Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.

Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.

Cbl Ubiquitin Ligases Control B Cell Exit from the Germinal-Center Reaction.

Selective expansion of high-affinity antigen-specific B cells in germinal centers (GCs) is a key event in antibody affinity maturation. GC B cells with improved affinity can either continue affinity-driven selection or exit the GC to differentiate into plasma cells (PCs) or memory B cells. Here we found that deleting E3 ubiquitin ligases Cbl and Cbl-b (Cbls) in GC B cells resulted in the early exit of high-affinity antigen-specific B cells from the GC reaction and thus impaired clonal expansion. Cbls were highly expressed in GC light zone (LZ) B cells, where they promoted the ubiquitination and degradation of Irf4, a transcription factor facilitating PC fate choice. Strong CD40 and BCR stimulation triggered the Cbl degradation, resulting in increased Irf4 expression and exit from GC affinity selection. Thus, a regulatory cascade that is centered on the Cbl ubiquitin ligases ensures affinity-driven clonal expansion by connecting BCR affinity signals with differentiation programs.

Regulation of immune system development and function by Cbl-mediated ubiquitination.

Ubiquitination is a form of posttranslational protein modification that affects the activity of target proteins by regulating their intracellular degradation, trafficking, localization, and association with other regulators. Recent studies have placed protein ubiquitination as an important regulatory mode to control immune system development, function, and pathogenesis. In this review, we will mainly update the research progress from our laboratory on the roles of the Cbl family of E3 ubiquitin ligases in the development and function of lymphocytes and non-lymphoid cells. In addition, we will highlight our current understanding of the mechanisms used by this family of proteins, especially Cbl and Cbl-b, to co-ordinately regulate the function of various receptors and transcription factors in the context of immune regulation and diseases.

First-in-human, phase I single-ascending-dose study of the safety, pharmacokinetics, and relative bioavailability of selatinib, a dual EGFR-ErbB2 inhibitor in healthy subjects.

We assessed the pharmacokinetics and safety of a single oral administration of selatinib to healthy Chinese subjects and evaluated the potential bioavailability advantage of selatinib relative to lapatinib. Healthy subjects aged 18-40 years were enrolled in this two-part study: Part 1, a single ascending dose (50-500 mg), randomized, double-blind, placebo-control study with 64 subjects; and Part 2, an open-label, positive control, randomized, three-treatment, three-period, three-sequence crossover design study, with 6 subjects administered a single 500-mg dose of selatinib tablets (A), selatinib suspension (B), or lapatinib tablets C) per cycle. In part 1, selatinib was well-tolerated up to the planned maximum dose of 500 mg; thus the maximum tolerated dose was not attained. Twenty-two adverse events were observed in 19 (36.5%) of the 52 subjects administered the test drug. The most common drug-related adverse event was diarrhea. The mean selatinib peak plasma concentration was 69.4-494 ng/mL, which was achieved in a median peak time of 3.5-4.5 h, with a mean elimination half-life between 13.8 and 15.8 h. In Part 2, A and B showed similar bioavailability. Plasma exposure to the active drug (selatinib plus the metabolite, lapatinib) after A intake was more than two-fold higher than that of the same dose of C. In the dose range of 50-500 mg, selatinib was safe and well-tolerated by healthy Chinese subjects, and it conformed with linear pharmacokinetics. Active exposure to selatinib was much greater than that to lapatinib, supporting its development as an adjuvant for anticancer treatment.

Utilization of rural domestic sewage tailwaters by Ipomoea aquatica in different hydroponic vegetable and constructed wetland systems.

