Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell ...and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.
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•Seasonal coronavirus memory B cells contribute to the early anti-SARS-CoV-2 response•Spike-specific memory B cells with a resting phenotype increase up to 6 months•Somatic mutations accumulate in SARS-CoV-2-specific memory B cells over time•Longitudinal study reveals a temporal switch to anti-RBD neutralizing memory B cells
The B cell response against SARS-CoV-2 shows a temporal shift from an extrafollicular reaction that includes memory B cells against seasonal coronaviruses toward a germinal center-dependent memory response encoding (spike-specific) neutralizing antibodies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Alloimmunization against red blood cells (RBCs) is the main immunological risk associated with transfusion in patients with sickle cell disease (SCD). However, about 50–70% of SCD patients never get ...immunized despite frequent transfusion. In murine models, CD4+ T cells play a key role in RBC alloimmunization. We therefore explored and compared the CD4+ T‐cell phenotypes and functions between a group of SCD patients (n = 11) who never became immunized despite a high transfusion regimen and a group of SCD patients (n = 10) who had become immunized (at least against Kidd antigen b) after a low transfusion regimen. We studied markers of CD4+ T‐cell function, including TLR, that directly control lymphocyte function, and their spontaneous cytokine production. We also tested responders for the cytokine profile in response to Kidd antigen b peptides. Low TLR2/TLR3 expression and, unexpectedly, strong expression of CD40 on CD4+ T cells were associated with the nonresponder status, whereas spontaneous expression of IL‐10 by CD4+ T cells and weak Tbet expression were associated with the responder status. A Th17 profile was predominant in responders when stimulated by Jbk. These findings implicate CD4+ T cells in alloimmunization in humans and suggest that they may be exploited to differentiate responders from nonresponders.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BACKGROUND
Transfusion‐transmitted bacterial infections (TTBIs) are the main residual infectious complications of transfusions. Escherichia coli and platelet (PLT) concentrates may be ...epidemiologically associated, leading to severe, if not lethal, TTBIs. We investigated the genotypic and phenotypic reasons for this clinically deleterious combination.
STUDY DESIGN AND METHODS
We investigated a French national E. coli strain collection related to six independent episodes of TTBIs. Their phenotypic characterizations included antibiotic susceptibility testing, growth testing under different culture conditions, serum survival assays, and virulence in a sepsis mouse model. Their genotypic characterizations included polymerase chain reaction phylotyping, whole genome sequencing, and a subsequent in silico analysis.
RESULTS
We highlighted a selection process of highly extraintestinal virulent strains, mainly belonging to the B2 phylogroup, adapted to the hostile environment (high citrate concentration and a bactericidal serum effect) of apheresis‐collected platelet concentrates (PCs). Compared to controls, the E. coli TTBI strains grew faster in the PCs due to a superior ability to capture iron. The in vitro growth performances were highly compatible with blood‐derived product real‐life conditions, including storage conditions and delays. The consistent serum resistance of TTBI strains promotes their survival in both the donor's and the receiver's blood and in the PCs.
CONCLUSION
This study pointed out that E. coli strains responsible for TTBI exhibit very specific traits. They belong to the extraintestinal pathogenic phylogroups and have a high intrinsic virulence. They can be resistant to complement, capture iron, and grow in the apheresis‐collected PCs. These findings therefore support the reinforcement of the postdonation information.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BACKGROUND: Delayed hemolytic transfusion reaction (DHTR) is a life‐threatening complication in sickle cell disease (SCD) characterized by recurrence of disease complications, recipient red blood ...cell (RBC) destruction, and frequently no detectable antibody. Phosphatidylserine (PS) exposure signs suicidal RBC death or eryptosis and is involved in vasoocclusive crisis (VOC).
STUDY DESIGN AND METHODS: Transfusion was monitored in 48 SCD patients for up to 20 days. PS exposure was evaluated in vivo on patient RBCs (PS‐RBCs) at five time points and in vitro after incubation of donor RBCs with pretransfusion plasma.
