Acute Myeloid Leukemia with Myelodysplasia - Related Changes after Isolated Myeloid Sarcoma.

BACKGROUND: As a tumor mass, a myeloid sarcoma consists of myeloid blasts and presents at an anatomical site other than the bone marrow. In about one quarter of cases, myeloid sarcoma happens without an underlying acute myeloid leukemia or other myeloid neoplasm, and it may precede or coincide with AML or form acute blastic transformation of MDSs, MPNs, or MDS/MPNs. METHODS: Herein, we described a rare case of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), with WT1 mutation and high expression of TP53 after isolated myeloid sarcoma of lymph nodes showing a higher proportion of blasts, dysplasia of both megakaryocytes and granulocytes. CONCLUSIONS: The case highlights the importance of a bone marrow examination, including morphology, immunophenotyping, cytogenetic, and molecular examination in all cases to exclude the possibility of myeloid sarcoma, especially the morphological feature of bone marrow dysplasia in the early stage before AML.

Chinese hospital staff in anxiety and depression: Not only comfort patients but also should be comforted - A nationwide cross-sectional study.

BACKGROUND: Healthcare professionals are in short supply worldwide, especially in China, which can result in increased stress in the work environment and allostatic load for Chinese hospital staff. This study aimed to investigate the prevalence of anxiety and depressive symptoms and their relationship with total stress, allostatic overload, sleep quality, and episodic memory among Chinese hospital staff. METHOD: In this cross-sectional study, self-assessments including Generalized Anxiety Disorder 7-item (GAD-7), Patient Health Questionnaire-9 (PHQ-9), PsychoSocial Index (PSI), Pittsburgh Sleeping Quality Index (PSQI), and MemTrax test were used to evaluate participants' anxiety symptoms, depressive symptoms, total stress, allostatic load/overload, sleep quality, and episodic memory. RESULTS: A total of 9433 hospital staff from 304 cities participated. Anxiety prevalence was 21.0 % (95 % confidential interval (CI) 20.2 %, 21.8 %), while the prevalence of depressive symptoms was at 21.4 % (95 % CI 20.5 %, 22.2 %). 79.8 % (95 % CI 79.0 %, 80.6 %) of the hospital staff had allostatic overload. Poor sleep quality affected 50.4 % of participants, and 32.1 % experienced poor episodic memory. LIMITATIONS: This study utilized a convenience sampling approach, relying on an online survey as its data collection method. CONCLUSIONS: Hospital staff in China are facing a stressful environment with a high prevalence of anxiety and depressive symptoms, significant allostatic overload, poor sleep quality, and compromised episodic memory. It is imperative that local management and community structures enhance their support and care for these essential workers, enabling them to manage and withstand the stresses of their professional roles effectively.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Is Associated with HLA-A*3303 and HLA-DPB1*0501.

We determined the genetic association between specific human leucocyte antigen (HLA) loci and autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. Our results showed that autoimmune GFAP astrocytopathy was associated with HLA-A*3303 (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.32-3.06, p = 0.00072, padj. = 0.046) and HLA-DBP1*0501 (OR = 0.51, 95% CI = 0.36-0.71, p = 0.000048, padj. = 0.0062). Moreover, HLA-A*3303 carriers with the disease had a longer hospital stay (p = 0.0005) than non-carriers. This study for the first time provides evidence for a role of genetic factor in the development of autoimmune GFAP astrocytopathy. ANN NEUROL 2024;95:901-906.

Luteolin peracetate and gossypolone inhibit immune complex-mediated neutrophil activation in vitro and dermal-epidermal separation in an ex vivo model of epidermolysis bullosa acquisita.

Introduction: Natural products have been shown to an important source of therapeutics for human disease. In this study, we aimed to identify natural compounds as potential therapeutics for epidermolysis bullosa acquisita (EBA), an autoimmune disease caused by autoantibodies to type VII collagen (COL7). Methods: Utilizing an in vitro experimental system, we screened a natural product library composed of 800 pure compounds for their inhibitory effect on COL7-anti-COL7 IgG immune complex (IC)-mediated neutrophil activation and on neutrophil-mediated tissue damage. Results: Three natural compounds, namely luteolin peracetate, gossypol, and gossypolone were capable in inhibiting the IC-induced neutrophil adhesion and oxygen burst in vitro. Furthermore, luteolin peracetate and gossypolone were able to inhibit the anti-COL7 IgG induced dermal-epidermal separation in an ex vivo model for EBA. Discussion: In summary, this study demonstrates that luteolin peracetate and gossypolone are potential therapeutics for experimental EBA, which deserves further investigation.