For the utilization of nitrogen and phosphorus in rural sewage tailwaters after biological treatment, four systems were examined regarding their ability to purify tailwaters of rural domestic sewage: a hydroponic vegetable system (HV), a subsurface flow constructed wetland (SFCW), a compound system with HV followed by SFCW (HV-SFCW), and a compound system with SFCW followed by HV (SFCW-HV). Parameters of the four systems were optimized to maximize the utilization efficiency of nitrogen and phosphorus, and the characteristics and pollutant removal efficiency of the process were investigated. Moreover, the edible security of vegetables was also evaluated. Results showed that the optimal hydraulic loadings for the four systems were 0.2, 0.3, 0.3, and 0.3 m3/(m2·d) (the lowest being the HV), respectively. In the combined system of HV-SFCW, high contribution proportions of the HV unit to the removal of chemical oxygen demand (COD), total nitrogen (TN) and total phosphorus (TP) were obtained, reaching 46.7%, 58.1%, and 53.7%. The heavy metal content of plants harvested met the standards of the National Food Safety Standard Limit of Pollutants in Food (GB 2762-2012). Overall, the compound HV-SFCW system achieved the best performance, ensuring that effluent water quality met national standards and realized the effective utilization of nitrogen and phosphorus.

Catheter-Based Renal Denervation Attenuates Kidney Interstitial Fibrosis in a Canine Model of High-Fat Diet-Induced Hypertension.

BACKGROUND/AIMS: Catheter-based renal denervation (RDN) has emerged as an innovative interventional approach for reducing blood pressure (BP), suppressing ventricular substrate remodeling, and attenuating heart failure, which suggests that it might reduce kidney fibrosis in a canine model of high-fat diet-induced hypertension. This study thus sought to assess whether RDN could reduce kidney fibrosis and halt the progression of renal impairment in a canine model of high-fat diet-induced hypertension. METHODS: Thirty-two beagles were randomized into either the normal control group (normal diet, n = 10) or the hypertension group (high-fat diet, n = 22). After successful establishment of the model, the hypertension model group was randomized to either the RDN group (n = 9) or the sham-surgery group (n = 8). Renal artery angiography, BP, heart rate (HR), and blood and urine biochemistry results were assessed at 1, 3, and 6 months after surgery. Canines were sacrificed at 6 months after surgery. The extent of kidney interstitial fibrosis, transforming growth factor-beta 1, alpha-smooth muscle actin, connective tissue growth factor, and E-cadherin protein were measured. RESULTS: The group fed a high-fat diet had significantly (p ˂ 0.05) increased body weight, BP, and HR and higher levels of urine albumin, serum noradrenaline (NE), and angiotensin II (AngII) than the control group. The sham-surgery group and RDN group also had higher levels than the control group (p ˂ 0.05). Compared with the sham-surgery group, the RDN group had lower BP, urine albumin, serum NE, and AngII and less fibrotic tissue (all p ˂ 0.05). CONCLUSION: RDN reduced BP, slowed progression of albuminuria, and suppressed renal remodeling in a canine model of high-fat diet-induced hypertension.

Comparative pharmacokinetics study of leonurine and stachydrine in normal rats and rats with cold-stagnation and blood-stasis primary dysmenorrhoea after the administration of Leonurus japonicus houtt electuary.

Leonurus japonicus houtt, a well-known herb of traditional Chinese medicine, is widely used to treat gynaecological diseases. In this study, a rapid and sensitive liquid chromatography with tandem mass spectrometry method for simultaneously quantifying leonurine and stachydrine, the two main bioactive components in Leonurus japonicus houtt, was developed and validated. Plasma samples were prepared by protein precipitation with acetonitrile and separation by a Hewlett Packard XDB-C8 column (150 × 4.6 mm, id, 5 µm) equipped with a gradient elution system containing methanol-water and 0.1% formic acid at a flow-rate of 0.4 mL/min. Components were then detected by a mass spectrometer in positive electrospray ionization mode. This method showed good linearity, precision, accuracy, recovery, stability, and negligible matrix effects, which were within acceptable ranges. The method was successfully applied to compare the pharmacokinetics in normal rats and rats with cold-stagnation and blood-stasis primary dysmenorrhoea treated with Leonurus japonicus houtt electuary. The result showed significant differences (p < 0.05) in the pharmacokinetic parameters between the primary dysmenorrhoea and normal groups. This result implied that Leonurus japonicus houtt electuary remained longer and was absorbed slower in rats with primary dysmenorrhoea and exhibited higher bioavailability and peak concentration.

