sciCSR infers B cell state transition and predicts class-switch recombination dynamics using single-cell transcriptomic data.

Class-switch recombination (CSR) is an integral part of B cell maturation. Here we present sciCSR (pronounced 'scissor', single-cell inference of class-switch recombination), a computational pipeline that analyzes CSR events and dynamics of B cells from single-cell RNA sequencing (scRNA-seq) experiments. Validated on both simulated and real data, sciCSR re-analyzes scRNA-seq alignments to differentiate productive heavy-chain immunoglobulin transcripts from germline 'sterile' transcripts. From a snapshot of B cell scRNA-seq data, a Markov state model is built to infer the dynamics and direction of CSR. Applying sciCSR on severe acute respiratory syndrome coronavirus 2 vaccination time-course scRNA-seq data, we observe that sciCSR predicts, using data from an earlier time point in the collected time-course, the isotype distribution of B cell receptor repertoires of subsequent time points with high accuracy (cosine similarity ~0.9). Using processes specific to B cells, sciCSR identifies transitions that are often missed by conventional RNA velocity analyses and can reveal insights into the dynamics of B cell CSR during immune response.

A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus.

Signals controlling the generation of regulatory B (Breg) cells remain ill-defined. Here we report an "auto"-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19(+)CD24(hi)CD38(hi) (immature) B cells into IL-10-producing CD24(+)CD38(hi) Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement. CD24(+)CD38(hi) Breg cells conversely restrained IFN-α production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α. Defective pDC-mediated expansion of CD24(+)CD38(hi) Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24(+)CD38(hi) Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24(+)CD38(hi) Breg cell interaction contributes to the pathogenesis of SLE.

Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae.

BACKGROUND: Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints. METHODS: 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms. RESULTS: Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms. CONCLUSIONS: We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC.

Evidence of Orientia spp. Endemicity among Severe Infectious Disease Cohorts, Uganda.

At 3 severe infection cohort sites in Uganda, Orientia seropositivity was common. We identified 4 seroconversion cases and 1 PCR-positive case. These results provide serologic and molecular support for Orientia spp. circulating in sub-Saharan Africa, possibly expanding its endemic range. Orientia infections could cause severe illness and hospitalizations in this region.

Transfusing Convalescent Plasma as Post-Exposure Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Double-Blinded, Phase 2 Randomized, Controlled Trial.

BACKGROUND: The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection. METHODS: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection. RESULTS: In total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups. CONCLUSIONS: Administration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection. CLINICAL TRIALS REGISTRATION: NCT04323800.

The incognito journey of a regulatory B cell.

Regulatory B cells have largely been reported as B cells at a developmental stage before plasma cell differentiation. Matsumoto et al. (2014) report that IL-10(+) plasmablasts restrain autoimmune inflammation and suggest an ontological connection between immature B cells and regulatory plasmablasts.

Differential Cytokine Signatures of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Influenza Infection Highlight Key Differences in Pathobiology.

BACKGROUND: Several inflammatory cytokines are upregulated in severe coronavirus disease 2019 (COVID-19). We compared cytokines in COVID-19 versus influenza to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease. METHODS: Thirty-seven cytokines and chemokines were measured in plasma from 135 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was used to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was used to identify cytokines that mediate the effect of BMI and age on disease severity. RESULTS: Interleukin-18 (IL-18), IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were significantly increased in COVID-19 versus influenza patients, whereas granulocyte macrophage colony-stimulating factor, interferon-γ (IFN-γ), IFN-λ1, IL-10, IL-15, and monocyte chemoattractant protein 2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF-α were elevated in severe COVID-19, but not in severe influenza. Random forest analysis identified high IL-6 and low IFN-λ1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity. CONCLUSIONS: These findings point to activation of fundamentally different innate immune pathways in severe acute respiratory syndrome coronavirus 2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.

Mechanisms of induction of regulatory B cells in the tumour microenvironment and their contribution to immunosuppression and pro-tumour responses.