Protective effects of KLF4 on blood-brain barrier and oxidative stress after cerebral ischemia-reperfusion in rats through the Nrf2/Trx1 pathway.

PURPOSE: To investigate the role of KLF4 in CI/R injury and whether Nrf2/Trx1 axis acted as a downstream pathway of KLF4 to exert the protective role in blood-brain barrier destruction after CI/R. METHODS: The tMCAO rat model in vivo was constructed and received the intracerebroventricular injection of 5 µg/kg and 10 µg/kg rhKLF4 before operation. TTC, brain water content, neurological function, ELISA, behavioral tests, HE, TUNEL, and qRT-PCR were performed to detect the protective role of KLF4 on CIR. Double-fluorescence staining and western blot were performed to determine the localization and spatiotemporal expression in brain tissues. Furthermore, we also analyzed the effect of KLF4 on the blood-brain barrier (BBB) and related mechanisms in vivo and in vitro. Nrf2 inhibitor tretinoin was applied, which was intraperitoneally injected into CIR rat. Evans blue staining was conducted. In vitro OGD/R models of bEnd.3 cells were also established, and received KLF4 overexpressed transfection and 12.5 µM tretinoin incubation. The permeability of bEnd.3 cells was evaluated by TEER and FITC-dextran leakage. BBB-related factors and oxidative stress were also analyzed, respectively. The tubular ability of KLF4 on OGD/R bEnd3 cells was also evaluated. RESULTS: In vivo study confirmed that KLF4 was expressed in astrocyte, and its content increased with time. KLF4 protected against brain injury caused by cerebral ischemia-reperfusion, reduced cerebral infarction area and oxidative stress levels, and promoted the recovery of behavioral ability in rats. Simultaneously, mechanism experiments confirmed that the repair effect of KLF4 on cerebral ischemia-reperfusion injury was closely related to the Nrf2/Trx1 pathway. KLF4 exerted the neuroprotective effect through upregulating Nrf2/Trx1 pathway. Consistent with in vivo animal study, in vitro study also confirmed the effect of KLF4 on the permeability of bEnd.3 cells after OGD/R injury through Nrf2/Trx1 pathway. CONCLUSION: Collectively, KLF4 played neuroprotective role in CIR induced MCAO and OGD/R, and the beneficial effects of KLF4 was partly linked to Nrf2/Trx1 pathway.

Effects of Talaromyces marneffei on Complete Blood Count by a Sysmex XN-9000 Analyzer.

BACKGROUND: Talaromyces marneffei (T. marneffei) infection detected in the peripheral blood smears has been described by several reports. We studied the effects of T. marneffei in peripheral blood samples on complete blood count (CBC) using a Sysmex XN-9000 analyzer. METHODS: In a simulated T. marneffei infection model, blood samples with and without infectious diseases were selected, with high, medium, and low levels of white blood cell (WBC) and platelet (PLT) count, respectively. All samples were detected immediately and after a warm bath of 37℃ for 2 hours. RESULTS: WBC count of all samples was significantly increased by T. marneffei from a certain concentration and higher. For all samples, the effect of T. marneffei on WBC count after warm bath was significantly reduced compared to that on immediate WBC count from 4 - 6 x 109/L T. Marneffei and higher (p < 0.05). The presence of T. marneffei in all blood samples did not affect the results of PLT count. For all samples, the obvious effects of T. marneffei on WBC differential (WDF) and white cell nucleated red blood cell (WNR) scatter plots were from 4 - 6 x 109 T Marneffei and higher. CONCLUSIONS: As a kind of intracellular yeast, T. marneffei may affect WBC count, NRBC count, and WBC differential count of peripheral blood samples when the yeast concentration is (4 - 6) x 109 T Marneffei and higher. Moreover, the unique scatter plot cloud on WDF and WNR scatter plots caused by T. marneffei, may become an important clue pointing toward T. marneffei in peripheral blood.

Both T and B cells are indispensable for the development of a PBMC transfer-induced humanized mouse model for SSc.

