Dense deposit disease (DDD), a subgroup of C3 glomerulopathy, is a rare glomerular disease characterised histologically by predominant C3 staining on immunofluorescence microscopy along with intramembranous osmiophilic dense deposits. C4 DDD is a recently identified form of complement-mediated glomerulonephritis, characterised by intense C4d staining with minimal or absent staining for C3 and immunoglobulin, and dense deposits along the glomerular basement membrane. We present a 27-year-old female patient who exhibited proteinuria during pregnancy. Following delivery, the patient continued to experience persistent non-nephrotic-range proteinuria, along with microscopic hematuria and dramatically decreased serum C3 level, while maintaining preserved renal function. Renal biopsy revealed mesangial proliferative glomerulonephritis with a focal membranoproliferative glomerulonephritis pattern by light microscopy. Electron microscopy demonstrated high-density banded deposits in the glomerular basement membrane, while immunofluorescence exhibited negative C3c and immunoglobulin staining. Immunohistochemical analysis showed diffuse expression of C3d and C4d in the capillary loops, mesangial region, focal tubular basement membrane, and focal arteriolar wall. Further investigation revealed elevated circulating levels of autoantibodies against complement factor H and the C3 convertase. Mass spectrometry confirmed that C3 was the predominant component of the deposits. Ultimately, this patient was diagnosed as DDD mediated by complement factor H autoantibodies and C3 nephritic factor.

BACKGROUND:Around 90% of global tuberculosis (TB) new cases occur in adolescents and adults. The BCG vaccine, which is widely administered to infants, is inadequate for adult protection, underscoring the necessity for developing an effective booster vaccine for adult TB prevention. However, the effectiveness of these booster vaccines, especially against primary Mycobacterium tuberculosis (M.tb) infection, remains contentious, and their underlying mechanisms are not fully understood. Emerging evidence, including our previous findings, suggests that interleukin-10 (IL-10)-mediated immune regulation may influence T cell responses following booster immunization and potentially contribute to the limited efficacy observed in preventing primary M.tb infection, although this remains to be further clarified. METHODS:This study evaluated subunit vaccines incorporating different M.tb antigens (A1D4 or CMFO) and adjuvants (DMT or DT) as booster interventions in mice previously primed with BCG. qRT-PCR was employed to assess IL-10 mRNA levels, FACS and ICS were used to detect IL-10 positive cell populations in lymph nodes, spleen, and lungs one to three weeks following the booster administration. Additionally, the effects of inhibiting IL-10 receptor signaling using a monoclonal antibody (mAb) on T cell responses and the protective efficacy against aerosolized M.tb infection were further explored. RESULTS:The administration of the same adjuvant DMT in combination with different recombinant antigens A1D4 and CMFO, or with a different adjuvant, DT, to formulate CMFO/DT as booster vaccines in BCG-primed mice, led to an increase in IL-10 levels in the lymph nodes, spleen, and lungs within three weeks. This occurred despite variations in expression levels, expression sites, and expression timings. Specifically, only modest increases in IL-10 levels were observed in the DMT-adjuvanted groups, whereas a more pronounced elevation was detected in the DT-adjuvanted group. This increase in IL-10 was primarily attributed to its expression by T and Th cells in the lungs. Blocking IL-10 signaling using mAb enhanced the resistance of mice, which had received the BCG prime-CMFO/DT boost, against aerosol infection with 300 CFU of M.tb. This enhancement was achieved by increasing the presence of antigen-specific and memory CD4+ T cells in the lungs. CONCLUSION:The adjuvant and antigen composition of the booster vaccine influenced IL-10 expression following BCG priming. While IL-10 induction was relatively modest in the DMT-adjuvanted groups and was not associated with a marked change in protective efficacy, elevated IL-10 levels in the DT-adjuvanted group were accompanied by improved protection upon IL-10 blockade. These results indicate that IL-10 may contribute to the modulation of vaccine-induced immunity in a context-dependent manner. Thus, IL-10 has the potential to serve as an auxiliary biomarker for the preliminary assessment of booster vaccine performance, although its utility requires further validation.

