and operational challenges for waste-fired CHP plants are further elaborated from a WtE plant supplier's perspective.status: publishe

JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analog suppressed patients with chronic hepatitis B : REEF-2

Abstract: Background & Aims Functional cure (FC) for chronic hepatitis B (CHB) requires finite treatment. Two agents under investigation aimed at achieving FC are small interfering RNA JNJ-73763989 (JNJ-3989) and capsid assembly modulator JNJ-56136379 (JNJ-6379; bersacapavir). Methods REEF-2, a phase 2b, double-blind, placebo-controlled, randomized study (ClinicalTrials.gov Identifier: NCT04129554), enrolled 130 nucleos(t)ide analog (NA)\u2013suppressed hepatitis B e-antigen (HBeAg)\u2013negative CHB patients who received JNJ-3989 (200 mg subcutaneously every 4 weeks)+JNJ-6379 (250 mg oral daily)+NA (oral daily; active arm) or placebos for JNJ-3989 and JNJ-6379 + active NA (control arm) for 48 weeks followed by 48 weeks off-treatment follow-up. Results At Follow-up Week 24, no patients achieved the primary endpoint of FC (off-treatment hepatitis B surface antigen [HBsAg] seroclearance). No patients achieved FC at Follow-up Week 48. There was pronounced on-treatment reduction in mean HBsAg from baseline at Week 48 in the active arm versus no decline in the control arm (1.89 vs 0.06 log10 IU/mL; P = 0.001). At Follow-up Week 48, reductions from baseline were >1 log10 IU/mL in 81.5% versus 12.5% of patients in the active and control arms, respectively, and 38/81 (46.9%) patients in the active arm achieved HBsAg <100 IU/mL versus 6/40 (15.0%) patients in the control arm. Off-treatment HBV DNA relapse and alanine aminotransferase (ALT) increases were less frequent in the active arm with 7/77 (9.1%) and 11/41 (26.8%) patients in the active and control arms, respectively, restarting NA during follow-up. Conclusions Finite 48-week treatment with JNJ-3989+JNJ-6379+NA resulted in fewer and less severe posttreatment HBV DNA increases and ALT flares, and a higher proportion of patients with off-treatment HBV DNA suppression, with or without HBsAg suppression, but did not result in FC

Presentation_1_Plasma cells are not restricted to the CD27+ phenotype: characterization of CD27-CD43+ antibody-secreting cells.pptx [Dataset]

Circulating antibody-secreting cells are present in the peripheral blood of healthy individuals reflecting the continued activity of the humoral immune system. Antibody-secreting cells typically express CD27. Here we describe and characterize a small population of antibody-secreting class switched CD19+CD43+ B cells that lack expression of CD27 in the peripheral blood of healthy subjects. In this study, we characterized CD27-CD43+ cells. We demonstrate that class-switched CD27-CD43+ B cells possess characteristics of conventional plasmablasts as they spontaneously secrete antibodies, are morphologically similar to antibody-secreting cells, show downregulation of B cell differentiation markers, and have a gene expression profile related to conventional plasmablasts. Despite these similarities, we observed differences in IgA and IgG subclass distribution, expression of homing markers, replication history, frequency of somatic hypermutation, immunoglobulin repertoire, gene expression related to Toll-like receptors, cytokines, and cytokine receptors, and antibody response to vaccination. Their frequency is altered in immune-mediated disorders.Peer reviewe