BACKGROUND: Recently, a novel humanized mouse model for systemic sclerosis (SSc) was established by transferring peripheral blood mononuclear cells (PBMC) from patients with SSc to Rag2-/-Il2rg-/- immunodeficient mice. Here, we aimed to investigate the role of T and B cells in this humanized mouse model. METHODS: T and B cells were depleted in vitro from freshly isolated PBMC using anti-CD3 and anti-CD19 magnetic microbeads, respectively. Subsequently, PBMC and T or B cell-depleted PBMC were transferred into Rag2-/-/Il2rg-/- mice via intraperitoneal injection. Twelve weeks after the transfer, mice were sacrificed and evaluated. RESULTS: Mice transferred with whole PBMC from SSc patients developed systemic inflammation in the lungs, kidneys, and liver, and 6 out of 11 mice died or had to be sacrificed during the experiment. By contrast, such inflammation and death were not observed in mice transferred with corresponding T or B cell-depleted PBMC. In line with this finding, transfer with whole PBMC restored the splenic white pulp composing of human T, B, and plasma cells and led to the production of a considerable amount of human autoantibodies in recipient mice, while those immunological features were rarely observed in mice that received T or B cell-depleted PBMC. In contrast to our previous findings demonstrating a transfer of the protective effect of a B cell therapy into the mouse, treatment of SSc patients with chemical immunosuppressive drugs did not affect the pathogenicity of PBMC. CONCLUSIONS: This study demonstrates that both T and B cells are indispensable for the pathogenesis of the PBMC transfer-induced mouse model for SSc.

Induced antibodies directed to the angiotensin receptor type 1 provoke skin and lung inflammation, dermal fibrosis and act species overarching.

OBJECTIVE: To determine contributions and functions of autoantibodies (Abs) directed to the angiotensin receptor type 1 (AT1R), which are suggested to be involved in the pathogenesis of AT1R Abs-related diseases such as systemic sclerosis (SSc). METHODS: C57BL/6J mice were immunised with membrane-embedded human AT1R or empty membrane as control. Mice deficient for CD4+ or CD8+ T cells and B cells were immunised with membrane-embedded AT1R or an AT1R peptide proposed to be a dominant T cell epitope. A monoclonal (m)AT1R Ab was generated by hybridoma technique and transferred into C57BL/6J and AT1Ra/b knockout mice. The induced phenotype was examined by histology, immunohistochemistry, immunofluorescence, apoptosis assay and ELISA. In vitro, Abs responses towards AT1R were measured in cells of different origins and species. RESULTS: AT1R-immunised mice developed perivascular skin and lung inflammation, lymphocytic alveolitis, weak lung endothelial apoptosis and skin fibrosis accompanied by Smad2/3 signalling, not present in controls or mice deficient for CD4+ T and B cells. The AT1R peptide 149-172 provoked lung inflammation. Application of the mAT1R Ab induced skin and lung inflammation, not observed in AT1Ra/b knockout mice. In vitro, AT1R Abs activated rat cardiomyocytes and human monocytes, enhanced angiotensin II-mediated AT1R activation in AT1R-transfected HEK293 cells via AT1R binding and mAT1R Ab-activated monocytes mediated the induction of profibrotic markers in dermal fibroblasts. CONCLUSION: Our immunisation strategy successfully induced AT1R Abs, contributing to inflammation and, possibly, to fibrosis via activation of AT1R. Therefore, AT1R Abs are valuable targets for future therapies of SSc and other AT1R Ab-related diseases.

Impact of COVID-19 vaccination on the use of PD-1 inhibitor in treating patients with cancer: a real-world study.