The impact of spike protein mutations on T cell responses, particularly in SARS-CoV-2 Omicron variants, remains incompletely elucidated. In this study, DNA vaccines encoding the spike protein of both the ancestral virus and Omicron variants were developed and administered in conjunction with a Th1-type adjuvant to BALB/c mice. Cross-reactive T cell responses to the spike proteins were assessed in the splenocytes of these mice using IFN-γ ELISPOT assays. Additionally, flow cytometry (FACS) was utilized to evaluate IFN-γ+ CD4+ and CD8+ T cell responses to various peptides covering the entire spike protein sequence. Our study demonstrated that only a limited number of mice, along with a minor subset of their splenocytes vaccinated with the DNA vaccine targeting the original spike protein, exhibited weak cross-reactivity with Omicron variants. This observation underscores the differences in T cell epitopes between Omicron variants and the prototype spikes, indicating that at least 50 and 37 mutations in Omicron variants contribute to their evasion of CD4+ and CD8+ T cell responses, respectively. Conversely, DNA vaccines encoding spike proteins from Omicron variants successfully elicited strong cross-reactive T cell responses in the immunized mice. In particular, Vaccines targeting the BA.1, BA.5, XBB.1.5, and JN.1 variants demonstrated the most robust and comprehensive T cell immune responses among Omicron variants. This efficacy is attributed to the presence of less than eleven T cell immune evasion mutations in their spike proteins, alongside numerous mutations that enhance T cell responses. These findings underscore the imperative to update WHO emergency vaccine policies and contribute to the development of more effective vaccines and immunization strategies, to better control the infections caused by emerging Omicron variants.

Objectives: Identifying immune-protective biomarkers is crucial for the effective management and mitigation of current and future COVID-19 outbreaks, particularly in preventing or counteracting the immune evasion exhibited by the Omicron variants. The emergence of SARS-CoV-2 variants, especially those within the Omicron lineage, has highlighted their capacity to evade neutralizing antibodies, emphasizing the need to understand the role of antibody-dependent cell-mediated cytotoxicity (ADCC) in combating these infections. Methods: This study, conducted in Qichun City, Hubei province, from December 2021 to March 2023, involved 50 healthy Chinese adults who had received two doses of inactivated vaccines and had subsequently experienced mild infections with the Omicron BA.5 variant. Blood samples from these 50 healthy Chinese adults were collected at six distinct time points: at baseline and at the 1st, 3rd, 6th, and 9th months following the third dose of the inactivated vaccine, as well as 3 months post-breakthrough infection. Their sera were analyzed to assess ADCC and neutralization effects. Results: The results indicated that the antibodies elicited by the inactivated SARS-CoV-2 vaccine targeted the spike protein, exhibiting both pre-existing neutralizing and ADCC activities against Omicron variants BA.5 and XBB.1.5. Notably, the ADCC activity demonstrated greater stability compared to that of the neutralizing effects, persisting for at least 15 months post-vaccination, and could be augmented by additional vaccine doses and breakthrough infections. The ADCC effect associated with hybrid immunity effectively targets a spectrum of prospective Omicron variants, including BA.2.86, CH.1.1, EG.5.1, and JN.1. Conclusions: In light of its stability and broad-spectrum efficacy, we recommend the use of the ADCC effect as a biomarker for assessing protective immunity and guiding the development of vaccines and monoclonal antibodies.

