B cell diversification in gut-associated lymphoid tissues: From birds to humans.

Several species generate their preimmune repertoire in gut-associated lymphoid tissues (GALT), compensating a reduced germline V gene repertoire by post-rearrangement diversification mechanisms (gene conversion and/or somatic hypermutation) in these environments that act as primary lymphoid organs. We summarize here these processes for three different species (chickens, sheep, and rabbits) and further discuss the analogous process that T-independent B cell responses in humans represent: we indeed recently showed that response against bacterial polysaccharides mobilize marginal zone B cells that prediversified against gut antigens. While the initial diversification strategy differs in these two cases, i.

Germinal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells.

HELLS/LSH (Helicase, Lymphoid Specific) is a SNF2-like chromatin remodelling protein involved in DNA methylation. Its loss-of-function in humans causes humoral immunodeficiency, called ICF4 syndrome (Immunodeficiency, Centromeric Instability, Facial anomalies). Here we show by our newly generated B-cell-specific Hells conditional knockout mouse model that HELLS plays a pivotal role in T-dependent B-cell responses.

SARS-CoV-2 Omicron BA.1 breakthrough infection drives late remodeling of the memory B cell repertoire in vaccinated individuals.

How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after SARS-CoV-2 Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of the COVID-19 mRNA vaccine.

AKT activity orchestrates marginal zone B cell development in mice and humans.

The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice.

T-independent responses to polysaccharides in humans mobilize marginal zone B cells prediversified against gut bacterial antigens.

Marginal zone (MZ) B cells are one of the main actors of T-independent (TI) responses in mice. To identify the B cell subset(s) involved in such responses in humans, we vaccinated healthy individuals with Pneumovax, a model TI vaccine. By high-throughput repertoire sequencing of plasma cells (PCs) isolated 7 days after vaccination and of different B cell subpopulations before and after vaccination, we show that the PC response mobilizes large clones systematically, including an immunoglobulin M component, whose diversification and amplification predated the pneumococcal vaccination.

The p.Pro2232Leu variant in the ChEL domain of thyroglobulin gene causes intracellular transport disorder and congenital hypothyroidism.

Thyroglobulin (TG), the predominant glycoprotein of the thyroid gland, functions as matrix protein in thyroid hormonegenesis. TG deficiency results in thyroid dyshormonogenesis. These variants produce a heterogeneous spectrum of congenital goitre, with an autosomal recessive mode of inheritance.

Barriers to Physical Activity in Children and Adults Living With Type 1 Diabetes: A Complex Link With Real-life Glycemic Excursions.

Objectives: Ever since the first research on barriers to physical activity (PA) highlighting fear of hypoglycemia as a major barrier, many studies have attempted to understand their demographic and behavioural determinants. However, no research has been conducted on whether these perceived barriers toward PA are based on real-life-experienced adverse glycemic effects of exercise.

Methods: Sixty-two adults and 53 children/adolescents living with type 1 diabetes, along with their parents, completed the Barriers to Physical Activity in Type 1 Diabetes-1 (BAPAD-1) questionnaire on barriers to PA.

The whole-cell pertussis vaccine imposes a broad effector B cell response in mouse heterologous prime-boost settings.

ÍSince the introduction of new generation pertussis vaccines, resurgence of pertussis has been observed in many developed countries. Former whole-cell pertussis (wP) vaccines are able to protect against disease and transmission but have been replaced in several industrialized countries because of their reactogenicity and adverse effects. Current acellular pertussis (aP) vaccines, made of purified proteins of Bordetella pertussis, are efficient at preventing disease but fail to induce long-term protection from infection.

B cell intrinsic and extrinsic factors impacting memory recall responses to SRBC challenge.

MBCs (MBCs) generated in T-dependent immune responses can persist for a lifetime and rapidly react upon secondary antigen exposure to differentiate into plasma cells (PCs) and/or to improve the affinity of their BCR through new rounds of hypermutation in germinal centers (GCs). The fate of a MBC in secondary immune reactions appears to depend upon multiple parameters, whose understanding is mandatory for the design of efficient vaccine strategies. We followed the behavior of MBCs in recall responses to SRBCs using an inducible AID fate mapping mouse model in which B cells engaged in a germinal center (GC) response are irreversibly labeled upon simultaneous tamoxifen ingestion and immunization.

Exposures and behavioural responses to wildfire smoke.