Anti-COVID-19 vaccination may have functional implications for immune checkpoint inhibitor treatment in patients with cancer. This study was undertaken to determine whether the safety or efficacy of anti-PD-1 therapy is reduced in patients with cancer during COVID-19 vaccination. A large multicenter observational study was conducted in 83 Chinese hospitals between January 28, 2021 and September 30, 2021. A total of 3552 patients were screened and 2048 eligible patients with cancer receiving PD-1 inhibitor treatment were recruited. All enrolled patients had received camrelizumab treatment alone or in conjunction with other cancer therapies. Among these, 1518 (74.1%) patients received the BBIBP-CorV vaccine and were defined as the vaccinated subgroup. The remaining 530 (25.9%) patients did not receive anti-COVID-19 vaccination and were defined as the non-vaccinated subgroup. For all participants, Response Evaluation Criteria in Solid Tumor and Common Terminology Criteria for Adverse Events criteria were used to evaluate the efficacy and safety of camrelizumab treatment, respectively. Propensity score match analysis with the optimal pair matching was used to compare these criteria between the vaccinated and non-vaccinated subgroups. A total of 2048 eligible patients with cancer were included (median age 59 years, 27.6% female). Most patients (98.8%) had metastatic cancer of the lung, liver or intestinal tract. Aside from the PD-1 inhibitor treatment, 55.9% of patients received additional cancer therapies. 1518 (74.1%) patients received the BBIBP-CorV vaccine with only mild side effects reported. The remaining patients did not receive COVID-19 vaccination and had a statistically greater percentage of comorbidities. After matching for age, gender, cancer stage/types, comorbidity and performance status, 1060 patients (530 pairs) were selected for propensity score match analysis. This analysis showed no significant differences in overall response rate (25.3% vs 28.9%, p=0.213) and disease control rate (64.6% vs 67.0%, p=0.437) between vaccinated and non-vaccinated subgroups. Immune-related adverse events (irAEs) were reported in both subgroups after camrelizumab treatment. Among vaccinated patients who experienced irAEs, the median interval between the first dose of camrelizumab treatment and the first vaccine shot was ≤16 days. Compared with the non-vaccinated subgroup, irAEs in vaccinated patients were more frequently reported as mild (grade 1 or 2 irAEs; 33.8% vs 19.8%, p<0.001) and these patients were less likely to discontinue the PD-1 inhibitor treatment (4.2% vs 20.4%, p<0.001). Severe irAEs (grade 3 irAE or higher) related to camrelizumab treatment were reported, however no significant differences in the frequency of such events were observed between the vaccinated and non-vaccinated subgroups. The COVID-19 vaccine, BBIBP-CorV, did not increase severe anti-PD-1-related adverse events nor did it reduce the clinical efficacy of camrelizumab in patients with cancer. Thus, we conclude that patients with cancer need not suspend anti-PD-1 treatment during COVID-19 vaccination.

Prediction of Radiation Pneumonitis Using Genome-Scale Flux Analysis of RNA-Seq Derived From Peripheral Blood.

Purpose: Radiation pneumonitis (RP) frequently occurs during a treatment course of chest radiotherapy, which significantly reduces the clinical outcome and efficacy of radiotherapy. The ability to easily predict RP before radiotherapy would allow this disease to be avoided. Methods and Materials: This study recruited 48 lung cancer patients requiring chest radiotherapy. For each participant, RNA sequencing (RNA-Seq) was performed on a peripheral blood sample before radiotherapy. The RNA-Seq data was then integrated into a genome-scale flux analysis to develop an RP scoring system for predicting the probability of occurrence of RP. Meanwhile, the clinical information and radiation dosimetric parameters of this cohort were collected for analysis of any statistical associations between these parameters and RP. A non-parametric rank sum test showed no significant difference between the predicted results from the RP score system and the clinically observed occurrence of RP in this cohort. Results: The results of the univariant analysis suggested that the tumor stage, exposure dose, and bilateral lung dose of V5 and V20 were significantly associated with the occurrence of RP. The results of the multivariant analysis suggested that the exposure doses of V5 and V20 were independent risk factors associated with RP and a level of RP ≥ 2, respectively. Thus, our results indicate that our RP scoring system could be applied to accurately predict the risk of RP before radiotherapy because the scores were highly consistent with the clinically observed occurrence of RP. Conclusion: Compared with the standard statistical methods, this genome-scale flux-based scoring system is more accurate, straightforward, and economical, and could therefore be of great significance when making clinical decisions for chest radiotherapy.

Transfer of PBMC From SSc Patients Induces Autoantibodies and Systemic Inflammation in Rag2-/-/IL2rg-/- Mice.