Background:Severe tubular atrophy/interstitial fibrosis are critical pathological features associated with poor prognosis in IgA nephropathy (IgAN). The early identification of patients at high risk for severe tubular damage could guide clinical management and improve outcomes. Objective:This study aimed to construct and validate a predictive model for assessing the risk of severe tubular atrophy and interstitial fibrosis in patients diagnosed with IgAN. Methods:A total of 3276 patients from the Hankou branch of Tongji Hospital were retrospectively enrolled for model development. A predictive model for severe tubular atrophy/interstitial fibrosis was constructed based on independent predictors identified through univariate analysis, least absolute shrinkage and selection operator regression, and stepwise logistic regression. Furthermore, the model underwent internal and external validation using an independent dataset (n=1062), and performance evaluation using six machine learning algorithms: random forest, generalized linear model, decision tree, gradient boosting decision tree, extreme gradient boosting, and support vector machine. Results:In this study, 8 variables were identified as independent predictors and used to construct a predictive model for severe tubular atrophy/interstitial fibrosis: Logit (P)=0.011×age (years)+0.324×hypertension history-0.302×education+.111×coefficient of variation of red cell distribution width-0.152×direct bilirubin (μmol/L)+0.003×uric acid (μmol/L)-0.021×estimated glomerular filtration rate (ml/min/1.73m²)+1.151×ln(24 h urine microalbumin) (mg/24h). The AUC for the predictive model was 0.860 (95% CI 0.847-0.873). The AUCs (95% CI) of the six machine learning algorithms ranged from 0.793 (0.765-0.822) to 0.880 (0.859-0.902) in internal validation and from 0.785 (0.756-0.814) to 0.862 (0.839-0.885) in external validation. Conclusions:We developed a concise and clinically useful model for predicting severe tubular atrophy/interstitial fibrosis in IgA nephropathy. It offers a non-invasive tool for risk assessment when biopsy is not feasible, aiding personalized treatment decisions.

Since the outbreak of the COVID-19 pandemic, SARS-CoV-2 has not stopped evolving, leading to the emergence of variants of concern (VoCs) involved in significant immune escape. Here, we compared the immunogenicity of different prime-boost vaccination regimens against SARS-CoV-2 wildtype (WT) and its Beta, Delta, and Omicron BA.1 VoCs. We used 5 databases to retrieve publications and random-effect models to estimate pooled neutralization titers. We included 11 randomized controlled trials (RCTs) and 16 non-RCTs, 10 prime-boost vaccination regimens, and 4598 subjects. We found neutralization activity against SARS-CoV-2 decreased with virus evolution. The heterologous immunization was more effective. The increase in neutralization titers against SARS-CoV-2 WT and Beta, Delta, and Omicron BA.1 VoCs after heterologous immunization was 1.41(95%CI:0.82-2.01), 0.90(95%CI:0.39-1.41), 1.23 (95%CI: 0.81-1.65), and 1.32 (95%CI: 0.99-1.65), respectively. Furthermore, the booster dose of viral vector vaccine did not show a higher increase in neutralization titers against SARS-CoV-2 WT(MD=0.48; 95%CI:-1.12-1.09), Beta (MD=0.20; 95%CI:-0.26-0.67), Delta (MD=0.35; 95%CI:-0.09-0.79), and Omicron BA.1 (MD=0.38; 95%CI:-0.14-0.89) VoCs. The combination of inactivated-recombinant protein vaccines showed a higher increase in neutralization titers (Beta: MD=1.88 and Delta: MD=1.70) than other combinations of vaccines. However, only a combination of mRNA-viral vector vaccines showed a higher increase in neutralization titers (MD:1.52; 95%CI:0.34-2.70) against Omicron BA.1 VoC. Interestingly, the viral vector-mRNA immunization regimen appears better compared to mRNA-viral vector regimen, especially against Beta and Delta VoCs. Overall, the type of combination followed by the order of administration of COVID-19 vaccines could be a potential vaccine strategy against the occurrence of SARS-CoV-2 variants.

Although COVID-19 is no longer classified as the first public health emergency, nevertheless, it still presents a serious menace to the health of the global population. Consequently, the development of COVID-19 vaccines possessing an optimal composition that can elicit broad-spectrum neutralizing responses against various SARS-CoV-2 variants is crucial. This meta-analysis aimed to compare the immunogenicity of prototype, monovalent-adapted, and bivalent COVID-19 vaccines against prototype SARS-CoV-2, Omicron BA.1 variant, and Omicron BA.4/5 subvariant in healthy adults. We utilized 4 medical databases to retrieve original studies and employed the fixed effect model to estimate pooled neutralization titers. A total of 12 studies concerning 4581 subjects were included in the meta-analysis. We found that participants who received prototype, monovalent-adapted, and bivalent vaccines as a second booster significantly developed neutralizing antibody (nAb) titers against prototype SARS-CoV-2, Omicron BA.1 variant, and Omicron BA.4/5 subvariant, with monovalent-adapted and bivalent vaccines exhibiting a higher increment. Furthermore, the bivalent(Prototype/Omicron BA.1) recombinant protein vaccine exhibited the highest increment in neutralization titers(MD = 1.95; 95 %CI:0.78-3.12; p < 0.01) against the prototype SARS-CoV-2 and Omicron BA.4/5 subvariant compared to the other vaccine regimens. Interestingly, only individuals who received the monovalent (Omicron BA.1)-adapted mRNA vaccine as a second booster showed the highest increase in neutralization titers (MD:1.37; 95 %CI:0.50-2.24; p < 0.01) against the Omicron BA.1 variant compared to the other vaccine regimens. These findings showed that bivalent recombinant protein vaccines seem more immunogenic than bivalent mRNA vaccines, and bivalent vaccines might not be superior immunogens for induced strong protective immune responses compared to monovalent-adapted vaccines.