The presence of tumour-infiltrating immune cells was originally associated with the induction of anti-tumour responses and good a prognosis. A more refined characterization of the tumour microenvironment has challenged this original idea and evidence now exists pointing to a critical role for immune cells in the modulation of anti-tumour responses and the induction of a tolerant pro-tumour environment. The coordinated action of diverse immunosuppressive populations, both innate and adaptive, shapes a variety of pro-tumour responses leading to tumour progression and metastasis. Regulatory B cells have emerged as critical modulators and suppressors of anti-tumour responses. As reported in autoimmunity and infection studies, Bregs are a heterogeneous population with diverse phenotypes and different mechanisms of action. Here we review recent studies on Bregs from animal models and patients, covering a variety of types of cancer. We describe the heterogeneity of Bregs, the cellular interactions they make with other immune cells and the tumour itself, and their mechanism of suppression that enables tumour escape. We also discuss the potential therapeutic tools that may inhibit Bregs function and promote anti-tumour responses.

Aetiology of hospitalized fever and risk of death at Arua and Mubende tertiary care hospitals in Uganda from August 2019 to August 2020.

BACKGROUND: Epidemiology of febrile illness in Uganda is shifting due to increased HIV treatment access, emerging viruses, and increased surveillance. We investigated the aetiology and outcomes of acute febrile illness in adults presenting to hospital using a standardized testing algorithm of available assays in at Arua and Mubende tertiary care hospitals in Uganda. METHODS: We recruited adults with a ≥ 38.0 °C temperature or history of fever within 48 h of presentation from August 2019 to August 2020. Medical history, demographics, and vital signs were recorded. Testing performed included a complete blood count, renal and liver function, malaria smears, blood culture, and human immunodeficiency virus (HIV). When HIV positive, testing included cryptococcal antigen, CD4 count, and urine lateral flow lipoarabinomannan assay for tuberculosis. Participants were followed during hospitalization and at a 1-month visit. A Cox proportional hazard regression was performed to evaluate for baseline clinical features and risk of death. RESULTS: Of 132 participants, the median age was 33.5 years (IQR 24 to 46) and 58.3% (n = 77) were female. Overall, 73 (55.3%) of 132 had a positive microbiologic result. Among those living with HIV, 31 (68.9%) of 45 had at least one positive assay; 16 (35.6%) had malaria, 14 (31.1%) tuberculosis, and 4 (8.9%) cryptococcal antigenemia. The majority (65.9%) were HIV-negative; 42 (48.3%) of 87 had at least one diagnostic assay positive; 24 (27.6%) had positive malaria smears and 1 was Xpert MTB/RIF Ultra positive. Overall, 16 (12.1%) of 132 died; 9 (56.3%) of 16 were HIV-negative, 6 died after discharge. High respiratory rate (≥ 22 breaths per minute) (hazard ratio [HR] 8.05; 95% CI 1.81 to 35.69) and low (i.e., < 92%) oxygen saturation (HR 4.33; 95% CI 1.38 to 13.61) were identified to be associated with increased risk of death. CONCLUSION: In those with hospitalized fever, malaria and tuberculosis were common causes of febrile illness, but most deaths were non-malarial, and most HIV-negative participants did not have a positive diagnostic result. Those with respiratory failure had a high risk of death.

Distinct Cytokine and Chemokine Dysregulation in Hospitalized Children With Acute Coronavirus Disease 2019 and Multisystem Inflammatory Syndrome With Similar Levels of Nasopharyngeal Severe Acute Respiratory Syndrome Coronavirus 2 Shedding.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe clinical phenotype of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that remains poorly understood. METHODS: Hospitalized children <18 years of age with suspected coronavirus disease 2019 (COVID-19) (N = 53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the US Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral ribonucleic acid (RNA) levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. RESULTS: The median ages for those with and without MIS-C were 8.7 years (interquartile range [IQR], 5.5-13.9) and 2.2 years (IQR, 1.1-10.5), respectively (P = .18), and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the 2 groups (median 63 848.25 copies/mL versus 307.1 copies/mL, P = .66); 75% of those with MIS-C were antibody positive compared with 44% without (P = .026). Levels of 14 of 37 cytokines/chemokines (interleukin [IL]-1RA, IL-2RA, IL-6, IL-8, tumor necrosis factor-α, IL-10, IL-15, IL-18, monocyte chemoattractant protein [MCP]-1, IP-10, macrophage-inflammatory protein [MIP]-1α, MCP-2, MIP-1ß, eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (false discovery rate <0.05; P < .05). CONCLUSIONS: The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.

Durability of SARS-CoV-2-Specific T-Cell Responses at 12 Months Postinfection.

