Moving toward personalized B cell depletion in multiple sclerosis?

B cell depletion is becoming a preferred long-term treatment even in early multiple sclerosis, but concerns about the risks of impaired immune competence persist. In their observational study Schuckmann et al. thoroughly assessed the impact of B cell-adapted extended interval dosing on immunoglobulin levels as a surrogate of adverse immunosuppressive effects.

Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging.

The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older individuals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. In aged mice, there is CXCR4-mediated mislocalization of T follicular helper (TFH) cells to the dark zone and a compressed network of follicular dendritic cells (FDCs) in the light zone. Here we show that TFH cell localization is critical for the quality of the antibody response and for the expansion of the FDC network upon immunization. The smaller GC and compressed FDC network in aged mice were corrected by provision of TFH cells that colocalize with FDCs using CXCR5. This demonstrates that the age-dependent defects in the GC response are reversible and shows that TFH cells support stromal cell responses to vaccines.

Comparing T- and B-cell responses to COVID-19 vaccines across varied immune backgrounds.

The emergence of adapted variants of the SARS-CoV-2 virus has led to a surge in breakthrough infections worldwide. A recent analysis of immune responses in people who received inactivated vaccines has revealed that individuals with no prior infection have limited resistance to Omicron and its sub-lineages, while those with previous infections exhibit a significant amount of neutralizing antibodies and memory B cells. However, specific T-cell responses remain largely unaffected by the mutations, indicating that T-cell-mediated cellular immunity can still provide protection. Moreover, the administration of a third dose of vaccine has resulted in a marked increase in the spectrum and duration of neutralizing antibodies and memory B cells in vivo, which has enhanced resistance to emerging variants such as BA.2.75 and BA.2.12.1. These results highlight the need to consider booster immunization for previously infected individuals and the development of novel vaccination strategies. The rapid spread of adapted variants of the SARS-CoV-2 virus presents a significant challenge to global health. The findings from this study underscore the importance of tailoring vaccination strategies based on individual immune backgrounds and the potential need for booster shots to combat emerging variants. Continued research and development are crucial to discovering new immunization strategies that will effectively protect public health against the evolving virus.

Altered somatic hypermutation patterns in COVID-19 patients classifies disease severity.

Introduction: The success of the human body in fighting SARS-CoV2 infection relies on lymphocytes and their antigen receptors. Identifying and characterizing clinically relevant receptors is of utmost importance. Methods: We report here the application of a machine learning approach, utilizing B cell receptor repertoire sequencing data from severely and mildly infected individuals with SARS-CoV2 compared with uninfected controls. Results: In contrast to previous studies, our approach successfully stratifies non-infected from infected individuals, as well as disease level of severity. The features that drive this classification are based on somatic hypermutation patterns, and point to alterations in the somatic hypermutation process in COVID-19 patients. Discussion: These features may be used to build and adapt therapeutic strategies to COVID-19, in particular to quantitatively assess potential diagnostic and therapeutic antibodies. These results constitute a proof of concept for future epidemiological challenges.

Immunomodulation of B Lymphocytes by Prebiotics, Probiotics and Synbiotics: Application in Pathologies.

INTRODUCTION: Prebiotics, probiotics and synbiotics are known to have major beneficial effects on human health due to their ability to modify the composition and the function of the gut mucosa, the gut microbiota and the immune system. These components largely function in a healthy population throughout different periods of life to confer homeostasis. Indeed, they can modulate the composition of the gut microbiota by increasing bacteria strands that are beneficial for health, such as Firmicute and Bifidobacteria, and decreasing harmful bacteria, such as Enteroccocus. Their immunomodulation properties have been extensively studied in different innate cells (dendritic cells, macrophages, monocytes) and adaptive cells (Th, Treg, B cells). They can confer a protolerogenic environment but also modulate pro-inflammatory responses. Due to all these beneficial effects, these compounds have been investigated to prevent or to treat different diseases, such as cancer, diabetes, allergies, autoimmune diseases, etc. Regarding the literature, the effects of these components on dendritic cells, monocytes and T cells have been studied and presented in a number of reviews, but their impact on B-cell response has been less widely discussed. CONCLUSIONS: For the first time, we propose here a review of the literature on the immunomodulation of B-lymphocytes response by prebiotics, probiotics and synbiotics, both in healthy conditions and in pathologies. DISCUSSION: Promising studies have been performed in animal models, highlighting the potential of prebiotics, probiotics and synbiotics intake to treat or to prevent diseases associated with B-cell immunomodulation, but this needs to be validated in humans with a full characterization of B-cell subsets and not only the humoral response.