Objective: The clinical course of COVID-19, as well as the immunological reaction, is notable for its extreme variability. Identifying the main associated factors might help understand the disease progression and physiological status of COVID-19 patients. The dynamic changes of the antibody against Spike protein are crucial for understanding the immune response. This work explores a temporal attention (TA) mechanism of deep learning to predict COVID-19 disease severity, clinical outcomes, and Spike antibody levels by screening serological indicators over time. Methods: We use feature selection techniques to filter feature subsets that are highly correlated with the target. The specific deep Long Short-Term Memory (LSTM) models are employed to capture the dynamic changes of disease severity, clinical outcome, and Spike antibody level. We also propose deep LSTMs with a TA mechanism to emphasize the later blood test records because later records often attract more attention from doctors. Results: Risk factors highly correlated with COVID-19 are revealed. LSTM achieves the highest classification accuracy for disease severity prediction. Temporal Attention Long Short-Term Memory (TA-LSTM) achieves the best performance for clinical outcome prediction. For Spike antibody level prediction, LSTM achieves the best permanence. Conclusion: The experimental results demonstrate the effectiveness of the proposed models. The proposed models can provide a computer-aided medical diagnostics system by simply using time series of serological indicators.

膜性肾病（membranous nephropathy,MN）是肾病综合征主要的病因之一，好发于中老年人。近年来的流行病学研究发现其在中国的发病频率平均以每年13%的速度提高 [1] ；另一项研究发现，MN在原发性肾小球疾病患者中，从2010年至2015年的占比16.18%上升至2016年至2020年的21.26% [2] 。同时，其发病存在一定的地域差异性，目前认为环境、种族等可能是导致这些差异的主要因素 [1,3-4] 。

The Bacillus Calmette-Guérin (BCG) vaccine, currently the sole authorized vaccine against tuberculosis (TB), demonstrates limited effectiveness in safeguarding adolescents and adults from active TB, even when administered as a booster with either BCG itself or heterologous vaccine candidates. To effectively control the persistent epidemic of adult TB, it is imperative to investigate the mechanisms responsible for the suboptimal efficacy of the BCG prime-boosting strategy against primary Mycobacterium tuberculosis (M.tb) infection. C57BL/6J mice were immunized with the BCG vaccine either once or twice, followed by analysis of lung tissue to assess changes in cytokine levels. Additionally, varying intervals between vaccinations and detection times were examined to study IL-10 expression across different organs. IL-10-expressing cells in the lungs, spleen, and lymph nodes were analyzed through FACS and intracellular cytokine staining (ICS). BCG-revaccinated IL-10−/− mutant mice were compared with wild-type mice to evaluate antigen-specific IgG antibody and T cell responses. Protection against M.tb aerosol challenge was evaluated in BCG-revaccinated mice, either untreated or treated with anti-IL-10R monoclonal antibody. IL-10 was significantly upregulated in the lungs of BCG-revaccinated mice shortly after the booster immunization. IL-10 expression peaked in the lungs 3–6 weeks post-revaccination and was also detected in lymph nodes and spleen as early as 2 weeks following the booster dose, regardless of the intervals between the prime and booster vaccinations. The primary sources of IL-10 in these tissues were identified as macrophages and dendritic cells. Blocking IL-10 signaling in BCG-revaccinated mice—either by using IL-10−/− mutant mice or administering anti-IL-10R monoclonal antibody increased levels of antigen-specific IFN-γ+ or IL-2+ CD4+ T cells, enhanced central and effector memory CD4+ T cell responses, and provided better protection against aerosol infection with 300 CFUs of M.tb. Our findings are crucial for formulating effective immunization strategies related to the BCG vaccine and for developing efficacious adult TB vaccines.