BACKGROUND: Characterizing the longevity and quality of cellular immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enhances understanding of coronavirus disease 2019 (COVID-19) immunity that influences clinical outcomes. Prior studies suggest SARS-CoV-2-specific T cells are present in peripheral blood 10 months after infection. Analysis of the function, durability, and diversity of cellular response long after natural infection, over a range of ages and disease phenotypes, is needed to identify preventative and therapeutic interventions. METHODS: We identified participants in our multisite longitudinal, prospective cohort study 12 months after SARS-CoV-2 infection representing a range of disease severity. We investigated function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry, and compared magnitude of SARS-CoV-2-specific antibodies. RESULTS: SARS-CoV-2-specific antibodies and T cells were detected 12 months postinfection. Severe acute illness was associated with higher frequencies of SARS-CoV-2-specific CD4 T cells and antibodies at 12 months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity. CONCLUSIONS: SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12 months postinfection, with higher frequency noted in those who experienced severe disease.

Intensive Care Unit-Like Care of Nonhuman Primates with Ebola Virus Disease.

BACKGROUND: Ebola virus disease (EVD) supportive care strategies are largely guided by retrospective observational research. This study investigated the effect of EVD supportive care algorithms on duration of survival in a controlled nonhuman primate (NHP) model. METHODS: Fourteen rhesus macaques were challenged intramuscularly with a target dose of Ebola virus (1000 plaque-forming units; Kikwit). NHPs were allocated to intensive care unit (ICU)-like algorithms (n = 7), intravenous fluids plus levofloxacin (n = 2), or a control group (n = 5). The primary outcome measure was duration of survival, and secondary outcomes included changes in clinical laboratory values. RESULTS: Duration of survival was not significantly different between the pooled ICU-like algorithm and control groups (8.2 vs 6.9 days of survival; hazard ratio; 0.50; P = .25). Norepinephrine was effective in transiently maintaining baseline blood pressure. NHPs treated with ICU-like algorithms had delayed onset of liver and kidney injury. CONCLUSIONS: While an obvious survival difference was not observed with ICU-like care, clinical observations from this model may aid in EVD supportive care NHP model refinement.

CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients.

The immunosuppressive function of regulatory B cells has been shown in several murine models of chronic inflammation, including collagen-induced arthritis, inflammatory bowel disease, and experimental autoimmune encephalomyelitis. Despite interest in these cells, their relevance to the maintenance of peripheral tolerance in humans remains elusive. Here, we demonstrate that human CD19(+)CD24(hi)CD38(hi) B cells possessed regulatory capacity. After CD40 stimulation, CD19(+)CD24(hi)CD38(hi) B cells suppressed the differentiation of T helper 1 cells, partially via the provision of interleukin-10 (IL-10), but not transforming growth factor-beta (TGF-beta), and their suppressive capacity was reversed by the addition of CD80 and CD86 mAbs. In addition, CD19(+)CD24(hi)CD38(hi) SLE B cells isolated from the peripheral blood of systemic lupus erythematosus (SLE) patients were refractory to further CD40 stimulation, produced less IL-10, and lacked the suppressive capacity of their healthy counterparts. Altered cellular function within this compartment may impact effector immune responses in SLE and other autoimmune disorders.

Endovascular treatment for ruptured abdominal aortic aneurysm.

