Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus. Magri et al. found that the human gut includes a large memory IgM+ B cell repertoire clonally related to plasma cells mounting SIgM responses against mucus-embedded commensals co-targeted by SIgA. Dually coated bacteria are detected in humans but not mice and show increased diversity and richness compared to SIgA-only-coated or uncoated bacteria.</p

Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

Secretory immunoglobulin A (SIgA) enhances host-microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut-specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell-independent or T cell-dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus-embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA-only-coated or uncoated bacteria. Thus, SIgM may emerge from pre-existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus. Magri et al. found that the human gut includes a large memory IgM+ B cell repertoire clonally related to plasma cells mounting SIgM responses against mucus-embedded commensals co-targeted by SIgA. Dually coated bacteria are detected in humans but not mice and show increased diversity and richness compared to SIgA-only-coated or uncoated bacteria.</p

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients

Characterizing the B cell response and understanding the mechanism of action of vedolizumab in ulcerative colitis and chronic HIV-1 infection

La rectocolite hémorragique (RCH) est une maladie inflammatoire chronique intestinale (MICI) qui est caractérisée par l’inflammation chronique du rectum et/ou du côlon. Bien que l’idée qu’il existe une réponse immunitaire exagérée contre le microbiote intestinal soit communément acceptée, la physiopathologie est encore insuffisamment connue. Parmi les dysfonctions immunitaires, il existe des arguments en faveur d’un dérèglement de la biologie des lymphocytes B. A l’aide de plusieurs techniques (dont la cytométrie en flux, le single-cell RNA sequencing et le single-cell BCR sequencing), nous avons mis en évidence des modifications marquées des populations plasmocytaires coliques chez des patients avec RCH, dont une augmentation de l’expression des IgG et IgA1 et une diminution en IgA2 associées à l’accroissement de la proportion des plasmocytes à durée de vie courte. Ce turnover accru se reflétait dans la circulation sanguine par l’élévation des plasmablastes ?7+ à tropisme intestinal, associé à l’activité de la maladie et à la survenue de complications. Notre second travail s’intéressait au mécanisme d’action du vedolizumab (anti-?4?7), traitement couramment utilisé dans les MICI et prometteur pour le VIH. Dans une cohorte de patients atteints à la fois de MICI et du VIH, mous avons mis en évidence un impact majeur sur les follicules lymphoïdes intestinaux avec une absence d’effet significatif sur la fréquence des lymphocytes T effecteurs de la lamina propria. Cette découverte, décrite pour la première fois chez l’homme, ouvre de nouvelles perspectives quant au mécanisme d’action du vedolizumab dans les MICI et le VIH.Ulcerative Colitis (UC) is an inflammatory bowel disease (IBD) that leads to chronic inflammation of the rectum and the colon. Even though it is commonly accepted that it results from an exaggerated immune response toward the gut microbiota, the pathophysiology is still not fully understood. Among immune defects, many evidences exist supporting a disturbed B cell system, including the presence of (auto-)antibodies and the infiltration of the lamina propria by plasma cells. Using multiple advanced techniques including single-cell RNA sequencing and single-cell BCR sequencing we extensively characterized the B cell compartment in the blood and the intestinal mucosa of UC patients. We found that the colonic plasma cells phenotype was skewed toward an increased expression of IgG and IgA1 and an increased proportion of short-lived plasma cells. This increased turnover was reflected in the blood by the expansion of ?7+ plasmablasts, which correlated with disease activity and predicted disease course. Our second work focused on the mechanism of action of vedolizumab, a monoclonal antibody targeting the ?4?7 integrin, for both IBD and HIV. In a unique cohort of patients with concomitant IBD and HIV, we unexpectedly found that memory T cells within the lamina propria were not significantly affected. Conversely, lymphoid aggregates, mostly in the terminal ileum were massively impacted. These findings are being further explored and may change the paradigm regarding the mechanism of action of vedolizumab

Etude de la biologie des lymphocytes B et du mécanisme d'action du vedolizumab dans la rectocolite hémorragique et au cours de l'infection chronique à VIH

Ulcerative Colitis (UC) is an inflammatory bowel disease (IBD) that leads to chronic inflammation of the rectum and the colon. Even though it is commonly accepted that it results from an exaggerated immune response toward the gut microbiota, the pathophysiology is still not fully understood. Among immune defects, many evidences exist supporting a disturbed B cell system, including the presence of (auto-)antibodies and the infiltration of the lamina propria by plasma cells. Using multiple advanced techniques including single-cell RNA sequencing and single-cell BCR sequencing we extensively characterized the B cell compartment in the blood and the intestinal mucosa of UC patients. We found that the colonic plasma cells phenotype was skewed toward an increased expression of IgG and IgA1 and an increased proportion of short-lived plasma cells. This increased turnover was reflected in the blood by the expansion of ?7+ plasmablasts, which correlated with disease activity and predicted disease course. Our second work focused on the mechanism of action of vedolizumab, a monoclonal antibody targeting the ?4?7 integrin, for both IBD and HIV. In a unique cohort of patients with concomitant IBD and HIV, we unexpectedly found that memory T cells within the lamina propria were not significantly affected. Conversely, lymphoid aggregates, mostly in the terminal ileum were massively impacted. These findings are being further explored and may change the paradigm regarding the mechanism of action of vedolizumab.La rectocolite hémorragique (RCH) est une maladie inflammatoire chronique intestinale (MICI) qui est caractérisée par l’inflammation chronique du rectum et/ou du côlon. Bien que l’idée qu’il existe une réponse immunitaire exagérée contre le microbiote intestinal soit communément acceptée, la physiopathologie est encore insuffisamment connue. Parmi les dysfonctions immunitaires, il existe des arguments en faveur d’un dérèglement de la biologie des lymphocytes B. A l’aide de plusieurs techniques (dont la cytométrie en flux, le single-cell RNA sequencing et le single-cell BCR sequencing), nous avons mis en évidence des modifications marquées des populations plasmocytaires coliques chez des patients avec RCH, dont une augmentation de l’expression des IgG et IgA1 et une diminution en IgA2 associées à l’accroissement de la proportion des plasmocytes à durée de vie courte. Ce turnover accru se reflétait dans la circulation sanguine par l’élévation des plasmablastes ?7+ à tropisme intestinal, associé à l’activité de la maladie et à la survenue de complications. Notre second travail s’intéressait au mécanisme d’action du vedolizumab (anti-?4?7), traitement couramment utilisé dans les MICI et prometteur pour le VIH. Dans une cohorte de patients atteints à la fois de MICI et du VIH, mous avons mis en évidence un impact majeur sur les follicules lymphoïdes intestinaux avec une absence d’effet significatif sur la fréquence des lymphocytes T effecteurs de la lamina propria. Cette découverte, décrite pour la première fois chez l’homme, ouvre de nouvelles perspectives quant au mécanisme d’action du vedolizumab dans les MICI et le VIH