Background: Renal tertiary lymphoid structures (TLSs) are involved in renal pathology and prognosis of IgA nephropathy (IgAN). CD30 and its ligands participate in the formation of renal TLSs. However, the relationship between circulating CD30 and renal prognosis is unclear. The objective of this study was to evaluate the relationship between circulating CD30 and prognosis in patients with IgAN. Methods: We conducted a retrospective study including 351 patients with biopsy proved IgAN. We collected clinical and pathologic features at the time of biopsy and recorded renal follow-up outcomes. Circulating CD30 levels in IgAN patients at the time of biopsy were measured via enzyme-linked immunosorbent assay (ELISA). The association between elevated CD30 levels and the composite endpoint (defined as a >= 50 % decline in eGFR from baseline, end-stage renal disease, or death) was investigated using Cox regression analysis. Results: During a median follow-up period of 5.12 years, 44 (12.5 %) patients in the cohort reached the composite endpoint. Kaplan-Meier survival curve analysis revealed a significant association between higher circulating CD30 levels and a poorer renal prognosis (log-rank P < 0.001). Cox regression analysis showed that high CD30 was an independent factor for the composite endpoints in multivariable-adjusted models (HR 3.397, 95 % CI: 1.230-9.384, P = 0.018). These associations were also observed in a subgroup of patients with concomitant renal TLSs formation (10.443, 95 % CI: 1.680-65.545, P = 0.012), proteinuria > 1 g/d (HR 12.287, 95 % CI: 1.499-100.711, P = 0.019), and female patients (HR 22.372, 95 % CI: 1.797-278.520, P = 0.016). Conclusion: Elevated level of circulating CD30 is an independent risk factor for renal disease progression in patients with IgAN.

Introduction: The only authorized tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG), has shown limited effectiveness in protecting adolescents and adults against active TB, even boosted with either BCG itself or heterologous vaccine candidates. Objectives: The mechanisms underlying the suboptimal efficacy of BCG revaccination against primary M.tb infection remain unknown. Methods: C57BL/6J mice were immunized with the BCG vaccine once or twice, with lung tissue analyzed for changes in cytokine levels. Different intervals between vaccinations and detection times were also studied for IL-10 expression in various organs. IL-10 expressing cells in lung, spleen, and lymph nodes were analyzed using FACS and intracellular cytokine staining (ICS). BCG revaccinated IL-10-/- mutant mice were compared to wild type mice for antigen-specific IgG antibody and T cell response. Protection against M.tb aerosol challenge was assessed in BCG revaccinated mice that untreated or treated with anti-IL-10R monoclonal antibody. Results: IL-10 was found to be upregulated in the lungs of BCG revaccinated mice shortly after the booster immunization. The expression of IL-10 reached its peak in the lungs 3-6 weeks post-revaccination, and was also observed in lymph nodes and spleens as early as 2 weeks after the booster dose, regardless of the time intervals between the prime and booster vaccinations. The main sources of IL-10 in these tissues were macrophages and dendritic cells. Blocking IL-10 signaling in BCG revaccinated mice, achieved through the use of IL-10-/- mutant mice or anti-IL-10R monoclonal antibody, increased levels of antigen-specific IFN-γ+ or IL-2+ CD4+ T cells, central and effector memory CD4+ T cell responses, leading to better protection against 300 CFU of aerosol M.tb infection. Conclusion: Our findings are crucial for formulating effective immunization strategies pertaining to the BCG vaccine, as well as developing efficacious adult TB vaccine.

