A checkpoint for autoreactivity in human IgM+ memory B cell development

Autoantibodies are removed from the repertoire at two checkpoints during B cell development in the bone marrow and the periphery. Despite these checkpoints, up to 20% of the antibodies expressed by mature naive B cells in healthy humans show low levels of self-reactivity. To determine whether self-reactive antibodies are also part of the antigen-experienced memory B cell compartment, we analyzed recombinant antibodies cloned from single circulating human IgM+ memory B cells. Cells expressing antibodies specific for individual bacterial polysaccharides were expanded in the IgM+ memory compartment. In contrast, B cells expressing self-reactive and broadly bacterially reactive antibodies were removed from the repertoire in the transition from naive to IgM+ memory B cell. Selection against self-reactive antibodies was implemented before the onset of somatic hypermutation. We conclude that a third checkpoint selects against self-reactivity during IgM+ memory B cell development in humans

Persistent expression of autoantibodies in SLE patients in remission

A majority of the antibodies expressed by nascent B cells in healthy humans are self-reactive, but most of these antibodies are removed from the repertoire during B cell development. In contrast, untreated systemic lupus erythematosus (SLE) patients fail to remove many of the self-reactive and polyreactive antibodies from the naive repertoire. Here, we report that SLE patients in clinical remission continue to produce elevated numbers of self-reactive and polyreactive antibodies in the mature naive B cell compartment, but the number of B cells expressing these antibodies is lower than in patients with active disease. Our finding that abnormal levels of self-reactive mature naive B cells persist in the majority of patients in clinical remission suggests that early checkpoint abnormalities are an integral feature of SLE

Defective B cell tolerance checkpoints in systemic lupus erythematosus

A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25–50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5–20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance

Clinical outcomes of patients with advanced synovial sarcoma or myxoid/round cell liposarcoma treated at major cancer centers in the United States

BACKGROUND: Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials. METHODS: In this multi-center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first-line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox regression. RESULTS: At start of first-line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first-line therapy for SS was 24.7 months (95% CI, 20.9-29.4) and 7.5 months, respectively (95% CI, 6.4-8.4). Median OS and median PFS from start of first-line therapy for MRCL was 29.9 months (95% CI, 27-44.6) and 8.9 months (95% CI 4.5-12.0). CONCLUSIONS: To the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real-world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature

Investigation on the Chlorophyll-<em>a</em> Content of Phytoplankton in the Sea of Azov and the Don River by the Fluorescence Method

Results of in situ fluorescence investigations on chlorophyll-a (chl-a) of phytoplankton in the Sea of Azov (May to June 2018) and in the Don River estuary (September to November 2019) are presented. Continuous data series of chl-a fluorescence were obtained with flow-through fluorometers. Discrete reference measurements of chl-a concentration and phytoplankton biomass were performed by standard methods for the sake of comparison and eventual corrections. The fluorescence intensity values measured in a lateral surface salinity gradient of the Sea of Azov were found correlating with the obtained data on the chl-a concentration (R2 = 0.88, n = 27) and phytoplankton biomass (R2 = 0.90, n = 11). Instead, there was a weak correlation (R2 = 0.40, n = 33) between the fluorescence and phytoplankton biomass found in the estuary. This disparity in correlations was explained by the difference in conditions during measurements, which affected the fluorescence. There were no significant changes in both temperature and coenotic composition of phytoplankton in the course of the marine expedition. The measurements on the river covered a period characterized by the seasonal variations in the phytoplankton composition and by noticeable temperature fluctuations

Autoreactivity in human IgG+ memory B cells

More than half of the nascent B cells in humans initially express autoreactive antibodies. However, most of these autoantibodies are removed from the repertoire at two checkpoints before maturation into naïve B cells. A third checkpoint excludes remaining autoantibodies from the antigenexperienced IgM+ memory B cell pool. Nevertheless, low-affinity self-reactive antibodies are frequently found in the serum of normal humans. To determine the source of these antibodies we cloned and expressed antibodies from circulating human IgG+ memory B cells. Surprisingly, we found that self-reactive antibodies including anti-nuclear antibodies were frequently expressed by IgG+ memory B cells in healthy donors. Most of these antibodies were created de-novo by somatic hypermutation during the transition between mature naïve and IgG+ memory B cells

Paradoxical Manifestations of Institutional Social Trust in Russian Regions: Corruption and Shadow Employment as Types of Social Trust

Introduction. The paradoxicality of which lies in the fact that with a lack of official institutional trust of the population in the authorities, it flows into informal, criminal and semi-criminal social spheres, into corrupt social ties and groups, and into the informal economy, shadow employment. The purpose of the article is to conduct a sociological theoretical and methodological analysis of the paradoxical forms of institutional social trust in Russian society in the form of corrupt and shadow economic ties. Materials and Methods. Empirical data on the shadow labor market in the Russian Federation were obtained in the course of mass and expert surveys conducted in 2021 in 10 regions of the Russian Federation and 2 megacities. In the course of preparing this publication, general scientific, logical methods were used, structural-functional, sociocultural, anthroposociocultural, projective approaches in modern sociology, the method of sociological imagination, the methodology of analysis and the formation of “we-groups”. Results. In the course of the authors’ research, it was found that such negative social phenomena as domestic and business corruption, shadow (informal) employment are a paradoxical form of expression of institutional trust in society. The paradox of the sociological correlation of corruption and shadow employment with institutional trust only at first glance seems illogical and contrary to sound scientific understanding. As a result of the analysis, the authors have revealed that with a lack of basic institutional trust of the Russian population in state and municipal authorities, social trust flows into informal, semi-criminal and criminal spheres. It has been proved that corruption and informal employment as forms of social practice become forms of expression of specific political trust based on strong social ties (blood related, kindred, friendly) in Russian regions. The authors’ team determined that corruption and informal employment are becoming a type of informal social self-organization of society, which close the gap between the political communications of the elite and the expectations of civil society. Discussion and Conclusion. Corruption and the informal economy are becoming a paradoxical form of manifestation of situational, horizontal, institutional trust based on strong (blood related, kindred, friendly) ties, on the social ties of “we-groups”, on the atomism of the Russian regional society. This research can be practically used by sociologists, lawyers, criminologists, social psychologists, law enforcement officers of the Russian Federation