Flow cytometry profiling of cellular immune response in COVID-19 infected, recovered and vaccinated individuals.

INTRODUCTION: SARS-CoV-2 has infected over 753 million individuals and caused more than 6.8 million deaths globally to date. COVID-19 disease severity has been associated with SARS-CoV-2 induced hyper inflammation and the immune correlation with its pathogenesis remains unclear. Acute viral infection is characterised by vigorous coordinated innate and adaptive activation, including an early cellular response that correlates well with the amplitude of virus specific humoral response. OBJECTIVE: The present study covers a wide spectrum of cellular immune response against COVID-19, irrespective of infection and vaccination. METHODS: We analysed immune status of (a) COVID-19 hospitalised patients including deceased and recovered patients, and compared with home isolated and non-infected healthy individuals, and (b) infected home isolated individuals with vaccinated individuals, using flow cytometry. We performed flow cytometry analysis of PBMCs to determine non-specific cell-mediated immune response. RESULTS: The immune response revealed extensive induction and activation of multiple immune lineages, including T and B cells, Th17 regulatory subsets and M1, M2 macrophages in deceased and hospitalised recovered patients, vaccinated and healthy individuals. Compromised immune cell expression was observed in deceased patients even in later stages, while expression was restored in hospitalised recovered patients and home isolated individuals. CONCLUSION: The findings associated with recovery and convalescence define a new signature of cellular immune response that persists in individuals with SARS-CoV-2 infection and vaccination. The findings will help in providing a better understanding of COVID-19 disease and will aid in developing better therapeutic strategies for treatment.

B cells in systemic lupus erythematosus.

PURPOSE OF REVIEW: New insight into altered B cell distribution including newly identified subsets and abnormalities in systemic lupus erythematosus (SLE) as well as their role in immune protection are summarized in this review. RECENT FINDINGS: SLE carries characteristic B cell abnormalities, which offer new insights into B cell differentiation and their disturbances including discoveries of pathogenic B cell subsets and intrinsic B cell abnormalities. A recent study in SLE found that antigen-experienced B cell subsets lacking expression of CD27 and IgD defined by their lack of CXCR5 and CD19low expression are expanded in SLE and represent plasmablasts likely escaping proper selection. In terms of therapeutic targeting with broader coverage than rituximab, second-generation anti-CD20, anti-CD38 and CD19-CART treatment experiences have advanced our understanding recently. However, the key role of qualitative and quantitative B cell requirements in connection with T cells became apparent during SARS-Cov2 infection and vaccination, especially in patients with gradual B cell impairments by rituximab, mycophenolate mofetil and cyclophosphamide. SUMMARY: Identification and characterization relevant B cell subsets together with altered regulatory mechanisms in SLE facilitates new approaches in targeting pathogenic B cells but require consideration of preservation of protection.

Human memory B cells show plasticity and adopt multiple fates upon recall response to SARS-CoV-2.