[Aortic valve degenerative disease with patent ductus arteriosus infective endocarditis: A case report].

OBJECTIVE: Infective endocarditis (IE) refers to the pathogenic microbial infect the endocardium, valves or intima adjacent to the cardiac arteries through the bloodstream with the formation of vegetations. Valves are the most frequently affected sites. Here, we described a 49-year-old female, who admitted to respiratory outpatient department in the Third Xiangya Hospital, Central South University for long time of fever. Chest computer tomography (CT) found a thick wall cavity in the apex of the right lung with smooth wall and fluid plane, without enhancement, which was considered as inflammation and tuberculosis to be excluded. Echocardiography showed vegetations on the aortic valve, where abscess was found on the root. Accidentally in surgery, a patent ductus arteriosus (PDA) was found. The surgeon closed the PDA and performed aortic valve prosthetic valve replacement. Bacterial colony of coccus was found in the pathological tissue, which was consistent with the diagnosis of valvular degeneration with infection. Lung lesion was obviously absorbed after 6 weeks of treatment with vancomycin, which has been confirmed as a sensitive antibacterial drug to Enterococcus faecalis. Overall, the pulmonary lesion was caused by the detachment of bacterial neoplasm of aortic valve, which has passed through the PDA and entered the pulmonary circulation.

Assessing the Impact of Morphine on Adverse Outcomes in ACS Patients Treated with P2Y12 Inhibitors: Insights from Multiple Real-World Evidence.

Purpose: Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators. Patients and Methods: Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis. Results: Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted-P =3.55*10-209). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI. Conclusion: The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.

Effect of Ticagrelor versus Clopidogrel on All-Cause and Cardiovascular Mortality in Acute Coronary Syndrome Patients with Hyperuricemia.

BACKGROUND AND OBJECTIVE: The relationship between hyperuricemia and mortality in patients with acute coronary syndrome (ACS) is considerably controversial. Additionally, the strategy of dual antiplatelet therapy (DAPT) has not been evaluated in patients with ACS with hyperuricemia. This study aims to evaluate the impact of hyperuricemia on the prognosis of ACS and explore the efficacy of ticagrelor compared with clopidogrel in patients with hyperuricemia. METHODS: The study enrolled 4319 patients divided into hyperuricemia (HUA, n = 1060) and normouricemia (NUA, n = 3259) groups. The inverse probability of treatment weighting (IPTW)-adjusted Cox regression analysis was used to evaluate the impact of ticagrelor versus clopidogrel on all-cause and cardiovascular mortality. RESULTS: Hyperuricemia significantly increased the risk of all-cause death compared with patients with NUA at 7 days [adjusted hazard ratio (HR): 4.292, 95% confidence interval (CI) 1.727-10.67]; P = 0.002), 14 days (adjusted HR: 2.871, 95% CI 1.326-6.219; P = 0.0074), 30 days (adjusted HR: 2.168, 95% CI 1.056-4.453; P = 0.035), 3 months (adjusted HR: 2.018, 95% CI 1.152-3.533; P = 0.0144) and 1 year (adjusted HR: 1.702, 95% CI 1.137-2.548; P = 0.009). No significant difference was found between ticagrelor and clopidogrel in 1-year all-cause mortality [7.0% versus 5.5%, adjusted HR: 1.114 (95% CI 0.609-2.037), P = 0.725] among patients with concomitant hyperuricemia. CONCLUSION: Hyperuricemia was independently related to an increased risk of all-cause and cardiovascular death in patients with ACS undergoing PCI. At 1-year follow-up, there were no significant differences between ticagrelor and clopidogrel concerning all-cause and cardiovascular death in patients with hyperuricemia.