Objective: The contribution of sustained autologous autoantibody production by B cells to the pathogenesis of systemic sclerosis (SSc) and granulomatosis with polyangiitis (GPA) is not fully understood. To investigate this, a humanized mouse model was generated by transferring patient-derived peripheral blood mononuclear cells (PBMC) into immunocompromised mice. Methods: PBMC derived from patients with SSc and GPA as well as healthy controls (HD) were isolated, characterized by flow cytometry, and infused into Rag2-/-/IL2rg-/- mice. In addition, PBMC from SSc patients treated with rituximab were transferred into mice. Twelve weeks later, human autoantibodies were determined in blood of the recipient mice and affected tissues were analyzed for pathological changes by histology and immunohistochemistry. Results: Mice engrafted with PBMC derived from SSc patients developed autoantibodies such as antinuclear antibodies (ANA) mimicking the pattern of the respective donors. Moreover, cellular infiltrates dominated by B cells were observed in lung, kidney and muscles of the recipient mice. By contrast, PBMC derived from HD or GPA patients survived in recipient mice after transfer, but neither human autoantibodies nor inflammatory infiltrates in tissues were detected. Furthermore, these pathological changes were absent in mice transferred with PBMC from rituximab-treated SSc patients. Conclusion: This humanized mouse model is indicative for cross-reactivity of human lymphocytes to murine autoantigens and argues for a pivotal role of B cells as well as of sustained autoimmunity in the pathogenesis of SSc. It provides a powerful tool to study interstitial lung disease and so far, under-recognized disease manifestations such as myositis and interstitial nephritis.

Autoimmunomic Signatures of Aging and Age-Related Neurodegenerative Diseases Are Associated With Brain Function and Ribosomal Proteins.

Biological aging is a complex process featured by declined function of cells and tissues, including those of the immune system. As a consequence, aging affects the expression and development of autoantibodies and autoreactive T cells, which can be seen in their sum as the autoimmunome of an individual. In this study we analyzed whether sets of autoimmune features are associated with specific phenotypes which form autoimmunomic signatures related to age and neurodegenerative diseases. The autoantibody profile data of healthy subjects and patients from the GEO database was used to explore autoimmunomic signatures of aging and three neurodegenerative diseases including Parkinson's disease (PD), Alzheimer disease (AD) and Multiple Sclerosis (MS). Our results demonstrate that the autoimmunomic signature of aging is featured by an undulated increase of IgG autoantibodies associated with learning and behavior and a consistent increase of IgG autoantibodies related to ribosome and translation, and the autoimmunomic signature of aging are also associated with age-related neurodegenerative diseases. Intriguingly, Differential Expression-Sliding Window Analysis (DE-SWAN) identified three waves of changes of autoantibodies during aging at an age of 30, 50, and 62 years, respectively. Furthermore, IgG autoantibodies, in particular those against ribosomal proteins, could be used as prediction markers for aging and age-related neurodegenerative diseases. Therefore, this study for the first time uncovers comprehensive autoimmunomic signatures for aging and age-related neurodegenerative diseases.

Hemophagocytic lymphohistiocytosis secondary to Candida albicans and reactivated EBV infections: A case report and review of the literature.

Hemophagocytic lymphohistiocytosis (HLH) has been recognized as a potentially life-threatening syndrome. This is the first case of acquired HLH caused by dual infections with Candida albicans and reactivated EBV infections, which focuses on the importance of morphological awareness of peripheral blood and bone marrow because sometimes they are the only locations that HLH and fungal microorganisms can be diagnosed. A 29-year-old woman with a history of abdominal distension and 9 months of intermittent fevers ($38.8°C) was admitted to the hematology department with treatment for leukopenia and thrombocytopenia. Severe infection of bilateral pulmonary and marked hepatosplenomegaly were detected by computed tomography. EB virus-CA IgG, EB virus-NA IgG and EB virus-CA IgM were positive. Scattered yeast-like fungi were found on peripheral blood and bone marrow (BM) smears. BM smears indicated prominent hemophagocytosis. Cultures of bronchoalveolar lavage and BM confirmed the growth of C. albicans. A diagnosis of HLH caused by dual infections with Candida albicans and reactivated EBV infections was established based on the clinical features of the patient because 7 of the 8 diagnostic criteria were met. She was treated with etoposide, dexamethasone for HLH, as well as highly active antifungal and antiviral therapies for the underlying etiology of dual infections. The patient eventually recovered following the effective treatment. A timely and accurate diagnosis is crucial to the prognosis of the dangerous disease.

Autoantibodies against C5aR1, C3aR1, CXCR3, and CXCR4 are decreased in primary Sjogren's syndrome.