BACKGROUND: An abdominal aortic aneurysm (AAA) (pathological enlargement of the aorta) is a condition that can occur as a person ages. It is most commonly seen in men older than 65 years of age. Progressive aneurysm enlargement can lead to rupture and massive internal bleeding, which is fatal unless timely repair can be achieved. Despite improvements in perioperative care, mortality remains high (approximately 50%) after conventional open surgical repair. Endovascular aneurysm repair (EVAR), a minimally invasive technique, has been shown to reduce early morbidity and mortality as compared to conventional open surgery for planned AAA repair. More recently emergency endovascular aneurysm repair (eEVAR) has been used successfully to treat ruptured abdominal aortic aneurysm (RAAA), proving that it is feasible in select patients; however, it is unclear if eEVAR will lead to significant improvements in outcomes for these patients or if indeed it can replace conventional open repair as the preferred treatment for this lethal condition. This is an update of the review first published in 2006. OBJECTIVES: To assess the advantages and disadvantages of emergency endovascular aneurysm repair (eEVAR) in comparison with conventional open surgical repair for the treatment of ruptured abdominal aortic aneurysm (RAAA). This will be determined by comparing the effects of eEVAR and conventional open surgical repair on short-term mortality, major complication rates, aneurysm exclusion (specifically endoleaks in the eEVAR treatment group), and late complications. SEARCH METHODS: For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (last searched June 2016), CENTRAL (2016, Issue 5), and trials registries. We also checked reference lists of relevant publications. SELECTION CRITERIA: Randomised controlled trials in which participants with a clinically or radiologically diagnosed RAAA were randomly allocated to eEVAR or conventional open surgical repair. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies identified for potential inclusion for eligibility. Two review authors also independently completed data extraction and quality assessment. Disagreements were resolved through discussion. We performed meta-analysis using fixed-effect models with odds ratios (ORs) and 95% confidence intervals (CIs) for dichotomous data and mean differences with 95% CIs for continuous data. MAIN RESULTS: We included four randomised controlled trials in this review. A total of 868 participants with a clinical or radiological diagnosis of RAAA were randomised to receive either eEVAR or open surgical repair. Overall risk of bias was low, but we considered one study that performed randomisation in blocks by week and performed no allocation concealment and no blinding to be at high risk of selection bias. Another study did not adequately report random sequence generation, putting it at risk of selection bias, and two studies were underpowered. There was no clear evidence to support a difference between the two interventions for 30-day (or in-hospital) mortality (OR 0.88, 95% CI 0.66 to 1.16; moderate-quality evidence). There were a total of 44 endoleak events in 128 participants from three studies (low-quality evidence). Thirty-day complication outcomes (myocardial infarction, stroke, composite cardiac complications, renal complications, severe bowel ischaemia, spinal cord ischaemia, reoperation, amputation, and respiratory failure) were reported in between one and three studies, therefore we were unable to draw a robust conclusion. We downgraded the quality of the evidence for myocardial infarction, renal complications, and respiratory failure due to imprecision, inconsistency, and risk of bias. Odds ratios for complications outcomes were OR 2.38 (95% CI 0.34 to 16.53; 139 participants; 2 studies; low-quality evidence) for myocardial infarction; OR 1.07 (95% CI 0.21 to 5.42; 255 participants; 3 studies; low-quality evidence) for renal complications; and OR 3.62 (95% CI 0.14 to 95.78; 32 participants; 1 study; low-quality evidence) for respiratory failure. There was low-quality evidence of a reduction in bowel ischaemia in the eEVAR treatment group, but very few events were reported (OR 0.37, 95% CI 0.14 to 0.94), and we downgraded the evidence due to imprecision and risk of bias. Six-month and one-year outcomes were evaluated in three studies, but only results from a single study could be used for each outcome, which showed no clear evidence of a difference between the interventions. We rated six-month mortality evidence as of moderate quality due to imprecision (OR 0.89, 95% CI 0.40 to 1.98; 116 participants). AUTHORS' CONCLUSIONS: The conclusions of this review are currently limited by the paucity of data. We found from the data available moderate-quality evidence suggesting there is no difference in 30-day mortality between eEVAR and open repair. Not enough information was provided for complications for us to make a well-informed conclusion, although it is possible that eEVAR is associated with a reduction in bowel ischaemia. Long-term data were lacking for both survival and late complications. More high-quality randomised controlled trials comparing eEVAR and open repair for the treatment of RAAA are needed to better understand if one method is superior to the other, or if there is no difference between the methods on relevant outcomes.

Mycobacterium fortuitum empyema associated with an indwelling pleural catheter: Case report and review of the literature.

Mycobacterium fortuitum is a rapidly growing mycobacterium (RGM) that is an uncommon cause of healthcare-associated infections. The most common infections caused by M. fortuitum include skin, soft tissue, and catheter-related infections. Although occasionally cultured from sputum samples, M. fortuitum is a rare cause of pulmonary disease. We report a case of M. fortuitum empyema associated with an infected pleural catheter and review M. fortuitum pulmonary infections.

Transitional-2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival.