Using machine learning to predict adverse events in acute coronary syndrome: A retrospective study.

BACKGROUND: Up to 30% of patients with acute coronary syndrome (ACS) die from adverse events, mainly renal failure and myocardial infarction (MI). Accurate prediction of adverse events is therefore essential to improve patient prognosis. HYPOTHESIS: Machine learning (ML) methods can accurately identify risk factors and predict adverse events. METHODS: A total of 5240 patients diagnosed with ACS who underwent PCI were enrolled and followed for 1 year. Support vector machine, extreme gradient boosting, adaptive boosting, K-nearest neighbors, random forest, decision tree, categorical boosting, and linear discriminant analysis (LDA) were developed with 10-fold cross-validation to predict acute kidney injury (AKI), MI during hospitalization, and all-cause mortality within 1 year. Features with mean Shapley Additive exPlanations score >0.1 were screened by XGBoost method as input for model construction. Accuracy, F1 score, area under curve (AUC), and precision/recall curve were used to evaluate the performance of the models. RESULTS: Overall, 2.6% of patients died within 1 year, 4.2% had AKI, and 4.7% had MI during hospitalization. The LDA model was superior to the other seven ML models, with an AUC of 0.83, F1 score of 0.90, accuracy of 0.85, recall of 0.85, specificity of 0.68, and precision of 0.99 in predicting all-cause mortality. For AKI and MI, the LDA model also showed good discriminating capacity with an AUC of 0.74. CONCLUSION: The LDA model, using easily accessible variables from in-hospital patients, showed the potential to effectively predict the risk of adverse events and mortality within 1 year in ACS patients after PCI.

Network Optimization of CNT Yarn Sensor Based on NNIA Algorithm in Damage Monitoring of 3D Braided Composites.

In order to solve the optimization problem of carbon nanotube (CNT) yarn sensor network embedded in three-dimensional (3D) braided composite materials and realize the structural health monitoring of internal damage of aerospace parts, the multi-objective optimization of the number and location of sensors was studied using non-dominated neighborhood immune algorithm (NNIA). Through the research of 3D six-direction braiding process, stress sensitivity of single CNT yarn sensor, and damage location of 3D braided composites, the number, position, and coverage constraint functions based on NNIA algorithm are constructed. In addition, the number and position of three-dimensional braided composite embedded CNT yarn sensors with different sizes are solved. Through the stress experiment and data analysis of damaged parts, it is proved that the optimized configuration result of CNT yarn sensor obtained by NNIA algorithm is suitable for the damage monitoring of 3D braided composites. The damage location error is less than 1 mm. This study lays a foundation for the establishment of damage source localization model of 3D braided composites.

Long-term electricity generation and denitrification performance of MFCs with different exchange membranes and electrode materials.

Different biocathode electrode materials (graphite felt and carbon brush, GF and CB) and exchange membranes (proton exchange membrane and cation exchange membrane, PEM and CEM) were used in three microbial fuel cell (MFC) configurations operated for 300-days to investigate the power generation and the COD and N removal performance. Results showed no effect on the COD removal (all above 96%); however, the power generation (46.11 mW·h) and denitrification performance (68.0 ± 1.6%) of the MFC-B (GF + PEM) system were higher than those of the other systems (MFC-A: CB + PEM; MFC-C: CB + CEM) (P < 0.01), and the power generation and denitrification performance of all three systems decreased with time (P < 0.01). By analyzing the physicochemical properties of the exchange membrane and cathode electrode materials, the reasons that affect the power generation performance of the system were clarified. Furthermore, the increase in bioelectricity enhanced the electricity-related nitrification and denitrification reactions. The average 300-day unit denitrification cost of MFC-A was 4.2 and 6.3 times that of MFC-B and MFC-C, respectively. Comprehensive consideration of electricity generation, denitrification, and service life, combined with cost analysis and better selection of construction materials, provides a theoretical basis for the long-term stable operation and sustainable application of MFCs.