Pollution from wildfires constitutes a growing source of poor air quality globally. To protect health, governments largely rely on citizens to limit their own wildfire smoke exposures, but the effectiveness of this strategy is hard to observe. Using data from private pollution sensors, cell phones, social media posts and internet search activity, we find that during large wildfire smoke events, individuals in wealthy locations increasingly search for information about air quality and health protection, stay at home more and are unhappier.

Analysis of mRNA vaccination-elicited RBD-specific memory B cells reveals strong but incomplete immune escape of the SARS-CoV-2 Omicron variant.

The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear.

mRNA vaccination of naive and COVID-19-recovered individuals elicits potent memory B cells that recognize SARS-CoV-2 variants.

In addition to serum immunoglobulins, memory B cell (MBC) generation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another layer of immune protection, but the quality of MBC responses in naive and coronavirus disease 2019 (COVID-19)-recovered individuals after vaccination remains ill defined. We studied longitudinal cohorts of naive and disease-recovered individuals for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of antibody repertoires, affinity, and neutralization against variants of concern (VOCs) using unbiased cultures of 2,452 MBCs.

SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations.

Insulin resistance is a key event in type 2 diabetes onset and a major comorbidity of obesity. It results from a combination of fat excess-triggered defects, including lipotoxicity and metaflammation, but the causal mechanisms remain difficult to identify. Here, we report that hyperactivation of the tyrosine phosphatase SHP2 found in Noonan syndrome (NS) led to an unsuspected insulin resistance profile uncoupled from altered lipid management (for example, obesity or ectopic lipid deposits) in both patients and mice.

Rituximab-resistant splenic memory B cells and newly engaged naive B cells fuel relapses in patients with immune thrombocytopenia.

Rituximab (RTX), an antibody targeting CD20, is widely used as a first-line therapeutic strategy in B cell-mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Here, we characterize the cellular basis responsible for disease relapse in secondary lymphoid organs in humans, taking advantage of the opportunity offered by therapeutic splenectomy in patients with relapsing immune thrombocytopenia.

Molecular Signatures of Kidney Antibody-Secreting Cells in Lupus Patients With Active Nephritis Upon Immunosuppressive Therapy.

Objective: This study was undertaken to characterize kidney and urine antibody-secreting cells (ASCs) from patients with active lupus nephritis, before and after induction therapy.

Methods: We included patients with biopsy-proven active lupus nephritis and performed anti-CD138 staining of kidney biopsy samples to visualize ASCs. We performed single-cell gene expression profiling on sorted ASCs from fresh biopsy samples using multiplex reverse transcriptase-polymerase chain reaction.

Efficacy, safety and immunological profile of combining rituximab with belimumab for adults with persistent or chronic immune thrombocytopenia: results from a prospective phase 2b trial.

B-cell activating factor may be involved in the failure of B-cell depleting therapy with rituximab in immune thrombocytopenia (ITP) by promoting the emergence of splenic long-lived plasma cells. From results obtained in mouse models, we hypothesized that combining rituximab with sequential injections of belimumab could increase the rate of response at one year in patients with persistent or chronic ITP by preventing the emergence of these long-lived plasma cells. The study was a single-center, single arm, prospective phase 2b trial (RITUX-PLUS, NCT03154385) investigating the safety and efficacy of rituximab given at a fixed dose of 1,000 mg, two weeks apart, combined with five infusions of belimumab, 10 mg/kg at week 0 (W0)+2 days, W2+2 days, W4, W8 and W12 for adults with primary persistent or chronic ITP.

Social distancing responses to COVID-19 emergency declarations strongly differentiated by income.

In the absence of a vaccine, social distancing measures are one of the primary tools to reduce the transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, which causes coronavirus disease 2019 (COVID-19). We show that social distancing following US state-level emergency declarations substantially varies by income. Using mobility measures derived from mobile device location pings, we find that wealthier areas decreased mobility significantly more than poorer areas, and this general pattern holds across income quantiles, data sources, and mobility measures.

Anti-CD20-mediated B-cell depletion in autoimmune diseases: successes, failures and future perspectives.

B-cell depletion with anti-CD20 monoclonal antibodies is widely used for the treatment of autoimmune diseases. This review will discuss mechanisms contributing to success or failure of B-cell depletion therapy in antibody-mediated autoimmune diseases. It will also explain how key information about disease pathogeny can be provided by the different outcomes observed after B-cell depletion therapy.