The B cell response to different pathogens uses tailored effector mechanisms and results in functionally specialized memory B (Bm) cell subsets, including CD21+ resting, CD21-CD27+ activated and CD21-CD27- Bm cells. The interrelatedness between these Bm cell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specific Bm cell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21- Bm cells were the predominant subsets during acute infection and early after severe acute respiratory syndrome coronavirus 2-specific immunization. At months 6 and 12 post-infection, CD21+ resting Bm cells were the major Bm cell subset in the circulation and were also detected in peripheral lymphoid organs, where they carried tissue residency markers. Tracking of individual B cell clones by B cell receptor sequencing revealed that previously fated Bm cell clones could redifferentiate upon antigen rechallenge into other Bm cell subsets, including CD21-CD27- Bm cells, demonstrating that single Bm cell clones can adopt functionally different trajectories.

B lymphocytes in COVID-19: a tale of harmony and discordance.

B lymphocytes play a vital role in the human defense against viral infections by producing specific antibodies. They are also critical for the prevention of infectious diseases by vaccination, and their activation influences the efficacy of the vaccination. Since the beginning of coronavirus disease 2019 (COVID-19), which became the main concern of the world health system, many efforts have been made to treat and prevent the disease. However, for the development of successful therapeutics and vaccines, it is necessary to understand the interplay between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, and the immune system. The innate immune system provides primary and nonspecific defense against the virus, but within several days after infection, a virus-specific immune response is provided first by antibody-producing B cells, which are converted after the resolution of disease to memory B cells, which provide long-term immunity. Although a failure in B cell activation or B cell dysfunction can cause a severe form of the disease and also lead to vaccination inefficiency, some individuals with B cell immunodeficiency have shown less production of the cytokine IL-6, resulting in a better disease outcome. In this review, we present the latest findings on the interaction between SARS-CoV-2 and B lymphocytes during COVID-19 infection.

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.

Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages.

Vaccination of SARS-CoV-2 convalescent individuals generates broad and potent antibody responses. Here, we isolate 459 spike-specific monoclonal antibodies (mAbs) from two individuals who were infected with the index variant of SARS-CoV-2 and later boosted with mRNA-1273. We characterize mAb genetic features by sequence assignments to the donors' personal immunoglobulin genotypes and assess antibody neutralizing activities against index SARS-CoV-2, Beta, Delta, and Omicron variants. The mAbs used a broad range of immunoglobulin heavy chain (IGH) V genes in the response to all sub-determinants of the spike examined, with similar characteristics observed in both donors. IGH repertoire sequencing and B cell lineage tracing at longitudinal time points reveals extensive evolution of SARS-CoV-2 spike-binding antibodies from acute infection until vaccination five months later. These results demonstrate that highly polyclonal repertoires of affinity-matured memory B cells are efficiently recalled by vaccination, providing a basis for the potent antibody responses observed in convalescent persons following vaccination.

B-Cell Receptor Features and Database Establishment in Recovered COVID-19 Patients by Combining 5'-RACE with PacBio Sequencing.

BACKGROUND: Antibodies induced by viral infection can not only prevent subsequent virus infection, but can also mediate pathological injury following infection. Therefore, understanding the B-cell receptor (BCR) repertoire of either specific neutralizing or pathological antibodies from patients convalescing from Coronavirus disease 2019 (COVID-19) infection is of benefit for the preparation of therapeutic or preventive antibodies, and may provide insight into the mechanisms of COVID-19 pathological injury. METHODS: In this study, we used a molecular approach of combining 5' Rapid Amplification of cDNA Ends (5'-RACE) with PacBio sequencing to analyze the BCR repertoire of all 5 IgH and 2 IgL genes in B-cells harvested from 35 convalescent patients after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RESULTS: We observed numerous BCR clonotypes within most COVID-19 patients, but not in healthy controls, which validates the association of the disease with a prototypical immune response. In addition, many clonotypes were found to be frequently shared between different patients or different classes of antibodies. CONCLUSIONS: These convergent clonotypes provide a resource to identify potential therapeutic/prophylactic antibodies, or identify antibodies associated with pathological effects following infection with SARS-CoV-2.

A Rapid Method for Detection of Antigen-Specific B Cells.