Kidney injury molecule-1 levels are associated with therapeutic outcomes and renal tubulointerstitial injury severity in idiopathic membranous nephropathy.

Kidney injury molecule-1 (KIM-1) has an important role in chronic kidney disease development. The present study aimed to retrospectively analyze patients with idiopathic membranous nephrology (IMN) with different therapeutic outcomes to investigate the association between KIM-1 levels and therapeutic outcomes. A total of 51 patients with IMN and 20 healthy controls were included. Patients were classified into three groups: Spontaneous remission, remission with immunosuppressive therapy (IST) and nonremission with IST. Clinical and biochemical variables were collected. Urinary KIM-1 levels were measured by ELISA and renal KIM-1 expression was evaluated by immunohistochemistry. Patients with IMN were characterized as having elevated urinary and renal KIM-1 levels compared with those in the controls. Significantly increased urinary and renal KIM-1 levels were observed in the nonremission with IST group compared with those in the spontaneous remission group, and the same trend was observed for the plasma anti-podocyte antigen phospholipase A2 receptor antibody levels. Patients with more severe tubular injury (T2 index) presented with significantly higher urinary and renal KIM-1 levels than those with the T0 index. Urinary and renal KIM-1 levels were positively correlated with blood urea nitrogen, serum creatinine, serum cystatin-C, urinary albumin/creatinine ratio, urinary ß2-microglobulin and the renal interstitial fibrosis index, and they were negatively correlated with serum albumin. Furthermore, urinary KIM-1 levels were positively correlated with the renal KIM-1 levels. In conclusion, the measurement of urinary and renal KIM-1 levels may be helpful in guiding medication selection and predicting therapeutic outcomes for patients with IMN.

Distribution and Antibiotic Susceptibility Pattern of Multidrug-Resistant Bacteria and Risk Factors Among Kidney Transplantation Recipients with Infections Over 13 Years: A Retrospective Study.

BACKGROUND: Infection ranks as the most common complication after kidney transplantation (KT) and threatens outcomes of kidney transplantation recipients (KTR). This study aimed to investigate the microbiological profile of infection, assess bacterial resistance and identify risk factors for multidrug-resistant (MDR) bacterial infection among KTR. METHODS: During the study period, 866 recipients underwent kidney transplant surgery. We studied the distribution of pathogens, resistance rate of MDR bacteria and the risk factors of MDR bacterial infection. RESULTS: Totally, 214 species of pathogens (110 species were MDR bacteria) were isolated in 119 KTR. Escherichia coli (E. coli) was the most common bacteria of the infection. MDR extended spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) were most resistant to ampicillin, cefazolin, ciprofloxacin and complex sulfamethoxazole, while quite sensitive to imipenem, amikacin and piperacillin/tazobactam (PIT). All MDR gram-positive bacteria were quite sensitive to linezolid and vancomycin, except that MDR Staphylococcus was also susceptible to rifampicin. Female gender (OR = 3.497, 95% CI = 1.445-8.467, P = 0.006), pathogen types > 1 (OR = 3.832, 95% CI = 1.429-10.273, P = 0.008) and postoperative time < 3 months (OR = 0.331, 95% CI = 0.137-0.799, P = 0.014) were independent risk factors for MDR bacterial infection. CONCLUSION: PIT and amikacin may be an alternative choice of ESBL-E infection. Rifampicin can also be prescribed for MDR Staphylococcus infection. MDR bacterial infection was associated with female gender, pathogen types more than 1 and 3 months postoperative period.

Ubiquitin Ligases CBL and CBL-B Maintain the Homeostasis and Immune Quiescence of Dendritic Cells.