In humans, tolerance to renal transplants has been associated with alterations in B-cell gene transcription and maintenance of the numbers of circulating transitional B cells. Here, we use a mouse model of transplantation tolerance to investigate the contribution of B cells to allograft survival. We demonstrate that transfer of B cells from mice rendered tolerant to MHC class I mismatched skin grafts can prolong graft survival in a dose-dependent and antigen-specific manner to a degree similar to that afforded by graft-specific regulatory T (Treg) cells. Tolerance in this model was associated with an increase in transitional-2 (T2) B cells. Only T2 B cells from tolerized mice, not naïve T2 nor alloantigen experienced T2, were capable of prolonging skin allograft survival, and suppressing T-cell activation. Tolerized T2 B cells expressed lower levels of CD86, increased TIM-1, and demonstrated a preferential survival in vivo. Furthermore, we demonstrate a synergistic effect between tolerized B cells and graft-specific Treg cells. IL-10 production by T2 B cells did not contribute to tolerance, as shown by transfer of B cells from IL-10(-/-) mice. These results suggest that T2 B cells in tolerant patients may include a population of regulatory B cells that directly inhibit graft rejection.

Late aneurysm rupture after delayed secondary open conversion with partial explantation for failed endovascular repair.

A delayed secondary open conversion (SOC) after endovascular aneurysm repair may be necessary due to a failing graft. Many surgical techniques can be performed, and one such approach is partial explantation of the graft with resuturing of a new graft to the retained components of the endograft. No guidelines exist with regards to the follow-up of retained endovascular components after a delayed SOC. The theoretical risk of endoleaks remains with retained components, and this case demonstrates the development of a type Ib endoleak after SOC leading to free flow of blood into a partially resected aneurysm sac and causing a symptomatic aneurysm rupture.

Regulatory B cells in CVID patients fail to suppress multifunctional IFN-γ+ TNF-α+ CD4+ T cells differentiation.

Common variable immunodeficiency (CVID) refers to primary hypogammaglobulinemia with unknown pathogenesis. Although there is evidence for intrinsic B cell defects in some CVID patient groups, various abnormalities in cytokine production by T cells in CVID patients are frequently observed. Here, we demonstrate a relationship in the production of pro-inflammatory Th1 cytokines and regulatory B cells producing IL-10 between CVID patients and healthy controls. We describe CD19(+)CD24(hi)CD38(hi)IL-10(+) regulatory B cells generated after T cell stimulation of human peripheral blood lymphocytes ex vivo are able to suppress IFN-γ(+)TNF-α(+) producing CD4(+) T cells. This process is impaired in CVID patients, who present with both low numbers of CD19(+)CD24(hi)CD38(hi)IL-10(+) B cells and increased numbers of IFN-γ(+)TNF-α(+)CD4(+) T cells. Disruption of the regulatory B cell response to T cell stimulation explains the excessive T cell activation regarded as an immunoregulatory abnormality that is a frequent finding in CVID patients.

Carotid-access transcatheter aortic valve replacement in a patient with a previous mitral valve replacement.

We describe a case of transcatheter aortic valve replacement (TAVR) using carotid artery access and regional anesthesia in a patient with rheumatic heart disease, previous mitral valve replacement, and multiple co-morbidities. It highlights the role of the multidisciplinary Heart Team and multimodality imaging in reaching and implementing an appropriate management plan in this complex patient group.

IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection.

A regulatory subset of B cells has been found to modulate immune responses in autoimmunity, infection, and cancer, but it has not been investigated in the setting of human persistent viral infection. IL-10 is elevated in patients with chronic hepatitis B virus infection (CHB), but its cellular sources and impact on antiviral T cells have not been addressed. We investigated the role of IL-10 and regulatory B cells in the pathogenesis of CHB. Serum IL-10 levels were studied longitudinally in patients with CHB undergoing spontaneous disease flares. There was a close temporal correlation between IL-10 levels and fluctuations in viral load or liver inflammation. Blockade of IL-10 in vitro rescued polyfunctional virus-specific CD8 T cell responses. To investigate the potential contribution of regulatory B cells, their frequency was measured directly ex vivo and after exposure to stimuli relevant to hepatitis B virus (HBV) (CpG or HBV Ags). IL-10-producing B cells were enriched in patients, and their frequency correlated temporally with hepatic flares, both after stimulation and directly ex vivo. Phenotypically, these cells were predominantly immature (CD19(+)CD24(hi)CD38(hi)) ex vivo; sorted CD19(+)CD24(hi)CD38(hi) cells suppressed HBV-specific CD8 T cell responses in an IL-10-dependent manner. In summary, these data reveal a novel IL-10-producing subset of B cells able to regulate T cell immunity in CHB.