RESULTS: Three VOC patients displayed DHTR with recurrent SCD features and no detectable antibody in two cases. In vitro, PS‐RBC percentage was significantly increased by incubating donor RBCs with pretransfusion plasma samples from DHTR patients with no detectable antibody. No such increase was observed with samples from other patients. This result indicates that donor RBCs may be damaged by the environment of SCD patients, increasing the physiologic clearance of apoptotic RBCs. In vivo, PS‐RBC percentage increased in all three cases after destruction of transfused RBCs, indicating that DHTR induces PS‐RBCs and, possibly, subsequent VOC and autologous RBC destruction.
CONCLUSION: This study clearly demonstrates that DHTR can occur in the absence of detectable antibody. In these cases, a mechanism of excessive eryptosis is proposed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Murine models of red blood cell transfusion show that inflammation associated with viruses or methylated DNA promotes red blood cell alloimmunization. In vaccination studies, the intensity of ...antigen-specific responses depends on the delay between antigen and adjuvant administration, with a short delay limiting immune responses. In mouse models of alloimmunization, the delay between the injection of Toll-like receptor agonists and transfusion is usually short. In this study, we hypothesized that the timing of Toll-like receptor 3 agonist administration affects red blood cell alloimmunization. Poly(I:C), a Toll-like receptor 3 agonist, was administered to B10BR mice at various time points before the transfusion of HEL-expressing red blood cells. For each time point, we measured the activation of splenic HEL-presenting dendritic cells, HEL-specific CD4(+) T cells and anti-HEL antibodies in serum. The phenotype of activated immune cells depended on the delay between transfusion and Toll-like receptor-dependent inflammation. The production of anti-HEL antibodies was highest when transfusion occurred 7 days after agonist injection. The proportion of HEL-presenting CD8α(+) dendritic cells producing interleukin-12 was highest in mice injected with poly(I:C) 3 days before transfusion. Although the number of early-induced HEL-specific CD4(+) T cells was similar between groups, a high proportion of these cells expressed CD134, CD40 and CD44 in mice injected with poly(I:C) 7 days before transfusion. This study clearly shows that the delay between transfusion and Toll-like receptor-induced inflammation influences the immune response to transfused red blood cells.
Background
Pneumococcal hemolytic uremic syndrome (P‐HUS) is a rare but severe complication of invasive pneumococcal disease (IPD) in young children. Consensual biologic diagnosis criteria are ...currently lacking.
Study Design and Methods
A prospective study was conducted on 10 children with culture‐confirmed IPD. Five presented with full‐blown P‐HUS, three had an incomplete form with hemolytic anemia and mild or no uremia (P‐HA), and two had neither HUS nor HA. Thomsen‐Friedenreich (T), Th, and Tk cryptantigens and sialic acid expression were determined on red blood cells (RBCs) with peanut (PNA), Glycine soja (SBA), Bandeiraea simplicifolia II, and Maackia amurensis lectins. Plasma concentrations of the major endogenous T‐antigen–binding protein, galectin‐3 (Gal‐3), were analyzed.
Results
We found that RBCs strongly reacted with PNA and SBA lectins in all P‐HUS and P‐HA patients. Three P‐HUS and three P‐HA patients showed also concomitant Tk activation. Direct antiglobulin test (DAT) was positive in three P‐HUS (one with anti‐C3d and two with anti‐IgG) and two P‐HA patients (one with anti‐C3d and one with anti‐IgG). RBCs derived from the two uncomplicated IPD patients reacted with PNA but not with SBA lectin. Gal‐3 plasma concentrations were increased in all P‐HUS patients.
Conclusions
The results indicate high levels of neuraminidase activity and desialylation in both P‐HUS and P‐HA patients. T‐antigen activation is more sensitive than DAT for P‐HUS diagnosis. Combining PNA and SBA lectins is needed to improve the specificity of T‐antigen activation. High concentrations of Gal‐3 in P‐HUS patients suggest that Gal‐3 may contribute to the pathogenesis of P‐HUS.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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