Dendritic cells (DCs) are composed of multiple lineages of hematopoietic cells and orchestrate immune responses upon detecting the danger and inflammatory signals associated with pathogen and damaged tissues. Under steady-state, DCs are maintained at limited numbers and the functionally quiescent status. While it is known that a fine balance in the DC homeostasis and activation status is also important to prevent autoimmune diseases and hyperinflammation, mechanisms that control DC development and activation under stead-state remain not fully understood. Here we show that DC-specific ablation of CBL and CBL-B (CBL-/-CBL-B-/-) leads to spontaneous liver inflammation and fibrosis and early death of the mice. The mutant mice have a marked expansion of classic CD8α+/CD103+ DCs (cDC1s) in peripheral lymphoid organs and the liver. These DCs exhibit atypical activation phenotypes characterized by an increased production of inflammatory cytokines and chemokines but not the cell surface MHC-II and costimulatory ligands. While the mutant mice also have massive T cell activation, lymphocytes are not required for the disease development. The CBL-/-CBL-B-/- mutation enhances FLT3-mTOR signaling, due to defective FLT3 ubiquitination and degradation. Blockade of FLT3-mTOR signaling normalizes the homeostasis of cDC1s and attenuates liver inflammation. Our result thus reveals a critical role of CBLs in the maintenance of DC homeostasis and immune quiescence. This regulation could be relevant to liver inflammatory diseases and fibrosis in humans.

Brain Endothelial Cells Regulate Glucagon-Like Peptide 1 Entry Into the Brain via a Receptor-Mediated Process.

Glucagon-like peptide 1 (GLP-1) in addition to regulating glucose-dependent insulin and glucagon secretion exerts anorexic and neuroprotective effects. While brain-derived GLP-1 may participate in these central actions, evidence suggests that peripherally derived GLP-1 plays an important role and GLP-1 analogs are known to cross the blood brain barrier. To define the role of brain microvascular endothelial cells in GLP-1 entry into the brain, we infused labeled GLP-1 or exendin-4 into rats intravenously and examined their appearance and protein kinase A activities in various brain regions. We also studied the role of endothelial cell GLP-1 receptor and its signaling in endothelial cell uptake and transport of GLP-1. Systemically infused labeled GLP-1 or exendin-4 appeared rapidly in various brain regions and this was associated with increased protein kinase A activity in these brain regions. Pretreatment with GLP-1 receptor antagonist reduced labeled GLP-1 or exendin-4 enrichment in the brain. Sub-diaphragmatic vagus nerve resection did not alter GLP-1-mediated increases in protein kinase A activity in the brain. Rat brain microvascular endothelial cells rapidly took up labeled GLP-1 and this was blunted by either GLP-1 receptor antagonism or protein kinase A inhibition but enhanced through adenylyl cyclase activation. Using an artificially assembled blood brain barrier consisting of endothelial and astrocyte layers, we found that labeled GLP-1 time-dependently crossed the barrier and the presence of GLP-1 receptor antagonist blunted this transit. We conclude that GLP-1 crosses the blood brain barrier through active trans-endothelial transport which requires GLP-1 receptor binding and activation.

Cbl and Cbl-b control the germinal center reaction by facilitating naive B cell antigen processing.

Antigen uptake and presentation by naive and germinal center (GC) B cells are different, with the former expressing even low-affinity BCRs efficiently capture and present sufficient antigen to T cells, whereas the latter do so more efficiently after acquiring high-affinity BCRs. We show here that antigen uptake and processing by naive but not GC B cells depend on Cbl and Cbl-b (Cbls), which consequently control naive B and cognate T follicular helper (Tfh) cell interaction and initiation of the GC reaction. Cbls mediate CD79A and CD79B ubiquitination, which is required for BCR-mediated antigen endocytosis and postendocytic sorting to lysosomes, respectively. Blockade of CD79A or CD79B ubiquitination or Cbls ligase activity is sufficient to impede BCR-mediated antigen processing and GC development. Thus, Cbls act at the entry checkpoint of the GC reaction by promoting naive B cell antigen presentation. This regulation may facilitate recruitment of naive B cells with a low-affinity BCR into GCs to initiate the process of affinity maturation.