The global SARS-CoV-2 pandemic has united the efforts of many scientists all over the world to develop wet-lab techniques and computational approaches aimed at the identification of antigen-specific T and B cells. The latter provide specific humoral immunity that is essential for the survival of COVID-19 patients, and vaccine development has essentially been based on these cells. Here, we implemented an approach that integrates the sorting of antigen-specific B cells and B-cell receptor mRNA sequencing (BCR-seq), followed by computational analysis. This rapid and cost-efficient method allowed us to identify antigen-specific B cells in the peripheral blood of patients with severe COVID-19 disease. Subsequently, specific BCRs were extracted, cloned, and produced as full antibodies. We confirmed their reactivity toward the spike RBD domain. Such an approach can be effective for the monitoring and identification of B cells participating in an individual immune response.

Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c+ B cells.

Down's syndrome (DS) presents with a constellation of cardiac, neurocognitive and growth impairments. Individuals with DS are also prone to severe infections and autoimmunity including thyroiditis, type 1 diabetes, coeliac disease and alopecia areata1,2. Here, to investigate the mechanisms underlying autoimmune susceptibility, we mapped the soluble and cellular immune landscape of individuals with DS. We found a persistent elevation of up to 22 cytokines at steady state (at levels often exceeding those in patients with acute infection) and detected basal cellular activation: chronic IL-6 signalling in CD4 T cells and a high proportion of plasmablasts and CD11c+TbethighCD21low B cells (Tbet is also known as TBX21). This subset is known to be autoimmune-prone and displayed even greater autoreactive features in DS including receptors with fewer non-reference nucleotides and higher IGHV4-34 utilization. In vitro, incubation of naive B cells in the plasma of individuals with DS or with IL-6-activated T cells resulted in increased plasmablast differentiation compared with control plasma or unstimulated T cells, respectively. Finally, we detected 365 auto-antibodies in the plasma of individuals with DS, which targeted the gastrointestinal tract, the pancreas, the thyroid, the central nervous system, and the immune system itself. Together, these data point to an autoimmunity-prone state in DS, in which a steady-state cytokinopathy, hyperactivated CD4 T cells and ongoing B cell activation all contribute to a breach in immune tolerance. Our findings also open therapeutic paths, as we demonstrate that T cell activation is resolved not only with broad immunosuppressants such as Jak inhibitors, but also with the more tailored approach of IL-6 inhibition.

SARS-CoV-2 Omicron boosting induces de novo B cell response in humans.

The primary two-dose SARS-CoV-2 mRNA vaccine series are strongly immunogenic in humans, but the emergence of highly infectious variants necessitated additional doses and the development of vaccines aimed at the new variants1-4. SARS-CoV-2 booster immunizations in humans primarily recruit pre-existing memory B cells5-9. However, it remains unclear whether the additional doses induce germinal centre reactions whereby re-engaged B cells can further mature, and whether variant-derived vaccines can elicit responses to variant-specific epitopes. Here we show that boosting with an mRNA vaccine against the original monovalent SARS-CoV-2 mRNA vaccine or the bivalent B.1.351 and B.1.617.2 (Beta/Delta) mRNA vaccine induced robust spike-specific germinal centre B cell responses in humans. The germinal centre response persisted for at least eight weeks, leading to significantly more mutated antigen-specific bone marrow plasma cell and memory B cell compartments. Spike-binding monoclonal antibodies derived from memory B cells isolated from individuals boosted with either the original SARS-CoV-2 spike protein, bivalent Beta/Delta vaccine or a monovalent Omicron BA.1-based vaccine predominantly recognized the original SARS-CoV-2 spike protein. Nonetheless, using a more targeted sorting approach, we isolated monoclonal antibodies that recognized the BA.1 spike protein but not the original SARS-CoV-2 spike protein from individuals who received the mRNA-1273.529 booster; these antibodies were less mutated and recognized novel epitopes within the spike protein, suggesting that they originated from naive B cells. Thus, SARS-CoV-2 booster immunizations in humans induce robust germinal centre B cell responses and can generate de novo B cell responses targeting variant-specific epitopes.