Coronavirus Disease 2019 (COVID-19), which emerged in 2019, has caused millions of deaths worldwide. Although effective vaccines have been developed to mitigate severe symptoms, certain populations, particularly the elderly and those with comorbidities, remain at high risk for severe outcomes and increased mortality. Consequently, early identification of the severity and clinical outcomes of the disease in these patients is vital to prevent adverse prognoses. Although traditional machine learning and deep learning models have been widely employed in this area, the potential of large language models (LLMs) remains largely unexplored. Our research focuses primarily on constructing specialized prompts and adopting multi-objective learning strategies. We started by selecting serological indicators that significantly correlate with clinical outcomes and disease severity to serve as input data for the model. Blood test samples often contain numerous missing values, and traditional models generally rely on imputation to handle these gaps in the data. In contrast, LLMs offer the advantage of robust semantic understanding. By setting prompts, we can explicitly inform the model when a feature's value is missing, without the need for imputation. For the multi-objective learning strategy, the model is designed to first predict disease severity and then predict clinical outcomes. Given that LLMs utilize both the input text and the generated tokens as input for generating the next token, the predicted severity is used as a basis for generating the clinical outcome. During the fine-tuning of the LLM, the two objectives influence and improve each other. Our experiments were implemented based on the ChatGLM model. The results demonstrate the effectiveness of LLMs in this task, suggesting promising potential for further development.

Introduction: This observational cohort study evaluated the prognostic value of mast cells in the pathogenesis and progression of IgA nephropathy. Methods: A total of 76 adult IgAN patients were enrolled into this study from Jan 2007 and June 2010. Immunohistochemistry and immunofluorescence were used to identify tryptase-positive mast cells in renal biopsy samples. Patients were classified into Tryptasehigh and Tryptaselow groups. Depending on an average of 96-month follow-up, the predictive value of tryptase-positive mast cells in IgAN progression was analyzed. Results: Tryptase-positive mast cells were found frequently in IgAN kidneys while rarely observed in normal kidneys. We also found IgAN patients in Tryptasehigh group presented both severe clinical and pathological renal manifestations. Furthermore, Tryptasehigh group contained more interstitial macrophages and lymphocytes infiltration than Tryptaselow group. Higher tryptase-positive cells density is associated with poor prognosis in patients with IgAN. Conclusions: High renal mast cells density is associated with severe renal lesions and poor prognosis in patients with Immunoglobulin A nephropathy. High renal mast cells density might be used as a predictor of poor prognosis in patients with IgAN.

Age has been found to be the single most significant factor in COVID-19 severity and outcome. However, the age-related severity factors of COVID-19 have not been definitively established. In this study, we detected SARS-CoV-2-specific antibody responses and infectious disease-related blood indicators in 2360 sera from 783 COVID-19 patients, with an age range of 1–92 years. In addition, we recorded the individual information and clinical symptoms of the patients. We found that the IgG responses for S1, N, and ORF3a and the IgM for NSP7 were associated with severe COVID-19 at different ages. The IgM responses for the S-protein peptides S1-113 (aa 673–684) and S2-97 (aa 1262–1273) were associated with severe COVID-19 in patients aged <60. Furthermore, we found that the IgM for S1-113 and NSP7 may play a protective role in patients aged <60 and >80, respectively. Regarding clinical parameters, we analyzed the diagnostic ability of five clinical parameters for severe COVID-19 in six age groups and identified three-target panel, glucose, IL-6, myoglobin, IL-6, and NT proBNP as the appropriate diagnostic markers for severe COVID-19 in patients aged <41, 41–50, 51–60, 61–70, 71–80, and >80, respectively. The age-associated severity factors revealed here will facilitate our understanding of COVID-19 immunity and diagnosis, and eventually provide meaningful information for combating the pandemic.

Age has been found to be one of the main risk factors for the severity and outcome of COVID-19. However, differences in SARS-CoV-2 specific antibody responses among COVID-19 patients of different age groups remain largely unknown. In this study, we analyzed the IgG/IgM responses to 21 SARS-CoV-2 proteins and 197 peptides that fully cover the spike protein against 731 sera collected from 731 COVID-19 patients aged from 1 to 92 years. We show that there is no overall difference in SARS-CoV-2 antibody responses in COVID-19 patients in the 4 age groups. By antibody response landscape maps, we find that the IgG response profiles of SARS-CoV-2 proteins are positively correlated with age. The S protein linear epitope map shows that the immunogenicity of the S-protein peptides is related to peptide sequence, disease severity and age of the COVID-19 patients. Furthermore, the enrichment analysis indicates that low S1 IgG responses are enriched in patients aged <50 and high S1 IgG responses are enriched in mild COVID-19 patients aged >60. In addition, high responses of non-structural/accessory proteins are enriched in severe COVID-19 patients aged >70. These results suggest the distinct immune response of IgG/IgM to each SARS-CoV-2 protein in patients of different age, which may facilitate a deeper understanding of the immune responses in COVID-19 patients.