BACKGROUND: Networks formed of numerous autoantibodies (aabs) directed against G-protein coupled receptors (GPCR) have been suggested to play important role in autoimmune disorders. In present study, we aimed to evaluate the association between anti-GPCR antibodies and primary Sjogren's syndrome (pSS) to determine the potential pathogenic factors. METHODS: By applying a cell membrane-based ELISA technique, which is capable of detecting aabs against conformational epitopes within GPCR, serum levels of fourteen GPCR were determined in well-characterized patients with pSS (n = 52) and gender-matched healthy controls (n = 54). Comparisons between groups were analyzed by two-tailed Mann-Whitney U test, Bonferroni correction was applied for multiple comparisons. Spearman`s rank correlation coefficients were calculated between variables and visualized by heat map. RESULTS: Compared to healthy subjects, sera of patients with pSS showed significantly higher binding to ß2AR and ETAR, but lower binding to C5aR1, C3aR1, CXCR3, and CXCR4. Autoantibodies against C5aR1, C3aR1, CXCR3, and CXCR4 were also decreased in patients with rheumatoid arthritis. In pSS patients, levels of anti-CXCR3 and anti-CXCR4 antibodies were negatively correlated with circulating lymphocyte counts. Furthermore, correlation signatures of anti-GPCR antibodies changed dramatically in the patients with pulmonary involvement. CONCLUSIONS: This study demonstrates an association between pSS and autoantibodies recognizing GPCR, especially those functionally involved in immune cell migration and exocrine glandular secretion.

Rare Case of Diffuse Large B-Cell Lymphoma Mimicking Acute Monocytic Leukemia, Associated with Complex Karyotype.

OBJECTIVE: Diffuse Large B-Cell Lymphoma (DLBCL), NOS, constitutes 25-35% of adult non-Hodgkin lymphomas in developed countries, and a higher percentage in developing countries; older people are prone to the disease. Three frequent morphological variants have been recognized, including centroblastic, immunoblastic, and anaplastic variants. However, there are still other rare morphological variants of DLBCL, presenting challenge in diagnosis and treatment. CASE PRESENTATION: A 62-year-old woman sought medical attention with a previous 6-month history of intermittent fever and leukocytosis. Bone marrow (BM) aspiration presented AML with acute monocytic leukemia-like morphologic features. The results of the immunophenotypic analysis suggested mature B cell lymphoma without obvious subtype characteristics. Lymph node biopsy indicated DLBCL of non-germinal centre B-cell subtype (n-GCB). Cytogenetic analysis of the BM cells revealed a 46,XX, trp(1)(q21q32),del(7)(q32q36),t(9;14)(p13;q32) [4]/46,XX [16] karyotype. The patient was diagnosed with EBV-positive DLBCL, NOS based on the combination of lymph node biopsy, clinical, cytological, immunophenotypic, and cytogenetic analyses. CONCLUSION: To date, no case reports of a patient diagnosed with DLBCL mimicking acute monocytic leukemia with complex karyotype have been reported. We present the case given its rarity, easy misdiagnosis, and poor prognosis. The case highlights the importance of awareness about the rare morphological variant to laboratory staff and hematologists.

Serum Levels of Autoantibodies Against Extracellular Antigens and Neutrophil Granule Proteins Increase in Patients with COPD Compared to Non-COPD Smokers.

Background: Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease leading to irreversible airflow limitation and is characterized by chronic pulmonary inflammation, obstructive bronchiolitis and emphysema. Etiologically, COPD is mediated by toxic gases and particles, eg, cigarette smoke, while the pathogenesis of the disease is largely unknown. Several lines of evidence indicate a link between COPD and autoimmunity but comprehensive studies are lacking. Methods: By using a protein microarray assaying more than 19,000 human proteins we determined in this study the autoantibody profiles of COPD and non-COPD smokers. The discovery cohort included 5 COPD patients under acute exacerbation (AECOPD) and 5 age- and gender-matched non-COPD smokers. One putative candidate autoantibody, anti-lactoferrin IgG, was further investigated by using immunoblotting with a large validation cohort containing 124 healthy controls, 92 patients with AECOPD and 52 patients with stable COPD. Results: We show that i) autoantigens targeted by autoantibodies with higher titers in COPD patients were enriched in extracellular regions, while those with lower titers in COPD patients were enriched in intracellular compartments. ii) levels of IgG autoantibodies against many neutrophil granule proteins were significantly higher in COPD patients than in non-COPD smokers. Furthermore, increased levels of anti-lactoferrin antibodies in COPD patients were confirmed in a cohort with a large number of samples. Conclusion: The comprehensive autoantibody profiles from COPD patients established in this study demonstrated for the first time a shift in the cellular localization of antigens targeted by autoantibodies in COPD.

Association of Cigarette Smoking, COPD, and Lung Cancer With Expression of SARS-CoV-2 Entry Genes in Human Airway Epithelial Cells.

SARS-CoV-2 enters into human airway epithelial cells via membrane fusion or endocytosis, and this process is dependent on ACE2, TMPRSS2, and cathepsin L. In this study, we examined the expression profiles of the three SARS-CoV-2 entry genes in primary human airway epithelial cells isolated from smokers, non-smokers, patients with chronic obstructive pulmonary disease or lung cancer. An exhaustive search of the GEO database was performed to identify eligible data on 1st June 2020. In total, 46 GEO datasets comprising transcriptomic data of 3,053 samples were identified as eligible data for further analysis. All meta-analysis were performed using RStudio. Standardized mean difference was utilized to assess the effect size of a factor on the expression of targeted genes and 95% confidence intervals (CIs) were calculated. This study revealed that (i) cigarette smoking is associated with an increased expression of ACE2 and TMPRSS2 and a decreased expression of cathepsin L; (ii) significant alternations in expression of ACE2, TMPRSS2, and cathepsin L were observed between current smokers and former smokers, but not between former smokers and never smokers; (iii) when compared with healthy controls with identical smoking status, patients with COPD or lung cancer showed negligible changes in expression of ACE2, TMPRSS2, and cathepsin L. Therefore, this study implicates cigarette smoking might contribute to the development of COVID-19 by affecting the expression of SARS-CoV-2 entry genes, while smoking cessation could be effective to reduce the potential risk.

Polymorphisms in the Mitochondrial Genome Are Associated With Bullous Pemphigoid in Germans.

Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230. Most intriguingly, BP is distinct from other autoimmune diseases because it predominantly affects elderly individuals above the age of 75 years, raising the question why autoantibodies and the clinical lesions of BP emerges mostly in this later stage of life, even in individuals harboring known putative BP-associated germline gene variants. The mitochondrial genome (mtDNA) is a potential candidate to provide additional insights into the BP etiology; however, the mtDNA has not been extensively explored to date. Therefore, we sequenced the whole mtDNA of German BP patients (n = 180) and age- and sex-matched healthy controls (n = 188) using next generation sequencing (NGS) technology, followed by the replication study using Sanger sequencing of an additional independent BP (n = 89) and control cohort (n = 104). While the BP and control groups showed comparable mitochondrial haplogroup distributions, the haplogroup T exhibited a tendency of higher frequency in BP patients suffering from neurodegenerative diseases (ND) compared to BP patients without ND (50%; 3 in 6 BP with haplogroup T). A total of four single nucleotide polymorphisms (SNPs) in the mtDNA, namely, m.16263T>C, m.16051A>G, and m.16162A>G in the D-loop region of the mtDNA, and m.11914G>A in the mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 4 gene (MT-ND4), were found to be significantly associated with BP based on the meta-analysis of our NGS data and the Sanger sequencing data (p = 0.0017, p = 0.0129, p = 0.0076, and p = 0.0132, respectively, Peto's test). More specifically, the three SNPs in the D-loop region were negatively, and the SNP in the MT-ND4 gene was positively associated with BP. Our study is the first to interrogate the whole mtDNA in BP patients and controls and to implicate multiple novel mtDNA variants in disease susceptibility. Studies using larger cohorts and more diverse populations are warranted to explore the functional consequences of the mtDNA variants identified in this study on immune and skin cells to understand their contributions to BP pathology.

A comprehensive comparison of hematological parameters among 39 common diseases.

Hematological parameters have been shown to be associated with morbidity and/or mortality of various disorders such as inflammatory diseases and cancer. In this study, we performed a comprehensive comparison of hematological parameters among 39 diseases, including cancer, inflammatory, autoimmune, allergic and infectious diseases as well as some further common disorders. In total, 19,038 patients and 23,610 matched healthy controls were recruited and evaluated. Our results revealed distinct hematological profiles among disease groups in which erythrocyte-related parameters were specifically associated with cancer, neutrophil- and lymphocyte-related parameters were associated with inflammatory diseases, viral infectious diseases, cancer, autoimmune and allergic diseases and platelets-related parameters were associated with viral infectious diseases. Furthermore, both neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios were significantly higher in patients with inflammatory diseases, cancer, autoimmune and allergic diseases than corresponding controls. In addition, receiver operating characteristic curve analysis showed that several hematological parameters showed good diagnostic values for cancer, inflammatory diseases, and viral infectious diseases. Therefore, our results provide a valuable resource of hematological abnormalities in common diseases.