膜性肾病是成人肾病综合征的常见病因，膜性肾病合并抗中性粒细胞胞质抗体相关性血管炎者罕见。本文报道1例老年男性，经肾活检及血清学检查，诊断为磷脂酶A2受体相关性膜性肾病合并杀菌/通透性增强蛋白-抗中性粒细胞胞质抗体相关性肾小球肾炎，经过糖皮质激素及环磷酰胺治疗，达到临床缓解。

IntroductionThe COVID-19 global pandemic is far from ending. There is an urgent need to identify applicable biomarkers for early predicting the outcome of COVID-19. Growing evidences have revealed that SARS-CoV-2 specific antibodies evolved with disease progression and severity in COIVD-19 patients.ObjectivesWe assumed that antibodies may serve as biomarkers for predicting the clinical outcome of hospitalized COVID-19 patients on admission.MethodsBy taking advantage of a newly developed SARS-CoV-2 proteome microarray, we surveyed IgG responses against 20 proteins of SARS-CoV-2 in 1034 hospitalized COVID-19 patients on admission and followed till 66 days. The microarray results were further correlated with clinical information, laboratory test results and patient outcomes. Cox proportional hazards model was used to explore the association between SARS-CoV-2 specific antibodies and COVID-19 mortality.ResultsNonsurvivors (n = 955) induced higher levels of IgG responses against most of non-structural proteins than survivors (n = 79) on admission. In particular, the magnitude of IgG antibodies against 8 non-structural proteins (NSP1, NSP4, NSP7, NSP8, NSP9, NSP10, RdRp, and NSP14) and 2 accessory proteins (ORF3b and ORF9b) possessed significant predictive power for patient death, even after further adjustments for demographics, comorbidities, and common laboratory biomarkers for disease severity (all with p trend < 0.05). Additionally, IgG responses to all of these 10 non-structural/accessory proteins were also associated with the severity of disease, and differential kinetics and serum positive rate of these IgG responses were confirmed in COVID-19 patients of varying severities within 20 days after symptoms onset. The area under curves (AUCs) for these IgG responses, determined by computational cross-validations, were between 0.62 and 0.71.ConclusionsOur findings might have important implications for improving clinical management of COVID-19 patients.

BACKGROUND:Mycobacterium bovis bacillus Calmette-Guérin (BCG) is an attenuated live vaccine that provides insufficient protection against tuberculosis (TB), the underlying mechanisms for which remain unknown. Assuming that the BCG vaccine inherits immune evasive strategies from virulent parent M. bovis strains, we aimed to identify the associated genes and assess their effects on the vaccine efficacy.METHODS:Three genes, BCG_3174, BCG_1782, and BCG_2432c, associated with immune evasion were first identified via bioinformatics analysis and then confirmed in the genome of M. bovis and 12 commercial BCG vaccine substrains using Polymerase Chain Reaction (PCR) and DNA sequencing. These genes were disrupted to develop mutant strains, and their effects on autophagy and their protective efficacy were further compared with the BCG vaccine in vitro and in vivo.RESULTS:Of the three identified genes, only the disruption of BCG_2432c, namely ΔBCG_2432c, conferred stronger protection against intranasal TB in vaccinated mice, when compared with the BCG vaccine. ΔBCG_2432c showed a stronger ability to trigger intracellular ROS-mediated complete autophagic flux in infected THP-1 cells that resulted in higher antigen presentation. The improved protection could be attributed to early and increased IFN-γ+ CD4+ TEM and IL-2+ CD4+ TCM cells in the spleens and lungs of ΔBCG_2432c-vaccinated mice.CONCLUSIONS:The insufficient efficacy of the BCG vaccine is attributable to the important autophagy-inhibition gene BCG_2432c that blocks the autophagosome-lysosome pathway of antigen presentation. ΔBCG_2432c provides a promising platform to either replace the current BCG vaccine or develop vaccines that are more effective against TB.